HK1212336B - Azaquinazoline inhibitors of atypical protein kinase c - Google Patents

Abstract

The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

Description

Azaquinazoline inhibitors of atypical protein kinase C

Background

PKC iota and PKC ζ (accession numbers NM _002740 and NM _002744, respectively) together define an atypical subclass of the Protein Kinase C (PKC) family. apkcs differ structurally and functionally from other PKC subclasses, i.e., classical/conventional and novel subclasses, in that their catalytic activity is independent of diacylglycerol and calcium (Ono, Y., Fujii, t., oigita, k., Kikkawa, U., Igarashi, k., and Nishizuka, Y. (1989) the subclass of Protein kinase C ζ from rat brain: its structure, expression, and properties (Protein kinase C zeta subspecies from strain: its structure, expression, and performance). Structurally, PKC iota and PKC ζ comprise a C-terminal serine/threonine kinase domain (AGC-like) and an N-terminal regulatory region comprised within a protein that mediates criticality to aPKC function: the Phox Bem1(PB1) domain involved in protein interactions. At the amino acid level, aPKC has 72% overall homology, however, the kinase domain has 84% identity and differs in the active site by only a single amino acid. This significant homology indicates that ATP-competitive ligands are not expected to exhibit significant aPKC isoform selectivity.

apkcs have been implicated in a variety of signal transduction pathways, exhibiting numerous and diverse signal transduction functions. Both isoforms appear as central participants in mechanisms regulating The establishment and maintenance of cellular polarity in a variety of Cell types (reviewed in Suzuki, A. and Ohno, S. (2006). PAR-aPKC system: experience in polarity (The PAR-aPKC system: lessons in polarity). J Cell Sci 119, 979-. Genetic analysis of their function using knockout mice also showed a preferential role for PKC ζ in regulating NF-kB signaling (Leitges, m., Sanz, l., Martin, p., Duran, a., Braun, u., Garcia, j.f., Camacho, f., Diaz-Meco, m.t., renert, p.d., and Moscat, J. (2001) Targeted disruption of the ζ gene resulted in impairment of the NF- κ B pathway (Targeted disruption of the zetta gene pathway in the insulin secretion and activation (fatty, r.v., john, m.p., Yang, synthetic, h., Li, cell, l.2007, 771-propinq 780), and preferential role for PKC in insulin secretion and activation (fatty, r.v., jan, m.p., Yang, synthetic, h., Li, cell, g., cell, and glucose-mediated metabolism) Clin Invest 117,2289 and 2301). In addition, both isoforms have been implicated in the pathogenesis of cancer, providing strong evidence that aPKC will be inhibited as a novel therapeutic approach.

PKC iota is a known oncogene in non-small cell lung cancer (NSCLC). In one study, it was shown to be overexpressed at the protein level in 69% of NSCLC cases. In line with this, the PKC iota gene (PRKCI located on chromosome 3q 26) was shown to be amplified in 36.5% of NSCLC tumors examined (Regala, r.p., Weems, C., Jamieson, l., Khoor, a., Edell, e.s., Lohse, c.m., and Fields, a.p. (2005 b.) Atypical protein kinase C iota is an oncogene in human non-small cell lung Cancer (appropriate protein kinase C iotaa an oncogen in human non-small cell lung Cancer) Cancer research 65, 8905-8911). It was reported that there was also an amplification of 3q26 in 44% of ovarian cancers (including > 70% of serosal epithelial ovarian cancers) where the amplification of 3q26 was translated to increased expression of PKC iota protein. Furthermore, increased expression of PKC iota is associated with a poor prognosis in NSCLC and ovarian cancer, where it may be identified as a diagnostic biomarker for aggressive disease (Eder, A.M., Sui, X., Rosen, D.G., Nolden, L.K., Cheng, K.W., Lahad, J.P., Kango-Singh, M., Lu, K.H., Warneke, C.L., Atkinson, E.N. et al (2005) Atypical PKC.t in ovarian cancer through loss of apical-basal polarity and overexpression of cyclin E. leading to a poor prognosis (Atypic PKC. kinase to protein kinase of epithelial-nuclear origin in ovarian cancer, J.S. 1253, J.A., Maskan.A., Zkan, N.K., Zkan, N.A.22, J.A.A.A.A. 4. and Zkan.A.A.A.A.A.A.A. 1. and PKC.A.A.A.A.A.A.A.A.A. 1. A.A.A. 1. typical PKC.A.A.A. 1. A. 1. typical PKC.A. 1. and PKC.A.A.A.A.A.A. A. 1. A.A. 1. A. a. typical biomarker, a. A. A. a. A. A. typical biomarker, a. A. a. A. a typical biomarker, a protein Genes (Integrated genetic analysis of Protein Kinase C (PKC) family identity sKCiotaa as a binary and genetic oncogene in an antisense carbon.) cancer Res 66, 4627-4635). Amplification of 3q26 has been observed in many other cancers, including esophageal squamous cell carcinoma (Yang, y.l., Chu, j.y., Luo, m.l., Wu, y.p., Zhang, y., Feng, y.b., Shi, z.z., Xu, x., Han, y.l., Cai, y. et al (2008). Amplification of PRKCI located in 3q26 is associated with lymph node metastasis in esophageal squamous cell carcinoma (Amplification of PRKCI, localized in 3q26, associated with breast cancer (Kojima, y, akk, akparticle y, early cancer cell carcinoma), Genes tumors cancer, 127-136) and breast cancer (Kojima, y, immune, Ak, gamma, early, cancer cell carcinoma, t. expression of proteins, t. located in esophagus squamous cell carcinoma, t. C. t. expression of prostate, t. expression of pathological tumor, t. located in 3 q. 26. and t ) It is suggested that PKC iota may also be involved in the pathogenesis of these diseases.

In NSCLC, the primary function of PKC iota is to drive the translational growth through the Rac1/PAK/MEK/ERK signaling axis. However, PKC iota also plays a role in NSCLC survival, resistance to chemotherapy, and invasion through different pathways (reviewed in Fields, A.P. and Regala, R.P. (2007): Protein kinase C iota: human oncogenes, prognostic markers, and therapeutic targets (reviewed in Protein kinase C iota: human oncogene, diagnostic marker and therapeutic target): Pharmacol Res 55, 487-497). In ovarian cancer, the transformed growth was associated with epithelial cell polarity imbalance and increased cyclin E expression (Eder et al, 2005), suggesting that PKC iota can affect the cancer phenotype through a variety of mechanisms. Emerging conclusive evidence suggests that inhibition of PKC ι may be a useful therapeutic modality for combating tumors characterized by increased PKC ι expression. In a transgenic model, mice with increased PKC iota activity in the colon are more susceptible to carcinogen-induced colon cancer development, and expression of PKC iota kinase-null mutants blocks the transformation of small intestine cells by oncogenic Ras (Murray, n.r., Jamieson, l., Yu, w., Zhang, J., Gokmen-Polar, y., Sier, d., antasiadis, p., Gatalica, z., Thompson, e.a. and Fields, a.p. (2004). Protein kinase C iota 164, 797. Cell 164. for Ras transformation and colon cancer development in vivo. Finally, the genetic or pharmacological inhibition of PKC iota by gold derivative thiomalate (ATM) blocks the growth of NSCLC cells in soft agar and significantly reduces tumor volume in a xenograft model of NSCLC (Regala, r.p., Thompson, e.a. and Fields, a.p. (2008). expression of the Atypical protein kinase C iota and aurothiomalate sensitivity in human lung Cancer cells.) (Cancer Res 68,5888 can 5895; Regala, r.p., Weems, C., jameson, l., coplast, j.a., Thompson, e.a. and Fields, a.p. 311311280. kinase plays a role in growth of lung Cancer cells and clinical lung Cancer cells (environmental growth promoter j.15, nutritional promoter).

Although there is a high similarity between the aPKC isoforms, the role of PKC ζ in cancer is different from that of PKC iota. PKC ζ plays a role in NSCLC cell survival by phosphorylating and antagonizing the pro-apoptotic effect of Bax in response to nicotine (Xin, m., Gao, f., May, w.s., flag, t. and ding, X. (2007). Protein kinase C ζ abolishes the pro-apoptotic function of Bax by phosphorylation (Protein kinase C zeta antagonists of the pro-apoptotic function of baxthreshold phosphorylation). J Biol Chem 282, 21268-21277). PKC ζ activity is also associated with resistance to a wide variety of cytotoxic and genotoxic agents. For example, in human leukemia cells, Overexpression of PKC ζ confers resistance to apoptosis induced by 1- β -D-arabinofuranosyl cytosine (ara-C), daunorubicin, etoposide, and mitoxantrone (Filomenko, R., Poirson-Bichat, F., Billerey, C., Belon, J.P., Garrido, C., Solary, E., and Bettaieb, A. (2002). Atypical protein kinase C ζ as a target for chemosensitization of tumor cells (antigenic protein kinase C zeta as a target for chemosensitization of tumor cells.) Cancer R Rescer 62, 1815-1821; Plo, I., Hernandez, H., Kohagen, G., Lazeier, D., Pommient, Y. and Lambdentin. A. kinase C ζ induces a reduction in cytotoxic activity of cytotoxic protein kinase C ζ in topologic cells (Octophronal kinase C. 2002. kinase C.) (6. beta. Tokyo. induce the formation of cytotoxic protein complex in tumor cells), clean compounds formation, and drug-induced cytoxicity in monocytic U937leukemia cells J Biol Chem 277, 31407-. In addition, inhibition of PKC zeta activity by expression of kinase null mutants sensitizes leukemia cells to the cytotoxic effects of etoposide both in vitro and in vivo (Filomenko et al, 2002). A dual pathway for atypical protein kinase C to modulate degradation of the oncogenic co-activator SRC-3/AIB1 (Mol Cell 29, 465-476), and both proteins have been hypothesized to play a Role in tamoxifen resistance in breast cancer (Iorns, E., Lord, C.J. and Ashworth, A. (2009).) Parallel RNAi and compound screening identified PDK1pathway as a target for tamoxifen sensitization (Parallel RNAi and complex science identity the PDK1pathway as a target for tamoxifen sensitization. Biochem J.361. 370; Osborne, C.K., Bardou, V., Hopp, T.A., chamnese, G.C., Schlsenbeck, S.G., Estrogen, S.A., Fung, J. Woord, H. C.3/AIB 3/E3. C. and HER. 3. C. 3/E. 3. C. and E. 3. C. and E. 3. C. in breast cancer receptor for tamoxifen resistance (AIrC. 3. C. 3. and E. 3. C. 3. C. receptor for tamoxifen. and compound screening Natl Cancer Inst 95, 353-361). Together, these studies suggest that inhibition of PKC ζ activity may have clinically beneficial therapeutic effects by acting as a chemosensitizer on a wide range of commonly used chemotoxic agents.

Additional evidence that small molecule inhibition of PKC ζ may have important therapeutic benefits has also recently emerged, which comes from tumor models that link PKC ζ signaling with the mTOR pathway. PKC ζ is constitutively activated in follicular lymphoma and has been identified as a novel target for the anti-CD 20 therapeutic antibody rituximab (Leseux, L., Laurent, G., Laurent, C., Rigo, M., Blanc, A., Olive, D., and Bezombes, C. (2008). PKC ζ pathway: a new mTOR target for rituximab therapy in follicular lymphoma (PKC zeta pathway: a new target for rituximab therapy in follicular lymphoma). Blood 111, 285. 291). Rituximab inhibits follicular lymphoma proliferation by targeting the PKC ζ -MAPK-mTOR pathway, indicating that PKC ζ is both a target of rituximab and a key regulator of its anti-leukemia effect. The regulation of the mTOR/p70S6K pathway by PKC ζ is also involved in the conversion of prostate cancer Cells to androgen-independent states (Inoue, t., Yoshida, t., Shimizu, y., Kobayashi, t., Yamasaki, t., Toda, y., Segawa, t., Kamoto, t., Nakamura, e., and Ogawa, O. (2006). androgen-dependent cell proliferation in LNCaP Cells requires androgen-dependent activation of protein kinase C ζ and its role in conversion to androgen-independent Cells (Requirement of androgen-dependent activation of protein kinase C. for androgen-dependent cell proliferation in lnp Cells and conversion to androgen-independent Cells 3063, 30620). Finally, mice containing a homozygous deletion of Par4 (a negative regulator of PKC ζ) showed greatly enhanced PKC ζ activity. These mice spontaneously develop prostate and endometrial tumors and potentiate Ras-induced lung cancer development consistent with the role of PKC ζ in lung cancer (Garcia-Cao, i., Duran, a., Collado, M., caroscosa, m.j., Martin-kabalendro, J., Flores, j.m., Diaz-Meco, m.t., Moscat, J. and Serrano, M. (2005.) tumor-inhibiting activity of the pro-apoptotic regulator Par4 (tumor-inhibiting activity of the pro-apoptotic regulator part 4. EMBO Rep 6, 577. 583; Joshi, J., Fernandez-marsos, p.j., galvano, a, amcandy, parr. 193, Ras-induced tumor development, Ras-induced by akraska et al, tumor-2, tumor-induced Ras, k-induced by PKC, k-2, k-Ras, k. 3, akshi et al.

There is a need for aPKC inhibitors for use as medicaments.

Disclosure of Invention

The present invention provides compounds of formula (I)

Or a salt thereof, wherein R⁷、R⁸、R⁹G and X are as defined herein.

Compounds of formula (I) and salts thereof have aPKC inhibitory activity and are useful for treating aPKC-dependent disorders or conditions.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient therefor.

In another aspect, the invention provides a method of treating a subject having an aPKC-dependent disorder or condition, comprising: administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a method of treating a proliferative disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Detailed Description

I. Definition of

As used herein, "about" when referring to a measurable value such as an amount, length of time, etc., is meant to encompass a reasonable variation of the stated value, such as ± 10% of the stated value. For example, the phrase "about 50" includes a reasonable variation of 50, such as ± 10% of the value 50, or from 45 to 55.

"alkyl" or "alkyl group" refers to a monovalent radical of a saturated hydrocarbon chain, branched or unbranched. Examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, and the like. The alkyl group typically contains 1 to 10 carbon atoms, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms, and may be substituted or unsubstituted.

"alkylene" or "alkylene group" refers to a divalent radical of a branched or unbranched saturated hydrocarbon chain. Examples include, but are not limited to, methylene (-CH)₂-) ethylene isomer (-CH (CH)₃) -and-CH₂CH₂-) and the propylene isomer (-CH (CH)₃)CH₂–、–CH(CH₂CH₃)–、–C(CH₃)₂-, and-CH₂CH₂CH₂-) and the like. The alkylene group typically contains 1 to 10 carbon atoms, for example 1 to 6 carbon atoms, and may be substituted or unsubstituted.

"alkenyl" or "alkenyl group" refers to a monovalent radical of a branched or unbranched hydrocarbon chain containing at least one double bond. Examples include, but are not limited to, vinyl, 3-buten-1-yl, 2-vinylbutyl, and 3-hexen-1-yl. Alkenyl groups typically contain 2 to 10 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms, and may be substituted or unsubstituted.

"alkynyl" or "alkynyl group" refers to a monovalent radical of a branched or unbranched hydrocarbon chain containing at least one triple bond. Examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl. Alkynyl groups typically contain 2-10 carbon atoms, for example 2-6 carbon atoms or 2-4 carbon atoms, and may be substituted or unsubstituted.

"aryl" or "aryl group" refers to a bicyclic or tricyclic hydrocarbon ring system of phenyl and 7-15 membered monovalent radicals, including bridged, spiro and/or fused ring systems, wherein at least one ring is aromatic. The aryl group may be substituted or unsubstituted. Examples include, but are not limited to, naphthyl, indanyl, 1,2,3, 4-tetrahydronaphthyl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl. An aryl group may contain 6 (i.e. phenyl) or 9 to 15 ring atoms, such as 6 (i.e. phenyl) or 9-11 ring atoms, such as 6 (i.e. phenyl), 9 or 10 ring atoms.

"arylene" or "arylene group" refers to phenylene (-C)₆H₄-) or a 7-15 membered divalent radical, including bridged, spiro and/or fused ring systems, wherein at least one ring is aromatic. The arylene group may be substituted or unsubstituted. For example, an arylene group may contain 6 (i.e., phenylene) or 9 to 15 ring atoms; for example 6 (i.e. phenylene) or 9 to 11 ring atoms; for example 6 (i.e. phenylene), 9 or 10 ring atoms. Arylene groups may also include ring systems substituted on a ring carbon with one or more-OH functional groups (which may further interconvert to give a ring C ═ O group).

"arylalkyl" or "arylalkyl group" refers to an alkyl group in which a hydrogen atom is replaced with an aryl group, wherein the alkyl group and the aryl group are as previously defined (i.e., arylalkyl-). The arylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl (C)₆H₅CH₂-)。

"cycloalkyl" or "cycloalkyl group" refers to a monovalent nonaromatic carbocyclic ring system which may be saturated or unsaturated, substituted or unsubstituted, and may be monocyclic, bicyclic or tricyclic, and may be bridged, spiro and/or fused. Examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo [2.2.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] heptene, bicyclo [3.1.1] heptane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, and bicyclo [3.3.2] decane. Cycloalkyl groups may contain 3 to 10 ring atoms, such as 3 to 7 ring atoms (e.g., 3 ring atoms, 5 ring atoms, 6 ring atoms, or 7 ring atoms).

"cycloalkylalkyl" or "cycloalkylalkyl group" refers to an alkyl group in which a hydrogen atom is replaced with a cycloalkyl group, where the alkyl group and cycloalkyl group are as previously defined (i.e., cycloalkylalkyl-). The cycloalkylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, cyclohexylmethyl (C)₆H₁₁CH₂-)。

"haloalkyl" or "haloalkyl group" refers to an alkyl group wherein one or more hydrogen atoms are replaced with a halogen atom. Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, e.g. -CF₃、–CHF₂、–CH₂F、–CF₂CF₃、–CHFCF₃、–CH₂CF₃、-CF₂CH₃、-CHFCH₃、-CF₂CF₂CF₃、-CF₂CH₂CH₃、-CF＝CF₂、-CCl＝CH₂、-CBr＝CH₂、-CI＝CH₂、-C≡C-CF₃、-CHFCH₂CH₃and-CHFCH₂CF₃。

"halogen" includes fluorine, chlorine, bromine and iodine atoms.

"heteroaryl" or "heteroaryl group" refers to (a) 5-and 6-membered monocyclic aromatic rings which contain, in addition to carbon atoms, at least one heteroatom such as nitrogen, oxygen or sulfur, and (b))7-15 membered bicyclic and tricyclic rings which contain in addition to carbon atoms at least one heteroatom such as nitrogen, oxygen or sulfur and wherein at least one ring is aromatic. Heteroaryl groups may be substituted or unsubstituted, and may be bridged, spiro-fused, and/or fused. Examples include, but are not limited to, 2, 3-dihydrobenzofuranyl, 1, 2-dihydroquinolinyl, 3, 4-dihydroisoquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, benzoquinolinylOxazinyl, benzothiazinyl, chromanyl, furyl, 2-furyl, 3-furyl, imidazolyl, isofurylAzolyl, isothiazolyl, thiazolyl,A diazolyl group,Oxazolyl, pyridyl, 2-, 3-or 4-pyridyl, pyrimidinyl, 2-, 4-or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2-or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3-or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzopyrazinyl, etc, Benzothiazolyl, benzothiophenyl, benzoAzolyl, cinnolinyl, furazolidinyl, indolinyl, indolizinyl, indolyl or 2-, 3-, 4-, 5-, 6-or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo [6.3.1.0 ]^2,7]Dodeca-2- (7),3, 5-trienyl, 12-oxa-10-aza-tricycles[6.3.1.0^2,7]Dodeca-2- (7),3, 5-trienyl, 12-aza-tricyclo [7.2.1.0 ]^2,7]Dodeca-2- (7),3, 5-trienyl, 10-aza-tricyclo [6.3.2.0 ]^2,7]Tridec-2 (7),3, 5-trienyl, 2,3,4, 5-tetrahydro-1H-benzo [ d ]]Aza derivativesRadical, 1,3,4, 5-tetrahydro-benzo [ d]Aza derivatives-2-keto, 1,3,4, 5-tetrahydro-benzo [ b ]]Aza derivatives-2-keto, 2,3,4, 5-tetrahydro-benzo [ c]Aza derivatives-1-keto, 1,2,3, 4-tetrahydro-benzo [ e ]][1,4]Diaza derivatives-5-keto, 2,3,4, 5-tetrahydro-1H-benzo [ e ]][1,4]Diaza derivativesA group, 5,6,8, 9-tetrahydro-7-oxa-benzocycloheptenyl group, 2,3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives1,2,4, 5-tetrahydro-benzo [ e ]][1,3]Diaza derivatives-3-keto, 3, 4-dihydro-2H-benzo [ b ]][1,4]Dioxa medicine3, 4-dihydro-2H-benzo [ f)][1,4]Oxazazem-5-keto group, 6,7,8, 9-tetrahydro-5-thia-8-azabenzocycloheptenyl group, 5-dioxo-6,7,8, 9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and 2,3,4, 5-tetrahydro-benzo [ f][1,4]OxazazemAnd (4) a base. For example, heteroaryl groups may contain 5,6 or 8 to 15 ring atoms. As another example, a heteroaryl group may contain 5 to 10 ring atoms, such as 5,6, 9, or 10 ring atoms.

"heteroarylalkyl" or "heteroarylalkyl group" refers to an alkyl group wherein a hydrogen atom is replaced by a heteroaryl group, wherein the alkyl group and heteroaryl group are as previously defined (i.e., heteroarylalkyl-). The heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, picolyl isomers

"heterocycloalkyl" or "heterocycloalkyl group" refers to a 3-15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring, which may be saturated or unsaturated, may be substituted or unsubstituted, may be bridged, spiro and/or fused, and which includes at least one heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus, in addition to carbon atoms. Examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl (piperidyl), piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S, S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl (piperidyl), tetrahydrothienyl, homopiperidinyl, thiomorpholinyl-S, S-dioxide, dihydromorpholinyl, piperidinyl, dihydromorpholinyl, morpholinyl,oxazolidone group, dihydropyrazolyl group, dihydropyrrolyl group, dihydropyrazinyl group, dihydropyridinyl group, dihydropyrimidyl group, dihydrofuranyl group, dihydropyranyl group, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S, SDioxides, homothiomorpholinyl-5-oxides, quinuclidinyl, 2-oxa-5-azabicyclo [2.2.1]Heptyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 3, 8-diaza-bicyclo [3.2.1]Octyl, 2, 5-diaza-bicyclo [2.2.1]Heptyl, 3, 8-diaza-bicyclo [3.2.1]Octyl, 3, 9-diaza-bicyclo [4.2.1]Nonyl, 2, 6-diaza-bicyclo [3.2.2]Nonyl, [1,4 ]]Oxyphosphinyl-4-oxide, [1,4 ] or a salt thereof]Azaphosphinoalkyl-4-oxide, [1,2]Oxyphosphine-2-oxide, phosphinoalkyl-1-oxide, [1,3 ]]azaphospholinynl-3-oxide, [1,3 ]]Oxyphosphatidyl-3-oxides and 7-oxabicyclo [2.2.1]A heptyl group. The heterocycloalkyl group may contain at least one nitrogen, oxygen or sulfur atom in addition to carbon atoms. For example, a heterocycloalkyl group may contain at least one nitrogen or oxygen atom in addition to carbon atoms. The heterocycloalkyl group may contain at least one nitrogen in addition to carbon atoms. A heterocycloalkyl group may contain carbon atoms and 1 or 2 nitrogen atoms. The heterocycloalkyl group may contain a carbon atom and an oxygen atom. Heterocycloalkyl groups may contain carbon, nitrogen and oxygen atoms. Heterocycloalkyl groups may contain carbon, nitrogen and sulfur atoms. The heterocycloalkyl group may contain a carbon atom and a sulfur atom. The heterocycloalkyl group may contain from 3 to 10 ring atoms. The heterocycloalkyl group may contain from 3 to 7 ring atoms. The heterocycloalkyl group may contain 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unless otherwise indicated, the heterocycloalkyl groups described above may be C-linked or N-linked where possible and result in the formation of a stable structure. For example, the piperidinyl group may be piperidin-1-yl (N-linked) or piperidin-4-yl (C-linked).

"Heterocycloalkylene" or "heterocycloalkylene group" refers to a divalent 3-15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring system, which may be saturated or unsaturated, may be substituted or unsubstituted, may be bridged, spiro and/or fused, and which contains at least one heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus, in addition to carbon atoms. Examples include, but are not limited to, aziridinyl (azridinylene) isomersThe heterocycloalkylene group may contain at least one nitrogen, oxygen or sulfur atom in addition to carbon atoms. The heterocycloalkylene group may contain at least one nitrogen or oxygen atom in addition to carbon atoms. The heterocycloalkylene group may contain at least one nitrogen in addition to carbon atoms. For example, a heterocycloalkylene group may contain 3 to 10 ring atoms, such as 3 to 7 ring atoms. The heterocycloalkylene group may contain 5 to 7 ring atoms, for example 5 ring atoms, 6 ring atoms or 7 ring atoms. Unless otherwise indicated, the heterocycloalkylene groups described above may be C-linked and/or N-linked where possible and result in the formation of a stable structure. Heterocycloalkylene groups may also include substitution on a ring carbon with one or more-OH functional groups (which may be further interconverted to give a ring C ═ O group) and/or substitution on a ring sulfur atom with one (1) or two (2) oxygen atoms to give S ═ O or SO, respectively₂The radicals and/or the substitution on the ring phosphorus by oxygen atoms to give a ring system of P ═ O.

"Heterocycloalkylalkyl" or "heterocycloalkylalkyl" refers to an alkyl group in which a hydrogen atom is replaced with a heterocycloalkyl group, where alkyl and heterocycloalkyl groups are as previously defined (i.e., heterocycloalkylalkyl-). The heterocycloalkylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, pyrrolidinemethyl (C)₄H₈NCH₂–)。

"pharmaceutically acceptable" refers to a physiologically tolerable substance that, when administered to a human, does not typically produce an allergic or other untoward reaction, such as gastric upset, dizziness and the like.

"pharmaceutical composition" refers to a composition that can be used to treat a disease, symptom, or condition in a human.

"pseudohalogen" means-OCN, -SCN, -CF₃and-CN.

"stable" or "chemically stable" refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture. Hair brushIt relates only to the preparation of stable compounds. When a list of optional substituents includes members that cannot be used to replace a particular group due to valence requirements, chemical stability, or other reasons, then that list should be read in context to include those members of the list that are suitable for replacing the particular group. For example, R¹May be optionally substituted with 1-13R¹⁹Substituted C_1-6An alkyl group; when R is¹When methyl, the methyl group is optionally substituted with 1-3R¹⁹And (4) substitution.

A "therapeutically effective amount" refers to an amount of a compound that is sufficient to inhibit, halt or cause an improvement in a condition or symptom being treated in a particular subject or population of subjects. A therapeutically effective amount may be determined experimentally, for example in a human or other mammal, in a laboratory or clinical setting, or may be the amount required by the United States Food and Drug Administration (United States Food and Drug Administration) or guidelines of equivalent foreign bodies for a particular disease and subject being treated. It will be understood that determination of the appropriate dosage form, dosage amount and route of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

"treatment" refers to an acute or prophylactic reduction or alleviation of at least one symptom or characteristic associated with or caused by the condition being treated. For example, treatment may include alleviation of several symptoms of the disorder or complete eradication of the disorder.

II. Compound

The compounds of the present invention are defined by the following numbered embodiments. When a higher numbered embodiment optionally recalls a plurality of the previous lower numbered embodiments and contains new limiting features not present in the lower numbered embodiments, then the higher numbered embodiment is intended to explicitly describe each and every alternative. For example, if embodiment 2 is reiterated to embodiment 1 and includes a limitation feature not present in embodiment 1, embodiment 3 is reiterated to embodiment 1 or 2 and includes a limitation not present in embodiment 1 or 2Feature, and embodiment 4 re-mentions any of embodiments 1-3 and includes a limitation feature not present in embodiments 1,2 or 3, then embodiment 4 is intended to specifically describe a class of solutions having the limitation features of embodiments 1 and 4, specifically describe a class of solutions having the limitation features of embodiments 2 and 4 (i.e., 1,2 and 4), and specifically describe a class of solutions having the limitation features of embodiments 3 and 4 (i.e., 1,3 and 4, and 1,2,3 and 4). For example, if embodiment 1 is to limit R⁷、R⁸And R⁹A compound of formula (I) independently being alkyl or aryl, embodiment 2 being defined as R⁷A compound of embodiment 1 that is alkyl, embodiment 3 being limited to R⁸A compound of embodiment 1 or 2 that is alkyl, and embodiment 4 is defined as⁹A compound of any one of embodiments 1-3 being alkyl, then embodiment 4 explicitly describes a class of protocols having the limiting characteristics of embodiments 1 and 4 (i.e., where R is⁷And R⁸Is alkyl or aryl and R⁹Compounds of formula (I) that are alkyl), a class of schemes (i.e., where R is the limiting feature of embodiments 2 and 4) is explicitly described⁸Is alkyl or aryl and R⁷And R⁹Compounds of formula (I) that are alkyl), a class of schemes (i.e., where R is the limiting feature of embodiments 3 and 4) is explicitly described⁷Is alkyl or aryl and R⁸And R⁹A compound of formula (I) which is alkyl; and wherein R⁷、R⁸And R⁹All alkyl compounds of formula (I). In this regard it should be noted that when a higher numbered embodiment refers to a lower numbered embodiment and contains a limiting feature for a group that is not present in the lower numbered embodiment, the higher numbered embodiment should be construed in context as ignoring the missing group. For example, if embodiment 1 recites wherein X is H, C_1-10Alkyl or-C (═ O) R²⁸Embodiment 2 lists compounds of formula (I) wherein X is H or C_1-10The compound of embodiment 1 of the alkyl group, and embodiment 3 exemplifies the compound wherein R²⁸The compound of embodiment 1 or 2 being an alkyl group, embodiment 3 is defined as having the limitations of embodiments 1 and 3A class of solutions featuring and a class of solutions featuring the defining features of embodiments 2 and 3 (i.e. 1,2 and 3). In a class of approaches defined by the limiting features of embodiments 2 and 3, X cannot be — C (═ O) R²⁸(ii) a This class of schemes should therefore be interpreted as omitting R in embodiment 3²⁸Alkyl (i.e. such embodiments 2 and 3 have the same scope as such embodiments 2).

The compounds of the present invention are defined herein using structural formulas that do not specifically list the mass numbers or isotopic proportions of the constituent atoms. The present invention is intended to include compounds in which the constituent atoms are present in isotopic form in any proportion. For example, the carbon atom may be substituted with¹²C、¹³C and¹⁴c is present in any proportion; the hydrogen atom may be represented by¹H、²H and³h is present in any proportion; and so on. Preferably, the constituent atoms in the compounds of the present invention are present in their natural proportions in isotopic form.

Embodiment 1 Compounds of formula (I)Or a salt form thereof, or a pharmaceutically acceptable salt form thereof,

wherein

G is formulaA group of (a);

x is selected from H, optionally substituted by 1-13R¹⁹Substituted C_1-10Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-C(＝O)C(＝O)R²⁸、-NR²⁴R²⁸、-NR²⁴NR²⁴R²⁸、-N＝NR²⁸、-NR²⁴OR²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OC(＝O)OR²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂OR²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸；

R⁷、R⁸、R⁹、R¹²、R¹³、R¹⁴、R¹⁵、R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰)；

Or R⁷And R⁸、R¹²And R¹³、R¹⁴And R¹⁵、R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay be substituted with an atom one to which they are attachedForm an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl;

R¹⁹independently at each occurrence is selected from the group consisting of optionally substituted 1-13R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-C(＝NR³⁵)R³⁰、-C(＝NR³⁵)NR³²R³³、-C(＝NOH)NR³²R³³、-C(＝NOR³⁶)R³⁰、-C(＝NNR³²R³³)R³⁰、-C(＝NNR³⁴C(＝O)R³¹)R³⁰、-C(＝NNR³⁴C(＝O)OR³¹)R³⁰、-C(＝S)NR³²R³³、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-N＝NR³⁴、＝NR³⁰、＝NOR³⁰、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴C(＝S)R³⁰、-NR³⁴C(＝S)OR³⁰、-NR³⁴C(＝S)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-NR³⁴P(＝O)R⁷⁸R⁷⁸、-NR³⁴P(＝O)(NR³²R³³)(NR³²R³³)、-NR³⁴P(＝O)(OR³⁰)(OR³⁰)、-NR³⁴P(＝O)(SR³⁰)(SR³⁰)、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-OS(＝O)R³⁰、-OS(＝O)₂R³⁰、-OS(＝O)₂OR³⁰、-OS(＝O)₂NR³²R³³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR³²R³³)(NR³²R³³)、-OP(＝O)(OR³⁰)(OR³⁰)、-OP(＝O)(SR³⁰)(SR³⁰)、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR³²R³³)(NR³²R³³)、-SP(＝O)(OR³⁰)(OR³⁰)、-SP(＝O)(SR³⁰)(SR³⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)；

R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-13R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁴⁹Substituted 6-21 membered heteroarylalkyl;

R²⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁴⁹Substituted C_1-10Alkyl, optionally substituted with 1-11R⁴⁹Substituted C_2-10Alkenyl, optionally substituted by 1-9R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁴⁹Substituted 6-21 membered heteroarylalkyl;

R²²、R²³、R³²and R³³Independently at each occurrence selected from H, optionally substituted with 1-13R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁵⁹Substituted 6-21 membered heteroarylalkyl;

or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl;

R³⁹、R⁴⁹、R⁵⁹and R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-C(＝NR⁷⁵)R⁷⁰、-C(＝NR⁷⁵)NR⁷²R⁷³、-C(＝NOH)NR⁷²R⁷³、-C(＝NOR⁷⁶)R⁷⁰、-C(＝NNR⁷²R⁷³)R⁷⁰、-C(＝NNR⁷⁴C(＝O)R⁷¹)R⁷⁰、-C(＝NNR⁷⁴C(＝O)OR⁷¹)R⁷⁰、-C(＝S)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、＝NR⁷⁰、＝NOR⁷⁰、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝NR⁷⁵)NR⁷²R⁷³、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝S)R⁷⁰、-NR⁷⁴C(＝S)OR⁷⁰、-NR⁷⁴C(＝S)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-NR⁷⁴P(＝O)(SR⁷⁰)(SR⁷⁰)、-OR⁷⁰、＝O、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OC(＝NR⁷⁵)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-OP(＝O)(SR⁷⁰)(SR⁷⁰)、-Si(R⁷⁴)₃、-SCN、＝S、–S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-P(＝O)(OR⁷⁰)(OR⁷⁰) and-P (═ O) (SR)⁷⁰)(SR⁷⁰)；

R⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl;

R⁷²and R⁷³Independently at each occurrence selected from H, optionally substituted with 1-13R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁹⁹Substituted C_3-11Cycloalkyl radical, renSelecting 1-32R⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁹⁹Substituted 6-21 membered heteroarylalkyl;

or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁰⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁰⁹Substituted 5-15 membered heteroaryl;

R⁷⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl;

or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-6R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-10 membered heterocycloalkyl;

R⁷⁹、R⁸⁹、R⁹⁹and R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹¹⁹Substituted C_6-11Aryl, heteroaryl, and heteroaryl,Optionally substituted by 1-19R¹¹⁹C substituted by one_7-16Arylalkyl, optionally substituted with 1-21R¹¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-C(＝O)C(＝O)R¹¹⁰、-C(＝NR¹¹⁵)R¹¹⁰、-C(＝NR¹¹⁵)NR¹¹²R¹¹³、-C(＝NOH)NR¹¹²R¹¹³、-C(＝NOR¹¹⁶)R¹¹⁰、-C(＝NNR¹¹²R¹¹³)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)R¹¹¹)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)OR¹¹¹)R¹¹⁰、-C(＝S)NR¹¹²R¹¹³、-NC、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴NR¹¹²R¹¹³、-N＝NR¹¹⁴、＝NR¹¹⁰、＝NOR¹¹⁰、-NR¹¹⁴OR¹¹⁶、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)OR¹¹⁰、-NR¹¹⁴C(＝NR¹¹⁵)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝S)R¹¹⁰、-NR¹¹⁴C(＝S)OR¹¹⁰、-NR¹¹⁴C(＝S)NR¹¹²R¹¹³、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-NR¹¹⁴P(＝O)R¹¹⁸R¹¹⁸、-NR¹¹⁴P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-NR¹¹⁴P(＝O)(OR¹¹⁰)(OR¹¹⁰)、-NR¹¹⁴P(＝O)(SR¹¹⁰)(SR¹¹⁰)、-OR¹¹⁰、＝O、-OCN、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-OC(＝NR¹¹⁵)NR¹¹²R¹¹³、-OS(＝O)R¹¹⁰、-OS(＝O)₂R¹¹⁰、-OS(＝O)₂OR¹¹⁰、-OS(＝O)₂NR¹¹²R¹¹³、-OP(＝O)R¹¹⁸R¹¹⁸、-OP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-OP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-OP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-Si(R¹¹⁴)₃、-SCN、＝S、–S(＝O)_nR¹¹⁰、-S(＝O)₂OR¹¹⁰、-SO₃R¹¹¹¹、-S(＝O)₂NR¹¹²R¹¹³、-S(＝O)NR¹¹²R¹¹³、-SP(＝O)R¹¹⁸R¹¹⁸、-SP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-SP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-SP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-P(＝O)R¹¹⁸R¹¹⁸、-P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-P(＝O)(OR¹¹⁰)(OR¹¹⁰) and-P (═ O) (SR)¹¹⁰)(SR¹¹⁰)；

R¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted by 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl;

R¹¹²and R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-13R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹³⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹³⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁴⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁴⁹Substituted 5-15 membered heteroaryl;

R¹¹⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl;

R¹¹⁹、R¹²⁹、R¹³⁹and R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁵⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁵⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-C(＝O)C(＝O)R¹⁵⁰、-C(＝NR¹⁵⁵)R¹⁵⁰、-C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-C(＝NOH)NR¹⁵²R¹⁵³、-C(＝NOR¹⁵⁶)R¹⁵⁰、-C(＝NNR¹⁵²R¹⁵³)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)R¹⁵¹)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)OR¹⁵¹)R¹⁵⁰、-C(＝S)NR¹⁵²R¹⁵³、-NC、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴NR¹⁵²R¹⁵³、-N＝NR¹⁵⁴、＝NR¹⁵⁰、＝NOR¹⁵⁰、-NR¹⁵⁴OR¹⁵⁶、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)OR¹⁵⁰、-NR¹⁵⁴C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝S)R¹⁵⁰、-NR¹⁵⁴C(＝S)OR¹⁵⁰、-NR¹⁵⁴C(＝S)NR¹⁵²R¹⁵³、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-NR¹⁵⁴P(＝O)R¹⁵⁸R¹⁵⁸、-NR¹⁵⁴P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-NR¹⁵⁴P(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-NR¹⁵⁴P(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-OR¹⁵⁰、＝O、-OCN、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-OC(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-OS(＝O)R¹⁵⁰、-OS(＝O)₂R¹⁵⁰、-OS(＝O)₂OR¹⁵⁰、-OS(＝O)₂NR¹⁵²R¹⁵³、-OP(＝O)R¹⁵⁸R¹⁵⁸、-OP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-OP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-OP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-Si(R¹⁵⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁵⁰、-S(＝O)₂OR¹⁵⁰、-SO₃R¹⁵¹⁵、-S(＝O)₂NR¹⁵²R¹⁵³、-S(＝O)NR¹⁵²R¹⁵³、-SP(＝O)R¹⁵⁸R¹⁵⁸、-SP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-SP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-SP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-P(＝O)R¹⁵⁸R¹⁵⁸、-P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-P(＝O)(OR¹⁵⁰)(OR¹⁵⁰) and-P (═ O) (SR)¹⁵⁰)(SR¹⁵⁰)；

R¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁵²and R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁷⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁷⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁸⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁸⁹Substituted 5-15 membered heteroaryl;

R¹⁵⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁵⁹、R¹⁶⁹、R¹⁷⁹and R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-C(＝O)C(＝O)R¹⁹⁰、-C(＝NR¹⁹⁵)R¹⁹⁰、-C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-C(＝NOH)NR¹⁹²R¹⁹³、-C(＝NOR¹⁹⁶)R¹⁹⁰、-C(＝NNR¹⁹²R¹⁹³)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)R¹⁹¹)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)OR¹⁹¹)R¹⁹⁰、-C(＝S)NR¹⁹²R¹⁹³、-NC、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴NR¹⁹²R¹⁹³、-N＝NR¹⁹⁴、＝NR¹⁹⁰、＝NOR¹⁹⁰、-NR¹⁹⁴OR¹⁹⁶、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)OR¹⁹⁰、-NR¹⁹⁴C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝S)R¹⁹⁰、-NR¹⁹⁴C(＝S)OR¹⁹⁰、-NR¹⁹⁴C(＝S)NR¹⁹²R¹⁹³、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-NR¹⁹⁴P(＝O)R¹⁹⁸R¹⁹⁸、-NR¹⁹⁴P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-NR¹⁹⁴P(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-NR¹⁹⁴P(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-OR¹⁹⁰、＝O、-OCN、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-OC(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-OS(＝O)R¹⁹⁰、-OS(＝O)₂R¹⁹⁰、-OS(＝O)₂OR¹⁹⁰、-OS(＝O)₂NR¹⁹²R¹⁹³、-OP(＝O)R¹⁹⁸R¹⁹⁸、-OP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-OP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-OP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-Si(R¹⁹⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁹⁰、-S(＝O)₂OR¹⁹⁰、-SO₃R¹⁹¹⁹、-S(＝O)₂NR¹⁹²R¹⁹³、-S(＝O)NR¹⁹²R¹⁹³、-SP(＝O)R¹⁹⁸R¹⁹⁸、-SP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-SP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-SP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-P(＝O)R¹⁹⁸R¹⁹⁸、-P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-P(＝O)(OR¹⁹⁰)(OR¹⁹⁰) and-P (═ O) (SR)¹⁹⁰)(SR¹⁹⁰)；

R¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁹²and R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-13R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²¹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²¹⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R²²⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R²²⁹Substituted 5-15 membered heteroaryl;

R¹⁹⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁹⁹、R²⁰⁹、R²¹⁹and R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-13 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-11Aryl radical, C_7-16Arylalkyl radical, C_3-11Cycloalkyl radical, C_4-17Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-C(＝O)C(＝O)R²³⁰、-C(＝NR²³⁰)R²³⁰、-C(＝NR²³⁰)NR²³⁰R²³⁰、-C(＝NOH)NR²³⁰R²³⁰、-C(＝NOR²³⁰)R²³⁰、-C(＝NNR²³⁰R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)OR²³⁰)R²³⁰、-C(＝S)NR²³⁰R²³⁰、-NC、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰NR²³⁰R²³⁰、-N＝NR²³⁰、＝NR²³⁰、＝NOR²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)C(＝O)R²³⁰、-NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)C(＝O)OR²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝NR²³⁰)NR²³⁰R²³⁰、-NR²³⁰C(＝O)C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝S)R²³⁰、-NR²³⁰C(＝S)OR²³⁰、-NR²³⁰C(＝S)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-NR²³⁰P(＝O)R²³¹R²³¹、-NR²³⁰P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-NR²³⁰P(＝O)(OR²³⁰)(OR²³⁰)、-NR²³⁰P(＝O)(SR²³⁰)(SR²³⁰)、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-OC(＝O)NR²³⁰R²³⁰、-OC(＝O)OR²³⁰、-OC(＝NR²³⁰)NR²³⁰R²³⁰、-OS(＝O)R²³⁰、-OS(＝O)₂R²³⁰、-OS(＝O)₂OR²³⁰、-OS(＝O)₂NR²³⁰R²³⁰、-OP(＝O)R²³¹R²³¹、-OP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-OP(＝O)(OR²³⁰)(OR²³⁰)、-OP(＝O)(SR²³⁰)(SR²³⁰)、-Si(R²³⁰)₃、-SCN、＝S、–S(＝O)_nR²³⁰、-S(＝O)₂OR²³⁰、-SO₃R²³⁰、-S(＝O)₂NR²³⁰R²³⁰、-S(＝O)NR²³⁰R²³⁰、-SP(＝O)R²³¹R²³¹、-SP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-SP(＝O)(OR²³⁰)(OR²³⁰)、-SP(＝O)(SR²³⁰)(SR²³⁰)、-P(＝O)R²³¹R²³¹、-P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-P(＝O)(OR²³⁰)(OR²³⁰) and-P (═ O) (SR)²³⁰)(SR²³⁰)；

R²³⁰Independently at each occurrence selected from H, C_1-6Alkyl and C_1-6-a haloalkyl group;

R²³¹is independently selected at each occurrence from C_1-6Alkyl and C_1-6-a haloalkyl group; and is

n is independently selected at each occurrence from 0, 1, and 2;

with the proviso that said compound is not

(a) Wherein D is H orOr a salt form thereof;

(b) wherein D isIs/are as followsOr a salt form thereof; or

(c) Wherein D is H or-CH₃Is/are as followsOr a salt form thereof.

Embodiment 2. the compound of embodiment 1 wherein G is a group of the formula

Embodiment 3. the compound of embodiment 1 wherein G is a group of the formula

Embodiment 4. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-10Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 memberedHeteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-C(＝O)C(＝O)R²⁸、-NR²⁴R²⁸、-NR²⁴NR²⁴R²⁸、-N＝NR²⁸、-NR²⁴OR²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OC(＝O)OR²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂OR²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸。

Embodiment 5. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-10Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted by5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸。

Embodiment 6. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-10Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸。

Embodiment 7. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-7Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-7 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-11 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸。

Embodiment 8. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-7Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-7 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-11 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 9. the compound of any of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-7Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-7 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-11 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)OR²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-NR²⁴S(＝O)₂NR²⁴R²⁸、-OR²⁸、-OC(＝O)R²⁸、-OC(＝O)NR²⁴R²⁸、-OS(＝O)R²⁸、-OS(＝O)₂R²⁸、-OS(＝O)₂NR²⁴R²⁸、-S(＝O)_nR²⁸、-S(＝O)₂NR²⁴R²⁸and-S (═ O) NR²⁴R²⁸。

Embodiment 10. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-7Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-7 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-11 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 11. the compound of any of embodiments 1 to 3 wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 12. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 13. the compound of any of embodiments 1 to 3 wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴S(＝O)₂R²⁸and-OR²⁸。

Embodiment 14. the compound of any one of embodiments 1 to 3 wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴S(＝O)₂R²⁸and-OR²⁸。

Embodiment 15. the compound of any of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-7Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-7 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-11 membered heteroarylalkyl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 16. the compound of any of embodiments 1 to 3 wherein X is selected from optionally substituted with 1 to 6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 17. the compound of any of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)OR²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴C(＝O)NR²⁴R²⁸、-NR²⁴S(＝O)₂R²⁸、-OR²⁸、-OC(＝O)R²⁸、-S(＝O)_nR²⁸and-S (═ O)₂NR²⁴R²⁸。

Embodiment 18. the compound of any of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴S(＝O)₂R²⁸and-OR²⁸。

Embodiment 19. the compound of any of embodiments 1 to 3 wherein X is selected from the group consisting of optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -C (═ O) R²⁸、-C(＝O)NR²⁴R²⁸、-NR²⁴R²⁸、-NR²⁴C(＝O)R²⁸、-NR²⁴S(＝O)₂R²⁸and-OR²⁸。

Embodiment 20. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -NR²⁴R²⁸and-OR²⁸。

Embodiment 21. the compound of any of embodiments 1 to 3 wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -NR²⁴R²⁸and-OR²⁸。

Embodiment 22. the compound of any one of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -NR²⁴R²⁸and-OR²⁸。

Embodiment 23. the compound of any one of embodiments 1 to 3 wherein X is selected from the group consisting of optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, -NR²⁴R²⁸and-OR²⁸。

Embodiment 24. the compound of any one of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, and-NR²⁴R²⁸。

Embodiment 25. the compound of any of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, and-NR²⁴R²⁸。

Embodiment 26. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, -NR²⁴R²⁸、-OR²⁸and-SR²⁸。

Embodiment 27. the compound of any one of embodiments 1 to 3, wherein X is selected from the group consisting of optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, and-NR²⁴R²⁸。

Embodiment 28. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-9 membered heterocycloalkyl, and-NR²⁴R²⁸。

Embodiment 29. the compound of any one of embodiments 1 to 3, wherein X is selected from the group consisting of optionally substituted with 1-6R¹⁹Substituted 3-9 membered heterocycloalkyl, and-NR²⁴R²⁸。

Embodiment 30. the compound of any of embodiments 1 to 3, wherein X is selected from H, optionally substituted with 1-6R¹⁹Substituted 3-7 membered heterocycloalkyl, and-NR²⁴R²⁸。

Embodiment 31. the compound of any one of embodiments 1 to 3, wherein X is selected from optionally substituted with 1-6R¹⁹Substituted 3-to 7-memberedHeterocycloalkyl, and-NR²⁴R²⁸。

Embodiment 32. the compound of any of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted 3-10 membered heterocycloalkyl.

Embodiment 33. the compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted 3-9 membered heterocycloalkyl.

Embodiment 34. the compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted 3-7 membered heterocycloalkyl.

Embodiment 35. the compound of any one of embodiments 1 to 3, wherein X is optionally substituted with 1 to 6R¹⁹Substituted 5-6 membered heterocycloalkyl.

Embodiment 36. the compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted 6-membered heterocycloalkyl.

Embodiment 37. the compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted morpholinyl, piperidinyl, or piperazinyl.

Embodiment 38. the compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1 to 6R¹⁹Substituted piperidinyl or piperazinyl.

An embodiment 39 compound of any one of embodiments 1 to 3 wherein X is optionally substituted with 1-6R¹⁹A substituted piperidinyl group.

Embodiment 40. the compound of any one of embodiments 1 to 3, wherein X is optionally substituted with 1 to 6R¹⁹A substituted piperazinyl group.

Embodiment 41. a compound of any one of embodiments 1 to 3, wherein X is-NR²⁴R²⁸。

Embodiment 42. the compound of any one of embodiments 1 to 3, wherein X is selected from H andwherein

A is-NR¹R²、-CRⁱR^jR^k、-OR^18aor-SR^18b；

Q is-NR¹¹–、-CR^mRⁿ-, -O-, or-S-;

R^kis H, halogen, -CN, -NO₂、-NR¹⁶R¹⁷、-OR^18c、-SR^18dor-CR^oR^pR^q；

R^qIs H, halogen, -CN, -NO₂、-NR^16aR^17aOR-OR^18e；

R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, and-OR⁷⁰；

R³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-C(＝NR⁷⁵)R⁷⁰、-C(＝NR⁷⁵)NR⁷²R⁷³、-C(＝NOH)NR⁷²R⁷³、-C(＝NOR⁷⁶)R⁷⁰、-C(＝NNR⁷²R⁷³)R⁷⁰、-C(＝NNR⁷⁴C(＝O)R⁷¹)R⁷⁰、-C(＝NNR⁷⁴C(＝O)OR⁷¹)R⁷⁰、-C(＝S)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝NR⁷⁵)NR⁷²R⁷³、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝S)R⁷⁰、-NR⁷⁴C(＝S)OR⁷⁰、-NR⁷⁴C(＝S)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-NR⁷⁴P(＝O)(SR⁷⁰)(SR⁷⁰)、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OC(＝NR⁷⁵)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-OP(＝O)(SR⁷⁰)(SR⁷⁰)、-Si(R⁷⁴)₃、-SCN、-S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-P(＝O)(OR⁷⁰)(OR⁷⁰) and-P (═ O) (SR)⁷⁰)(SR⁷⁰)；

Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl;

or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form together with the atoms to which they are attached an optionally substituted1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl;

or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond;

or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿMay form ═ O or ═ NR⁷⁰、＝NOR⁷⁰Or ═ S.

Embodiment 43. the compounds of any of embodiments 1 to 3 wherein X isWherein

A is-NR¹R²、-CRⁱR^jR^k、-OR^18aor-SR^18b；

Q is-NR¹¹–、-CR^mRⁿ-, -O-, or-S-;

R^kis H, halogen, -CN, -NO₂、-NR¹⁶R¹⁷、-OR^18c、-SR^18dor-CR^oR^pR^q；

R^qIs H, halogen, -CN, -NO₂、-NR^16aR^17aOR-OR^18e；

R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, and-OR⁷⁰；

R³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-C(＝NR⁷⁵)R⁷⁰、-C(＝NR⁷⁵)NR⁷²R⁷³、-C(＝NOH)NR⁷²R⁷³、-C(＝NOR⁷⁶)R⁷⁰、-C(＝NNR⁷²R⁷³)R⁷⁰、-C(＝NNR⁷⁴C(＝O)R⁷¹)R⁷⁰、-C(＝NNR⁷⁴C(＝O)OR⁷¹)R⁷⁰、-C(＝S)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝NR⁷⁵)NR⁷²R⁷³、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝S)R⁷⁰、-NR⁷⁴C(＝S)OR⁷⁰、-NR⁷⁴C(＝S)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-NR⁷⁴P(＝O)(SR⁷⁰)(SR⁷⁰)、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OC(＝NR⁷⁵)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-OP(＝O)(SR⁷⁰)(SR⁷⁰)、-Si(R⁷⁴)₃、-SCN、-S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-P(＝O)(OR⁷⁰)(OR⁷⁰) and-P (═ O) (SR)⁷⁰)(SR⁷⁰)；

Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl;

or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl;

or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond;

or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿMay form ═ O or ═ NR⁷⁰、＝NOR⁷⁰Or ═ S.

Embodiment 44. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-21 membered heteroarylalkyl, and-OR⁷⁰；R³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-10R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted with 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-Si(R⁷⁴)₃、-SCN、-S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³) and-P (═ O) (OR)⁷⁰)(OR⁷⁰) (ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿMay form ═ O or ═ NR⁷⁰、＝NOR⁷⁰Or ═ S.

Embodiment 45, a compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-21 membered heterocycloalkylalkanesOptionally substituted by 1-10R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-21 membered heteroarylalkyl, and-OR⁷⁰；R³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-10R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted with 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-SCN、-S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³) and-P (═ O) (OR)⁷⁰)(OR⁷⁰) (ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-15 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 46. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-11Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-11 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl, and optionally substituted with 1-10R⁷⁹Substituted 6-12 membered heteroarylalkyl; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-10R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted with 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-11Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-11 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-12 membered heteroarylalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-SCN、-S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³and-S (═ O) NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 47. the compounds of embodiments 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-11Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-11 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl, and optionally substituted with 1-10R⁷⁹Substituted 6-12 membered heteroarylalkyl; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-10R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted with 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted C_4-11Cycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-10R⁷⁹Substituted 4-11 membered heterocycloalkylalkyl, optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl, optionally substituted with 1-10R⁷⁹Substituted 6-12 membered heteroarylalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-SCN、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 48. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-10R⁷⁹Substituted 5-11 membered heteroaryl; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-10R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-10R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted with 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-10 membered heterocyclic ringsAlkyl, optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-10R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-10R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-10R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-10R⁷⁹Substituted 5-11 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 49. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R⁷⁹Substituted 5-11 membered heteroaryl; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_6-11Aryl, optionallyBy 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R⁷⁹Substituted 5-11 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-6R⁷⁹Substituted 5-11 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-6R⁷⁹Substituted 5-11 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 50. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkyl, halogen,–CN、-C(＝O)R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_3-10Cycloalkyl, or optionally substituted by 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 51. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹And R^18cAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_3-10Cycloalkyl, or optionally substituted by 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 52. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹And R^18cAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 53. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 54, the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R¹⁶And R⁵、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴Together may form ═ O.

Embodiment 55. the compounds of embodiments 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,And optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl, -CN, -C (═ O) OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³and-OR⁷⁰(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R¹⁶And R⁵、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴Together may form ═ O.

Embodiment 56. the compound of embodiment 42 or 43, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_7-16Arylalkyl radical, NSelecting 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-6R⁷⁹Substituted 5-11 membered heteroaryl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl or optionally substituted with 1-6R⁷⁹Substituted 5-11 membered heteroaryl; or R⁴And R⁵Or RⁿAnd R⁵May together form a double bond; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 57 a compound of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r²Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkanesRadical, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_3-10A cycloalkyl group, a,Or optionally substituted with 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 58. the compound of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r²Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹And R^18cAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted C_3-10Cycloalkyl, or optionally substituted by 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 59. the compound of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r²Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, and optionally substituted with 1-6R⁷⁹Substituted C_7-16An arylalkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIndependently selected from H and optionally substituted with 1-6R⁷⁹Substituted C_1-6An alkyl group; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹And R^18cAnd RⁿMay form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Implementation methodA compound of formula 60 any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 0-3 in (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 61. the compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 0-2 in (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 62. the compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 1-2 together with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 63, the compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 64. the compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 65. a compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTwo groups of (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 66. the compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 0-3 in (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 67. compounds of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 0-2 in (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 68. compounds of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿGroups 1-2 in (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 69.a compound of any one of embodiments 42 to 59 wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 70. a compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl.

Embodiment 71. the compound of embodiment 70, wherein the optionally substituted heterocarbocyclyl is optionally substituted with 1-4R⁷⁹A substituted 3-7 membered heterocarbocycle (heterocarbocycle).

Embodiment 72 a compound of embodiment 70, wherein the optionally substituted heterocarbocyclyl is optionally substituted with 1-4R⁷⁹A substituted 5-6 membered heterocarbocycle.

Embodiment 73, a compound of any one of embodiments 42 to 59, wherein R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹、R^18aAnd R³、R^18aAnd R⁵、R^18aAnd R¹¹、R^18aAnd Rⁿ、R^18bAnd R³、R^18bAnd R⁵、R^18bAnd R¹¹、R^18bAnd Rⁿ、R^18cAnd Rⁱ、R^18cAnd R³、R^18cAnd R⁵、R^18cAnd R¹¹、R^18cAnd Rⁿ、R^18dAnd Rⁱ、R^18dAnd R³、R^18dAnd R⁵、R^18dAnd R¹¹And R^18dAnd RⁿTwo groups of (a) together with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 74. the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroup 0-2 together with the atoms to which they are attached form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 75. the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroup 0-1 together with the atoms to which they are attached form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 76. compounds of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 77, compounds of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 78A compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroups 0-2 in (a) together with the atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

Embodiment 79A compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroup 0-1 together with the atoms to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

Embodiment 80. the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.

Embodiment 81. the compound of any one of embodiments 42 to 73 wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl.

Embodiment 82, the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroup 0-2 together with the atoms to which they are attached form an optional substitutionThe heterocycloalkyl group of (1).

Embodiment 83. the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mGroup 0-1 together with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 84. the compound of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl group.

Embodiment 85, the compounds of any one of embodiments 42 to 73, wherein R³And R⁴、R³And R⁶、R⁵And R⁶、RⁱAnd R^j、RⁱAnd R⁴、RⁱAnd R⁵、RⁱAnd Rⁿ、R^mAnd Rⁿ、R⁴And R^mAnd R⁶And R^mTogether with the atoms to which they are attached form an optionally substituted heterocycloalkyl.

Embodiment 86, the compound of embodiment 85, wherein the optionally substituted heterocarbocyclyl is optionally substituted with 1-4R⁷⁹Substituted 3-a 7-membered heterocarbocycle.

Embodiment 87. the compound of embodiment 85, wherein the optionally substituted heterocarbocyclyl is optionally substituted with 1-4R⁷⁹A substituted 5-6 membered heterocarbocycle.

Embodiment 88. the compound of any one of embodiments 42 to 87, wherein R⁴And R⁵Or RⁿAnd R⁵None of the groups together form a double bond.

Embodiment 89 the compound of any one of embodiments 42 to 88, wherein R³And R⁴、R⁵And R⁶、RⁱAnd R^jOr R^mAnd RⁿNone of the groups together form ═ O, ═ NR⁷⁰、＝NOR⁷⁰Or ═ S.

Embodiment 90. the compound of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIs H; r²Selected from H and optionally substituted by 1-6R⁷⁹Substituted C_1-6An alkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIs H; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R⁶And R¹¹、R¹⁶And R¹⁷、R¹⁶And Rⁱ、R¹⁶And R³、R¹⁶And R⁵、R¹⁶And R¹¹、R¹⁶And Rⁿ、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴、R⁵And R⁶、RⁱAnd R^jAnd R^mAnd RⁿAny one of the groups may together form ═ O.

Embodiment 91. the compound of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIs H; r²Selected from H and optionally substituted by 1-6R⁷⁹Substituted C_1-6An alkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIs H; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R¹⁶And R⁵、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴Together may form ═ O.

Embodiment 92. the compounds of embodiment 42 or 43, wherein R¹、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIs H; r²Selected from H and optionally substituted by 1-6R⁷⁹Substituted C_1-6An alkyl group; r⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIs H; r³Selected from H, optionally substituted with 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl, -CN, -C (═ O) OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NR⁷²R⁷³and-OR⁷⁰(ii) a Or R¹And R²、R¹And R³、R¹And R⁵、R¹And R¹¹、R¹And Rⁿ、R⁴And R¹¹、R¹⁶And R⁵、R^jAnd R¹¹And R^18aAnd R¹¹May form, together with the atoms to which they are attached, an optionally substituted 1-6R⁷⁹Substituted 3-11 membered heterocycloalkyl; or R³And R⁴Together may form ═ O.

Embodiment 93. compounds of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least five of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least four of (a) are H.

Embodiment 94. the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least five of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least five of (a) are H.

Embodiment 95.a compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least six of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least five of (a) are H.

Embodiment 96. the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least six of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least six of (a) are H.

Embodiment 97. the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least seven of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least six of (a) are H.

Embodiment 98. the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least seven of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least seven of (a) are H.

Embodiment 99. embodimentA compound of any one of formulas 42-89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least eight of (a) is H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least seven of (a) are H.

Embodiment 100 the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least eight of (a) is H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least eight of which are H.

The compound of embodiment 101, any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least nine of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least eight of which are H.

Embodiment 102 the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least nine of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least nine of (a) are H.

Embodiment 103. compounds of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least ten of (a) is H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least nine of (a) are H.

Embodiment 104 the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least eleven of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least nine of (a) are H.

Embodiment 105 the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eIs H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pAt least nine of (a) are H.

Embodiment 106 the compound of any one of embodiments 42 to 89, wherein R¹、R²、R¹¹、R¹⁶、R¹⁷、R^16a、R^17a、R^18a、R^18b、R^18c、R^18dAnd R^18eAt least eleven of (a) are H; and R is³、R⁴、R⁵、R⁶、Rⁱ、R^j、R^m、Rⁿ、R^oAnd R^pIs H.

Embodiment 107, the compounds of any one of embodiments 42 to 106, wherein R^qIs H, -NR^16aR^17aOR-OR^18e。

Embodiment 108. the compound of any one of embodiments 42 to 106, wherein R^qis-NR^16aR^17aOR-OR^18e。

Embodiment 109 the compound of any one of embodiments 42 to 108 wherein R^kIs H, halogen, -CN, -NR¹⁶R¹⁷、-OR^18c、-SR^18dor-CR^oR^pR^q。

Embodiment 110 the compound of any one of embodiments 42 to 108 wherein R^kIs H, -CN, -NR¹⁶R¹⁷、-OR^18c、-SR^18dor-CR^oR^pR^q。

Embodiment 111, embodiment 42-108, wherein R^kIs H, -CN, -NR¹⁶R¹⁷、-OR^18cor-CR^oR^pR^q。

Embodiment 112 the compound of any one of embodiments 42 to 108 wherein R^kIs H, -NR¹⁶R¹⁷、-OR^18cor-CR^oR^pR^q。

Embodiment 113 a compound of any one of embodiments 42 to 108 wherein R^kis-NR¹⁶R¹⁷、-OR^18cor-CR^oR^pR^q。

Embodiment 114 the compound of any one of embodiments 42 to 106, wherein R^kIs H.

Embodiment 115 the compound of any one of embodiments 42 to 106, wherein R^kis-NR¹⁶R¹⁷。

Embodiment 116. the compound of any one of embodiments 42 to 106, wherein R^kis-OR^18c。

Embodiment 117. the compound of any one of embodiments 42 to 108, wherein R^kis-CR^oR^pR^q。

Embodiment 118, a compound of any one of embodiments 42 to 117, wherein a is-NR¹R²、-CRⁱR^jR^kOR-OR^18a。

Embodiment 119, a compound of any one of embodiments 42 to 106, wherein a is-NR¹R²OR-OR^18a。

Embodiment 120. the compound of any one of embodiments 42 to 117, wherein A is-CRⁱR^jR^k。

Embodiment 121, a compound of any one of embodiments 42 to 106, wherein a is-NR¹R²。

Embodiment 122 the compound of any one of embodiments 42 to 106, wherein a is-OR^18a。

Embodiment 123, a compound of any one of embodiments 42 to 122, wherein Q is-NR¹¹–、-CR^mRⁿ-, or-O-.

Embodiment 124, a compound of any one of embodiments 42 to 122, wherein Q is-NR¹¹–。

Embodiment 125. a compound of any one of embodiments 42 to 122, wherein Q is-CR^mRⁿ–。

Embodiment 126 a compound of any one of embodiments 42 to 122 wherein Q is-O-.

Embodiment 127. the compound of any one of embodiments 42 to 106, whereinA is-NR¹R²、-CRⁱR^jR^kOR-OR^18a(ii) a Q is-NR¹¹–、-CR^mRⁿ-, or-O-; and R is^kis-NR¹⁶R¹⁷OR-OR^18c。

Embodiment 128 the compound of any one of embodiments 42 to 106, wherein a is-NR¹R²、-CRⁱR^jR^kOR-OR^18a(ii) a Q is-NR¹¹-; and R is^kis-NR¹⁶R¹⁷OR-OR^18c。

Embodiment 129 the compound of any one of embodiments 42 to 106, wherein a is-NR¹R²、-CRⁱR^jR^kOR-OR^18a(ii) a Q is-NR¹¹-; and R is^kis-OR^18c。

Embodiment 130 the compound of any one of embodiments 42 to 106, wherein a is-NR¹R²OR-OR^18a(ii) a And Q is-NR¹¹–。

Embodiment 131 compounds of any one of embodiments 42 to 106, wherein a is-NR¹R²(ii) a And Q is-NR¹¹–。

Embodiment 132. the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And 3-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 133 the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 134 the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And 5-9 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 135 the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 136 the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-15 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 137 the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 138. the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 139. the compound of any of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 140. the compound of any one of embodiments 1 to 3, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, and-OH.

Embodiment 141 a compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-6R)⁴⁹Substituted C_7-11Arylalkyl), -NH (optionally substituted with 1-6R)⁴⁹Substituted 3-10 membered heterocycloalkyl), -NH (optionally substituted with 1-6R)⁴⁹Substituted 4-11 membered heterocycloalkyl alkyl), and 3-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 142. compounds of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-6R)⁴⁹Substituted C_7-11Arylalkyl), -NH (3-10 membered heterocycloalkyl), -NH (4-11 membered heterocycloalkyl alkyl), and 3-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 143. the compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (C)_5-6Membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl isSelecting 1-6R¹⁹And (4) substitution.

Embodiment 144A compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-9 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 145 the compound of any one of embodiments 1-3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

Embodiment 146, the compounds of any of embodiments 1-3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-15 membered heterocycloalkyl, halogen, -CN,-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 147. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1 to 6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 148. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 149. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (C)_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 150. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1 to 6R)⁴⁹Substituted C_1-6Alkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 151. a compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (5-6 membered heterocycloalkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, and-OH。

Embodiment 152. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1 to 6R)⁴⁹Substituted C_1-6Alkyl), -NH (C)_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), -NH (6-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 153 a compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted with 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (benzyl), -NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), -NH (6-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 154. the compound of any of embodiments 1 to 3, wherein X is selected from-NH (optionally)By 1-6R⁴⁹Substituted C_1-6Alkyl), -NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), -NH (6-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

Embodiment 155. the compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1 to 6R)⁴⁹Substituted C_1-6Alkyl), -NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, and-OH.

Embodiment 156 the compound of any one of embodiments 1 to 3, wherein X is selected from-NH (optionally substituted by 1 to 6R)⁴⁹Substituted C_1-6Alkyl) and-NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms).

Embodiment 200 a compound of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl radical, NSelecting 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 201. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 202 a compound of any one of embodiments 1 to 156 wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl radical, renSelecting 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 203. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-4R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-4R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-4R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-4R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-4R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-4R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-4R¹⁹Substituted C_4-8Cycloalkylalkyl, optionally substituted with 1-4R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-4R¹⁹Substituted 4-8 membered heterocycloalkylalkyl, optionally substituted with 1-4R¹⁹Substituted 5-6 membered heteroaryl, optionally substituted with 1-4R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-4R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-4R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-4R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-4R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 204. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionallyBy 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted C_4-8Cycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 4-8 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, optionally substituted with 1-3R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 205 a compound of any one of embodiments 1 to 156 wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted C_4-8Cycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 4-8 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, optionally substituted with 1-3R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OS(＝O)₂R²⁰、-OS(＝O)₂NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 206. the compound of any one of embodiments 1 to 156 wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl radical, renSelecting 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted C_4-8Cycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 4-8 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, optionally substituted with 1-3R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、–NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 207. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-7Cycloalkyl radical, C_4-8Cycloalkylalkyl, 3-7 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-6 membered heteroaryl, 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、–NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S(＝O)₂NR²²R²³(ii) a Or R⁷And R⁸May form C together with the atom connecting them_6-10Aryl radical, C_3-7Cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl.

Embodiment 208 a compound of any one of embodiments 1 to 156 wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted C_4-8Cycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 4-8 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, optionally substituted with 1-3R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 209 compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from HOptionally substituted by 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 210. the compound of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_3-7CycloalkanesOr optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl.

Embodiment 211. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, C_1-6Alkyl radical, C_2-6Alkynyl, C_6-10Aryl radical, C_3-7Cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form C together with the atom connecting them_3-7Cycloalkyl, or 3-7 membered heterocycloalkyl.

Embodiment 212. a compound of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³and-OR²⁰(ii) a OrR is⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 213. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halogen, -CN, -C (═ O) NR²²R²³、-NO₂、-NR²²R²³and-OR²⁰(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 214 compounds according to any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹SubstitutionC of (A)_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NR²²R²³、-NR²⁴C(＝O)R²⁰and-OR²⁰(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 215, a compound of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NR²²R²³、-NR²⁴C(＝O)R²⁰and-OR²⁰；R⁸Selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NR²²R²³、-NR²⁴C(＝O)R²⁰and-OR²⁰(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 216. compounds of any one of embodiments 1 to 156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 217 a compound of any one of embodiments 1 to 156, wherein R is⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³and-S (═ O) NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

EXAMPLE 218 practiceThe compound of any one of embodiments 1-156, wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-10R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³and-S (═ O) NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 219, compounds of any one of embodiments 1 to 156,wherein R is⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-Si(R²⁴)₃、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R⁷And R⁸May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 220. the compound of any one of embodiments 1 to 156 wherein R⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-Si(R²⁴)₃、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 221 a compound of any one of embodiments 1 to 156 wherein R is⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 222 the compound of any one of embodiments 1 to 156 wherein R is⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 222 the compound of any one of embodiments 1 to 156 wherein R is⁷、R⁸And R⁹Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-S (═ O)_nR²⁰。

Embodiment 223. the compound of any one of embodiments 1-156 or 200-222, wherein R⁸Is not phenyl or morpholinyl.

Embodiment 224. compounds of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionallyBy 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³；R⁸Selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, halogen, -NR²²R²³and-OR²⁰(ii) a And R is⁹Selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 225 compounds of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³；R⁸Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, halogen, -NR²²R²³and-OR²⁰(ii) a And R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 226. the compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³；R⁸Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, halogen, -NR²²R²³and-OR²⁰(ii) a And R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 227, a compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³；R⁸Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, and halogen; and R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 228. a compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, halogen, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰and-OC (═ O) R²⁰；R⁸Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, and halogen; and R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 229. the compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_3-10Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰and-S (═ O)_nR²⁰。

Embodiment 230. the compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_3-10Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-S (═ O)_nR²⁰。

Embodiment 231. the compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_3-10Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-S (═ O)_nR²⁰。

Embodiment 232. the compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_3-6Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-S (═ O)_nR²⁰。

Embodiment 233. a compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_3-6Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or9-membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-S (═ O)_nR²⁰。

Embodiment 234, the compound of any one of embodiments 1 to 156 or 200 and 233, wherein R⁸Is H.

Embodiment 235. compounds of any one of embodiments 1 to 156, wherein R⁷Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_3-10Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 236. the compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, -NR²²R²³and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, C_2-6Alkynyl, C_6-10Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 237. compounds of any of embodiments 1 to 156, wherein R⁷Selected from H, C_3-6Cycloalkyl radicals, and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

An embodiment 238. compounds according to any of embodiments 1 to 156, wherein R⁷Selected from H, C_3-6Cycloalkyl, and-OR²⁰；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or 9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

The compound of any one of embodiments 1 to 156, wherein R is⁷Selected from H, C_3-6Cycloalkyl, and-O (C)_1-6Alkyl groups); r⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or 9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 240 the compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, C_3-6Cycloalkyl, and-OR²⁰；R⁸Is H; and R is⁹Is H.

Embodiment 241 compounds of any one of embodiments 1 to 156, wherein R⁷Selected from H, C_3-6Alkylcycloalkyl, and-O (C)_1-6Alkyl groups); r⁸Is H; and R is⁹Is H.

Embodiment 242 the compound of any one of embodiments 1-156, wherein R⁷Selected from H, cyclopropyl, and-O (C)_1-6Alkyl groups); r⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or 9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 243. compounds of any one of embodiments 1 to 156, wherein R⁷Selected from H, cyclopropyl, and-OR²⁰；R⁸Is H; and R is⁹Is H.

Embodiment 244 a compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, cyclopropyl, and-O (C)_1-6Alkyl groups); r⁸Is H; and R is⁹Is H.

Embodiment 245 a compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, cyclopropyl, and-O (CH)₃)；R⁸Is H; and R is⁹Is H.

Embodiment 246. compounds of any one of embodiments 1 to 156, wherein R⁷Is H; r⁸Is H; and R is⁹Is H.

Embodiment 247 a compound of any one of embodiments 1 to 156 wherein R is⁷Is cyclopropyl; r⁸Is H; and R is⁹Is H.

An embodiment 248 is a compound of any one of embodiments 1 to 156, wherein R⁷is-O (CH)₃)；R⁸Is H; and R is⁹Is H.

Embodiment 249. the compound of any one of embodiments 1 to 156, wherein R⁷Selected from H, cyclopropyl, and-O (C)_1-6Alkyl groups); r⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or 9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 250 a compound of any one of embodiments 1 to 156 wherein R⁷Selected from H, C_3-6Cycloalkyl, and-O (CH)₃)；R⁸Selected from H and halogen; and R is⁹Selected from H, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5,6 or 9 membered heteroaryl, halogen, -NR²²R²³、-OR²⁰and-SR²⁰。

Embodiment 300, embodiments 1 and 2,4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-A 15 membered heteroaryl group.

Embodiment 301 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 302. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 303. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, alkynyl,Optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 304, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹SubstitutionC of (A)_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 305. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 306. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³) and-P (═ O) (OR)²⁰)(OR²⁰) (ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 307, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹SubstitutionC of (A)_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 308 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenylOptionally substituted by 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 309 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³and-S (═ O) NR²²R²³(ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 310 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³and-S (═ O) NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 311 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,And halogen; r¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-SCN、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 312 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenylOptionally substituted by 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 313. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 314 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-SCN、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 315, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

EXAMPLE 316 implementationThe compound of any one of modes 1,2, 4-156, or 200-250, wherein R is¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 317 the compound of any one of embodiments 1,2,4 to 156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 318 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹SubstitutionThe 5-to 10-membered heteroaryl group of (1).

Embodiment 319, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 320, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, halogen, -CN, -C (═ O) NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰And-S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 321. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, halogen, -C (═ O) NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹and-NR²⁴S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 322, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, halogen, -C (═ O) NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹and-NR²⁴S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 323, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹and-NR²⁴S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 324 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹and-NR²⁴S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 325. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 326 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 327. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 328 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴And R¹⁵Is H; r¹²Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 329. the compound of any one of embodiments 1,2,4 to 156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-membered heteroaryl.

Embodiment 330 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-membered heteroaryl.

Embodiment 331, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴And R¹⁵Is H; r¹²Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-membered heteroaryl.

Embodiment 332. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-2R¹⁹A substituted 5-membered heteroaryl.

Embodiment 333. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-2R¹⁹A substituted 5-membered heteroaryl.

Embodiment 334, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴And R¹⁵Is H; r¹²Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-2R¹⁹A substituted 5-membered heteroaryl.

Embodiment 335. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted 5-membered heteroaryl.

Embodiment 336. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted 5-membered heteroaryl.

Embodiment 337. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴And R¹⁵Is H; r¹²Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted 5-membered heteroaryl.

Embodiment 338 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted pyrrolyl ring.

Embodiment 339. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²And R¹⁴Is H; r¹⁵Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted pyrrolyl ring.

Embodiment 340, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹⁴And R¹⁵Is H; r¹²Selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted pyrrolyl ring.

Embodiment 341 the compound of any one of embodiments 300-340, wherein R¹⁴Is H.

Embodiment 342. the compound of any one of embodiments 300-341, wherein R¹⁵Is H.

Embodiment 343 the compound of any one of embodiments 300-342, wherein R¹²Is H.

Embodiment 344 the compound of any one of embodiments 300-343, wherein R¹³Is H.

Embodiment 345 the compound of any one of embodiments 300-340, wherein R¹⁴And R¹⁵Is H.

Embodiment 346, the compound of any one of embodiments 300-340, wherein R¹²And R¹⁵Is H.

Embodiment 347 the compound of any one of embodiments 300-340, wherein R is¹²、R¹⁴And R¹⁵Is H.

Embodiment 348 the compound of any one of embodiments 300-340, wherein R¹²And R¹⁴Is H.

Embodiment 349 the compound of any one of embodiments 1,2, 4-156, 200-250, or 300-340, wherein R¹²、R¹³、R¹⁴And R¹⁵Is H.

Embodiment 350 embodiment 30A compound of any one of 0 to 342, wherein R¹²And R¹³Together with the atom to which they are attached form an optionally substituted 1-2R¹⁹A substituted 5-membered heteroaryl.

Embodiment 351 the compound of any one of embodiments 300-342, wherein R¹²And R¹³Together with the atom to which they are attached form an optionally substituted 1R¹⁹A substituted 5-membered heteroaryl.

Embodiment 352 the compound of any one of embodiments 300-342, wherein R¹²And R¹³Together with the atom to which they are attached form an optionally substituted 1R¹⁹A substituted pyrrolyl ring.

Embodiment 353 the compound of any one of embodiments 300-342, wherein R¹²And R¹³Together with the atoms to which they are attached form an azolyl ring.

Embodiment 354 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 355 the compound of any one of embodiments 1,2, 4-156, or 200-250In which R is¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 356, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 357A compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 358. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 359. the compound of any one of embodiments 1,2, 4-156, or 200-250 wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon and 1 nitrogen, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

Embodiment 360. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-to 10-membered heterocycloalkyl,Or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 361 the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 362. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon and 1 nitrogen, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

Embodiment 363. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl radicals, renSelecting 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 364. the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 365, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon and 1 nitrogen, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

Embodiment 366, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 367. the compound of any one of embodiments 1,2,4 to 156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 368, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

Embodiment 369, any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H and-NHR²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 370, the compound of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H and-NHR²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises a carbon atomAnd 1 or 2 nitrogen atoms.

Embodiment 371 compounds of any one of embodiments 1,2, 4-156, or 200-250, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H and-NHR²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

Embodiment 400, embodiment 1, 3-156, 200-371, or 300-371 compounds, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 401, embodiment 1, embodiment 3-156, embodiment 200-250, or embodiment 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, cycloalkyl,Optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 402, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted by1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 403, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 404, embodiment 1, embodiment 3-156, embodiment 200-250, or embodiment 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 405, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 406 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted by 1 to 3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 407, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 408 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted by 1-3R¹⁹Substituted C_7-11Arylalkyl, halogen, -NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰and-NR²⁴S(＝O)₂R²¹。

Embodiment 409 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, -NR²²R²³、-NR²⁴C(＝O)R²⁰and-NR²⁴S(＝O)₂R²¹。

Embodiment 410, embodiment 1, embodiment 3-156, embodiment 200-250, or embodiment 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, -NR²²R²³and-NR²⁴C(＝O)R²⁰。

Embodiment 411 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and optionally substituted with 1-3R¹⁹Substituted C_7-11An arylalkyl group.

Embodiment 412, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and optionally substituted with 1-3R¹⁹A substituted benzyl group.

Embodiment 413, embodiment 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1R¹⁹Substituted C_1-6Alkyl, and optionally substituted by 1R¹⁹A substituted benzyl group.

Embodiment 414, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1R¹⁹Substituted C_1-6Alkyl, and benzyl.

Embodiment 415, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1R¹⁹Substituted methyl, and optionally substituted with 1R¹⁹A substituted benzyl group.

Embodiment 416 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hIndependently selected from H, optionally substituted with 1R¹⁹Substituted methyl groups, and benzyl groups.

The compound of any one of embodiments 417, 400 and 416, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAt least three of (a) are H.

The compound of any one of embodiments 418-416, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAt least four of (a) are H.

Embodiment 419. the compound of any one of embodiments 400-416, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAt least five of (a) are H.

Embodiment 420 the compound of any one of embodiments 400-416, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAt least six of (a) are H.

Embodiment 421, the compound of any one of embodiments 400-416, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd R^hAt least eight of which are H.

The compound of any one of embodiments 422, 400 and 416, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H.

Embodiment 423, embodiment 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰) (ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 424, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) And, and–P(＝O)(SR²⁰)(SR²⁰) (ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 425 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-15 membered heteroaryl.

Embodiment 426 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 427 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-6R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ S)O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 428, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R^aAnd R^b、R^aAnd R^c、R^aAnd R^e、R^aAnd R^g、R^bAnd R^d、R^bAnd R^f、R^bAnd R^h、R^cAnd R^d、R^cAnd R^e、R^cAnd R^g、R^dAnd R^f、R^dAnd R^h、R^eAnd R^f、R^eAnd R^g、R^fAnd R^hAnd R^gAnd R^hMay form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 429, embodiment 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 430 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-OC(＝O)R²⁰、-OC(＝O)OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³。

Embodiment 431, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, halogen, -NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰and-NR²⁴S(＝O)₂R²¹。

Embodiment 432. the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, -NR²²R²³、-NR²⁴C(＝O)R²⁰and-NR²⁴S(＝O)₂R²¹。

Embodiment 433, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted C_7-11Arylalkyl, -NR²²R²³and-NR²⁴C(＝O)R²⁰。

Embodiment 434 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and optionally substituted with 1-3R¹⁹Substituted C_7-11An arylalkyl group.

Embodiment 435 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and optionally substituted with 1-3R¹⁹A substituted benzyl group.

Embodiment 436, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted by 1R¹⁹Substituted C_1-6Alkyl, and optionally substituted by 1R¹⁹A substituted benzyl group.

Embodiment 437 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted by 1R¹⁹Substituted C_1-6Alkyl, and benzyl.

Embodiment 438 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted by 1R¹⁹Substituted methyl, and optionally substituted with 1R¹⁹A substituted benzyl group.

Embodiment 439 the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^e、R^f、R^gAnd R^hIs H; and R is^dSelected from H, optionally substituted by 1R¹⁹Substituted methyl groups, and benzyl groups.

Embodiment 440, the compound of any one of embodiments 1, 3-156, 200-371, or 300-371, wherein R^a、R^b、R^c、R^d、R^e、R^f、R^gAnd, andR^his H.

Embodiment 500 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-C(＝NR³⁵)R³⁰、-C(＝NR³⁵)NR³²R³³、-C(＝NOH)NR³²R³³、-C(＝NOR³⁶)R³⁰、-C(＝NNR³²R³³)R³⁰、-C(＝NNR³⁴C(＝O)R³¹)R³⁰、-C(＝NNR³⁴C(＝O)OR³¹)R³⁰、-C(＝S)NR³²R³³、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-N＝NR³⁴、＝NR³⁰、＝NOR³⁰、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴C(＝S)R³⁰、-NR³⁴C(＝S)OR³⁰、-NR³⁴C(＝S)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-NR³⁴P(＝O)R⁷⁸R⁷⁸、-NR³⁴P(＝O)(NR³²R³³)(NR³²R³³)、-NR³⁴P(＝O)(OR³⁰)(OR³⁰)、-NR³⁴P(＝O)(SR³⁰)(SR³⁰)、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-OS(＝O)R³⁰、-OS(＝O)₂R³⁰、-OS(＝O)₂OR³⁰、-OS(＝O)₂NR³²R³³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR³²R³³)(NR³²R³³)、-OP(＝O)(OR³⁰)(OR³⁰)、-OP(＝O)(SR³⁰)(SR³⁰)、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR³²R³³)(NR³²R³³)、-SP(＝O)(OR³⁰)(OR³⁰)、-SP(＝O)(SR³⁰)(SR³⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 501. The compound of any one of embodiments 1-156, 200-371, 300-371, or 400-440, wherein R is¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R³⁹Substituted C_6-11Aryl, optionally substituted with 1-6R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-C(＝NR³⁵)R³⁰、-C(＝NR³⁵)NR³²R³³、-C(＝NOH)NR³²R³³、-C(＝NOR³⁶)R³⁰、-C(＝NNR³²R³³)R³⁰、-C(＝NNR³⁴C(＝O)R³¹)R³⁰、-C(＝NNR³⁴C(＝O)OR³¹)R³⁰、-C(＝S)NR³²R³³、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-N＝NR³⁴、＝NR³⁰、＝NOR³⁰、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴C(＝S)R³⁰、-NR³⁴C(＝S)OR³⁰、-NR³⁴C(＝S)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-NR³⁴P(＝O)R⁷⁸R⁷⁸、-NR³⁴P(＝O)(NR³²R³³)(NR³²R³³)、-NR³⁴P(＝O)(OR³⁰)(OR³⁰)、-NR³⁴P(＝O)(SR³⁰)(SR³⁰)、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-OS(＝O)R³⁰、-OS(＝O)₂R³⁰、-OS(＝O)₂OR³⁰、-OS(＝O)₂NR³²R³³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR³²R³³)(NR³²R³³)、-OP(＝O)(OR³⁰)(OR³⁰)、-OP(＝O)(SR³⁰)(SR³⁰)、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR³²R³³)(NR³²R³³)、-SP(＝O)(OR³⁰)(OR³⁰)、-SP(＝O)(SR³⁰)(SR³⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 502, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R³⁹Substituted C_6-11Aryl, optionally substituted with 1-6R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 503, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-3R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 504 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 505 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)。

Embodiment 506 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰、-S(＝O)₂NR³²R³³and-S (═ O) NR³²R³³。

Embodiment 507, the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 508 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 509, the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴S(＝O)₂R³¹、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、-S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 510 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from optionally substituted1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴S(＝O)₂R³¹、-OR³⁰、＝O、-S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 511 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-OR³⁰And ═ O.

Embodiment 512 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl radical, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-OR³⁰And ═ O.

Embodiment 513 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl radical, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³and-OR³⁰。

Embodiment 514, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R³⁹Substituted 6-21 membered heteroarylalkyl, halogen, -CN, -C (═ O) NR³²R³³、-NO₂、-NR³²R³³and-OR³⁰。

Embodiment 515 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrenceOptionally selected from the group consisting of 1-13R³⁹Substituted C_1-6An alkyl group.

Embodiment 516, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

Embodiment 517, any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted phenyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

Embodiment 518 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted phenyl, C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

Embodiment 519, any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl, optionally substituted by 1R³⁹Substituted phenyl, C_3-6Cycloalkyl optionally substituted by 1R³⁹Substituted 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

Embodiment 520, any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

The compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R is¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 522 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴S(＝O)₂R³¹、-OR³⁰、＝O、-OC(＝O)R³⁰、-S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

Embodiment 523, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 524 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹and-OR³⁰。

Embodiment 525 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, optionally substituted with 1-3R³⁹Substituted cyclopropyl, optionally substituted with 1-3R³⁹Substituted 6-membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 526, the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, optionally substituted with 1-3R³⁹Substituted cyclopropyl, optionally substituted with 1-3R³⁹Substituted 6-membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹and-OR³⁰。

Embodiment 527, any of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R is¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, optionally substituted with 1-3R³⁹Substituted cyclopropyl, optionally substituted with 1-3R³⁹Substituted morpholinyl, optionally substituted with 1-3R³⁹Substituted pyrazolyl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 528. the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, optionally substituted with 1-3R³⁹Substituted cyclopropyl, optionally substituted with 1-3R³⁹Substituted morpholinyl, optionally substituted with 1-3R³⁹Substituted pyrazolyl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹and-OR³⁰。

Embodiment 529, any of embodiments 1-156, 200-250, 300-371, or 400-440Compound (I) wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 530 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹and-OR³⁰。

Embodiment 531 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 532 the compound of any one of embodiments 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹and-OR³⁰。

Embodiment 533, embodiment 1-156, 200-250, 300-371, or 400-440, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted benzyl, cyclopropyl, morpholinyl, pyrazolyl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

Embodiment 600, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R⁴⁹Substituted 3-15 membered heterocycloalkyl,Optionally substituted by 1-6R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-6R⁴⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 601, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-6R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R⁴⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁴⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 602 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁴⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 603 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 604 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 605, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 606, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and optionally substituted with 1-3R⁴⁹Substituted C_3-6A cycloalkyl group.

Embodiment 607, the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 608, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and optionally substituted with 1-3R⁴⁹Substituted C_3-6A cycloalkyl group; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 609, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 610. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-6R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 611, the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 612, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 613 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 614, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 615 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and optionally substituted with 1-3R⁴⁹A substituted cyclopropyl group.

Embodiment 616 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, cyclopropyl, thiophenesA phenyl group, and a pyrazinyl group.

Embodiment 617 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, optionally substituted by 1-3R⁴⁹Substituted benzyl, cyclopropyl, thienyl, and pyrazinyl.

Embodiment 618, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl.

Embodiment 619 the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, or 500, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl.

Embodiment 620, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 621 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 622, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 623 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Each occurrence is independently selected from H, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkylAnd 5-6 membered heteroaryl.

Embodiment 624 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl.

Embodiment 625 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Each occurrence is independently selected from the group consisting of H, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl.

Embodiment 626, any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533, wherein R is²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 627 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R is²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted cyclopropyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 628, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted cyclopropyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 629, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533 wherein R is a compound²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 5-6 membered heterocycloalkylAnd optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 630 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R ²⁰Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 631 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 632 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 633, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and cyclopropyl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 634, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533, wherein R is²⁰Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 635, embodiment 250, 300, 371, 400, 440, or 500, 533 wherein R²⁰Independently at each occurrence selected from H, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 636, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 637 the compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533 wherein R is²⁰Each occurrence is independently selected from H, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 638, embodiment 250, 300, 371, 400, 440, or 500, 533 wherein R²⁰Independently at each occurrenceIs selected from H, C_1-6Alkyl, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 639 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence, selected from the group consisting of H, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁴⁹Substituted C_1-6An alkyl group.

Embodiment 640 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 641, embodiments 1-156, 200-250, 300-371, 40Any one of compounds of 0-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 642 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and optionally substituted with 1-3R⁴⁹Substituted C_3-6A cycloalkyl group; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 643 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 644, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533, wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and C_3-6A cycloalkyl group; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 645 the compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 646, embodiment 250, 300, 371, 400, 440, or 500, 533 wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Is independently selected at each occurrence from H andC_1-6an alkyl group.

Embodiment 647 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 648 of any one of the compounds of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, optionally substituted by 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 649 the compound of any one of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, optionally substituted by 1-3R⁴⁹Substituted benzyl, cyclopropyl, thienyl, and pyrazinyl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 650 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 651. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰Each occurrence is independently selected from H, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 652, embodiment 250, 300, 371, 400, 440, or 500, 533 wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 653, embodiment 1-156. 200-250, 300-371, 400-440 or 500-533, wherein R is²⁰Independently at each occurrence, selected from the group consisting of H, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 654, the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 655, the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 656, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl, and optionally substituted with 1-3R⁴⁹Substituted 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 657 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 658 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R is²⁰Independently at each occurrence, selected from H, phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 659 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹A substituted cyclopropyl group; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 660 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R is²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and cyclopropyl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 661, embodiment 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R is a compound²⁰Independently at each occurrence, selected from H, phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, cyclopropyl, thienyl, and pyrazinyl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 662, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533 wherein R is²⁰Independently selected at each occurrenceFrom H, C_1-6Alkyl, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 663 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-, 533, wherein R²⁰Independently at each occurrence selected from H, optionally substituted by 1R⁴⁹Substituted phenyl, C_3-6Cycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 664 the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533, wherein R is²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 665 the compound of any one of embodiments 1 to 156, 200-²⁰Each occurrence is independently selected from H, phenyl, C_3-6Cycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 666, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, or 500-533, wherein R²⁰Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 667 the compound of any of embodiments 1-156, 200-250, 300-371, 400-440, or 500-533 wherein R²⁰Independently at each occurrence, selected from the group consisting of H, phenyl, cyclopropyl, 5-membered heterocycloalkyl, and 5-membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 668 the compound of any one of embodiments 1 to 156, 200-250, 300-371, 400-440, or 500-533, wherein R is²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

Embodiment 700, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁴⁹Substituted C_1-6Alkyl, optionally substituted by 1-11R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁴⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 701, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁴⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R⁴⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 702, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁴⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 703, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is a compound of any one of embodiments 1-156, 200-533²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁴⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁴⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 704, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, optionally substituted with 1-3R⁴⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁴⁹Substituted 5-6 membered heteroaryl.

Embodiment 705, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-668, wherein R is a compound²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl radicalOptionally substituted by 1-3R⁴⁹Substituted phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 706, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl and optionally substituted by 1-3R⁴⁹Substituted 3-6 membered heterocycloalkyl.

Embodiment 707 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-, 668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl and optionally substituted by 1-3R⁴⁹Substituted 5-6 membered heterocycloalkyl.

Embodiment 708, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-, 668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl and 5-6 membered heterocycloalkyl.

Embodiment 709 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-, 668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl and optionally substituted by 1-6R⁴⁹Substituted 5-membered heterocycloalkyl.

Embodiment 710, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, or 600-668, wherein R is²⁸Is independently selected from any at each occurrenceSelecting 1-6R⁴⁹Substituted C_1-6Alkyl and 5-membered heterocycloalkyl.

Embodiment 711 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-, 668, wherein R is²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁴⁹Substituted C_1-6Alkyl and pyrrolidinyl.

Embodiment 712, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-668, wherein R is a compound²⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁴⁹Substituted C_1-6Alkyl and 5-membered heterocycloalkyl.

Embodiment 713, embodiment 250, 300, 371, 400, 440, 500, 533, or 600, 668, wherein R is any one of the compounds of embodiments 1-156, 200, 500, 533, or 600²⁸Optionally substituted by 1-6R at each occurrence⁴⁹Substituted C_1-6An alkyl group.

Embodiment 714 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, or 600-, 668, wherein R is²⁸Optionally substituted by 1-3R at each occurrence⁴⁹Substituted C_1-6An alkyl group.

Embodiment 750 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-13R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁵⁹Substituted 6-21 membered heteroarylalkyl; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 751, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, or 700-714, wherein R is a compound²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R⁵⁹Substituted 6-21 membered heteroarylalkyl; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted1-3R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 752. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; or R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁶⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 753 the compound of any of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, or 700-, 714, wherein R²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl.

Embodiment 754, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-714, wherein R is a hydroxy-substituted alkyl group²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl.

Embodiment 755, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl.

Embodiment 756, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-714, wherein R is a pharmaceutically acceptable salt thereof²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl.

Embodiment 757 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 4-5 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-9 membered heteroaryl.

Embodiment 758. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 3-6 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl.

Embodiment 759 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 4-5 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-9 membered heteroaryl.

Embodiment 760, any one of the embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, or 700-714In which R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 5-6 membered heteroaryl.

Embodiment 761. the compound of any one of embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, or 700-714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 6-membered heteroaryl.

Embodiment 762 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted by 1R⁵⁹Substituted phenyl, and optionally substituted with 1R⁵⁹Substituted 6-membered heteroaryl.

Embodiment 763 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-13R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁵⁹Substituted C_3-11A cycloalkyl group, a,Optionally substituted by 1-32R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁵⁹Substituted 6-21 membered heteroarylalkyl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 764, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-714, wherein R is a pharmaceutically acceptable salt thereof²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R⁵⁹Substituted 6-21 membered heteroarylalkyl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 765 the compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted benzyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 766 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 767 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted benzyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 768, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-714, wherein R is a hydroxy group-containing compound²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 4-5 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-9 membered heteroaryl; r²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 769 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²And R³²Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 770, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-714, wherein R is a compound²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 3-6 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³Independently at each occurrenceSelected from H and optionally substituted by 1-3R⁵⁹Substituted C_1-6An alkyl group.

Embodiment 771 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, benzyl, C_3-10Cycloalkyl, 4-5 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-9 membered heteroaryl; r²³And R³³Independently at each occurrence, selected from H and optionally substituted with 1-3R⁵⁹Substituted C_1-6An alkyl group.

Embodiment 772 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 773 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 5-6 membered heteroaryl; r²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 774 embodiments 1-156, 200, 300, 371, 400, 440, 500, 533, 600, 668, or 700-714 of any item, wherein R²²And R³²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted phenyl, benzyl, and optionally substituted with 1-3R⁵⁹Substituted 6-membered heteroaryl; r²³And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 775 the compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted by 1R⁵⁹Substituted phenyl, and optionally substituted with 1R⁵⁹Substituted 6-membered heteroaryl; r²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 776 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R²²Independently at each occurrence selected from H, optionally substituted with 1-13R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁵⁹Substituted 6-21 membered heteroarylalkyl; r²³、R³²And R³³At each occurrence is H; or any R²²And R²³And/or R³²And R³³Nitrogen atoms to which they may be attachedTogether form an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 777 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R⁵⁹Substituted 6-21 membered heteroarylalkyl; r²³、R³²And R³³At each occurrence is H; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁵⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 778, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, or 700-714, wherein R²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁵⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁶⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 779 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, optionally substituted with 1-3R⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 780 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 3-6 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R⁶⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 781. the compound of any one of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 3-6 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 782 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 4-5 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 783 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl optionally substituted by 1-3R⁵⁹Substituted 4-5 membered heterocycloalkyl, and optionally substituted 1-3R⁵⁹Substituted 5-9 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

EXAMPLE 784 EXAMPLES 1-156, 200-250, 300-371, 400-440, 500-533, 600-668 or 700-714, wherein R²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, C_3-10Cycloalkyl, 4-5 membered heterocycloalkyl, and optionally substituted with 1-3R⁵⁹Substituted 5-9 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 785 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_6-10Aryl, and optionally substituted with 1-3R⁵⁹Substituted 5-10 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 786 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 5-6 membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 787 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 6-membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Practice of788, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²Independently at each occurrence selected from H, optionally substituted by 1R⁵⁹Substituted phenyl, and optionally substituted with 1R⁵⁹Substituted 6-membered heteroaryl; r²³、R³²And R³³At each occurrence is H.

Embodiment 789 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 790, the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³At each occurrence is H.

Embodiment 791. the compound of any one of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence, selected from H and optionally substituted with 1-13R⁵⁹Substituted C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 792 the compound of any one of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence, selected from H and optionally substituted with 1-6R⁵⁹Substituted C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R⁶⁹Substituted 5-15 membered heteroaryl.

Embodiment 793 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence, selected from H and optionally substituted with 1-6R⁵⁹Substituted C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R⁶⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-6R⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 794 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently at each occurrence, selected from H and optionally substituted with 1-6R⁵⁹Substituted C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R⁶⁹Substituted 3-6 membered heterocycloalkyl or optionally substituted with 1-6R⁶⁹Substituted 5-6 membered heteroaryl.

Embodiment 795 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, or 700-, 714, wherein R is²²、R²³、R³²And R³³Independently selected at each occurrenceFrom H and C_1-6An alkyl group; or any R²²And R²³And/or R³²And R³³May form together with the nitrogen atom to which they are attached a 3-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 800, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of the above-mentioned embodiments³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-C(＝NR⁷⁵)R⁷⁰、-C(＝NR⁷⁵)NR⁷²R⁷³、-C(＝NOH)NR⁷²R⁷³、-C(＝NOR⁷⁶)R⁷⁰、-C(＝NNR⁷²R⁷³)R⁷⁰、-C(＝NNR⁷⁴C(＝O)R⁷¹)R⁷⁰、-C(＝NNR⁷⁴C(＝O)OR⁷¹)R⁷⁰、-C(＝S)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、＝NR⁷⁰、＝NOR⁷⁰、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝NR⁷⁵)NR⁷²R⁷³、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝S)R⁷⁰、-NR⁷⁴C(＝S)OR⁷⁰、-NR⁷⁴C(＝S)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-NR⁷⁴P(＝O)(SR⁷⁰)(SR⁷⁰)、-OR⁷⁰、＝O、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OC(＝NR⁷⁵)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-OP(＝O)(SR⁷⁰)(SR⁷⁰)、-Si(R⁷⁴)₃、-SCN、＝S、–S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-P(＝O)(OR⁷⁰)(OR⁷⁰) and-P (═ O) (SR)⁷⁰)(SR⁷⁰)。

Embodiment 801, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, or 750-795, wherein R is a compound of any one of³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R⁷⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、＝O、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-Si(R⁷⁴)₃、-SCN、＝S、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³。

Embodiment 802. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-, 795, wherein R is³⁹、R⁴⁹、R⁵⁹And R⁶⁹At each occurrence is individuallySelected from the group consisting of optionally substituted 1-6R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁷⁹Substituted C_6-10Aryl, optionally substituted with 1-6R⁷⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R⁷⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、＝O、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-Si(R⁷⁴)₃、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³。

Embodiment 803, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁷⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R⁷⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、＝O、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-Si(R⁷⁴)₃、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³。

Embodiment 804, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of embodiments 1-156, 200-, 440-, 500-, 533-, 600-, 668-, 700-, or 750-, 795³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, optionally substituted with 1-3R⁷⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R⁷⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-OR⁷⁰、＝O、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-Si(R⁷⁴)₃、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³。

Embodiment 805, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R represents a compound of any one of embodiments 1-156, 200-, 440-, 500-, 533-, 600-, 668-, 700-, or 750-, 795³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, optionally substituted with 1-3R⁷⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R⁷⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-NO₂、-NR⁷²R⁷³、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴S(＝O)₂R⁷¹、-OR⁷⁰、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-S(＝O)_nR⁷⁰and-S (═ O)₂NR⁷²R⁷³。

Embodiment 806, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of embodiments 1-156, 200-, 440-, 500-, 533-, 600-, 714-, or 750-, 795³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, optionally substituted with 1-3R⁷⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁷⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R⁷⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) NR⁷²R⁷³、-NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

Embodiment 807. the embodimentA compound of any one of formulas 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, or 750-795, wherein R is³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) NR⁷²R⁷³、-NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

Embodiment 808, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, cyclopropyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) NR⁷²R⁷³、-NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

Embodiment 809, the compound of any one of embodiments 800-808, wherein R³⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, and 5-6 membered heteroaryl.

Embodiment 810. the compound of any one of embodiments 800-808, wherein R³⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, and 6-membered heteroarylAnd (4) a base.

Embodiment 811, embodiment 800 and 810, wherein R⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) NR⁷²R⁷³and-NR⁷²R⁷³。

The compound of any one of embodiments 812, 800 and 810, wherein R⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, 5-6 membered heterocycloalkyl, 6 membered heteroaryl, halogen, -C (═ O) NR⁷²R⁷³and-NR⁷²R⁷³。

Embodiment 813 any one of embodiments 800-812, wherein R⁵⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, cyclopropyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

Embodiment 814 the compound of any one of embodiments 800-812, wherein R⁵⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, cyclopropyl, 6-membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

The compound of any one of embodiments 815, 800-814, wherein R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6An alkyl group.

Embodiment 816, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-795, wherein R is a compound of any one of³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6An alkyl group.

Embodiment 817. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, or 750-, 795, wherein R is³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is C_1-6An alkyl group.

Embodiment 850. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 851, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-817, wherein R is a compound of any one of⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-6R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁸⁹Substituted C_6-10Aryl, optionally substituted with 1-6R⁸⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R⁸⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R⁸⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R⁸⁹Substituted 5-10 membered heteroaryl.

Embodiment 852, embodiment 250, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, or 800, 817, wherein R is a compound of any one of embodiments 1-156, 200, 440, 533, 600, 668, 700, 750, 795, or 800, 817⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁸⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁸⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁸⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁸⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-10 membered heteroaryl.

Embodiment 853. the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, or 800, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted phenyl, optionally substituted with 1-3R⁸⁹Substituted benzyl, optionally substituted with 1-3R⁸⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-10 membered heteroaryl.

Embodiment 854. Compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 855. the compound of any one of embodiments 1 to 156, 200, 250, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, or 800, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted phenyl, optionally substituted with 1-3R⁸⁹Substituted benzyl, optionally substituted with 1-3R⁸⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-6 membered heteroaryl.

Embodiment 856, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-817, wherein R is a compound of any one of⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 857. the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, or 800, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 858, any of the compounds of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl optionally substituted by 1R⁸⁹Substituted 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 859. the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, or 800, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁸⁹Substituted C_1-6An alkyl group.

Embodiment 860, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, or 800-817, wherein R is a compound of any one of embodiments 1-156, 200-714, 300-371, 400-440, 500-533, 600-668⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 861 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, or 800-, 817, wherein R is⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷At each occurrence is H.

Embodiment 862, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-DEG 861, wherein R is a compound of any one of the above-mentioned embodiments⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-13R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁹⁹Substituted 6-21 membered heteroarylalkyl; or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁰⁹Substituted 3-15 membered heterocycloalkyl orOptionally substituted by 1-15R¹⁰⁹Substituted 5-15 membered heteroaryl.

Embodiment 863, embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is a compound of any one of the above formulas⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-6R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R⁹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-6R⁹⁹Substituted 6-21 membered heteroarylalkyl; or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R¹⁰⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁰⁹Substituted 5-15 membered heteroaryl.

Embodiment 864, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-861, wherein R is a compound of any one of⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, optionally substituted with 1-3R⁹⁹Substituted benzyl, optionally substituted with 1-3R⁹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁹⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁹⁹Substituted 5-10 membered heteroaryl; or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁰⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R¹⁰⁹Substituted 5-15 membered heteroaryl.

Embodiment 865. any of the compounds of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 861, wherein R is a halogen atom⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, optionally substituted with 1-3R⁹⁹Substituted benzyl, optionally substituted with 1-3R⁹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁹⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁹⁹Substituted 5-10 membered heteroaryl.

Embodiment 866. Compounds of any of embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, optionally substituted with 1-3R⁹⁹Substituted benzyl, optionally substituted with 1-3R⁹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁹⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁹⁹Substituted 5-6 membered heteroaryl; or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁰⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 867, any one of embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861Wherein R is⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, optionally substituted with 1-3R⁹⁹Substituted benzyl, optionally substituted with 1-3R⁹⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R⁹⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R⁹⁹Substituted 5-6 membered heteroaryl.

Embodiment 868, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is a compound of any one of the above-mentioned embodiments⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, optionally substituted with 1-3R⁹⁹Substituted benzyl, optionally substituted with 1-3R⁹⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R⁹⁹Substituted 5-6 membered heteroaryl.

Embodiment 869, embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, 700-, 714, 750-, 795, 800-, 817, or 850-, 861, wherein R is a compound of any one of the above formulas⁷²And R⁷³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 870, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is a compound of any one of the above-mentioned embodiments⁷²And R⁷³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl、C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 871 Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 861, wherein R is a halogen atom⁷²And R⁷³Independently at each occurrence selected from H, optionally substituted with 1-3R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁹⁹Substituted phenyl, and optionally substituted with 1-3R⁹⁹A substituted benzyl group.

Embodiment 872, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is a compound of any one of⁷²And R⁷³Independently at each occurrence, selected from H and optionally substituted with 1-3R⁹⁹Substituted C_1-6An alkyl group.

Embodiment 873 embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-⁷⁹5. 800-817 or 850-861, wherein R⁷²And R⁷³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, and benzyl.

Embodiment 874, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R is a compound of any one of the above formulas⁷²And R⁷³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 875, embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-861 of any compounds, wherein R⁷²And R⁷³At each occurrence is H.

Embodiment 876, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound of any one of⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-6R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-10 membered heterocycloalkyl.

Embodiment 877. Compound according to any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 875, wherein R is⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁸⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-3R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R⁸⁹Substituted 6-21 membered heteroarylalkyl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-6R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-10 membered heterocycloalkyl.

Embodiment 878. Compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 875, wherein R is⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R⁸⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R⁸⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁸⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁸⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-10 membered heteroaryl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-6 membered heterocycloalkyl.

Embodiment 879. Compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 875, wherein R is⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted C_6-10Aryl, optionally substituted with 1-3R⁸⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R⁸⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-10 membered heteroaryl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-6 membered heterocycloalkyl.

Embodiment 880, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound of any one of the above embodiments⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted phenyl, optionally substituted with 1-3R⁸⁹Substituted benzyl, optionally substituted with 1-3R⁸⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R⁸⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R⁸⁹Substituted 5-6 membered heteroaryl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-6 membered heterocycloalkyl.

Embodiment 881, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound⁷⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted 6-membered heterocycloalkyl.

Embodiment 882. Compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-, 875, wherein R⁷⁸At each timeAll occurrences are independently selected from optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, phenyl, and benzyl.

Embodiment 883, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound of any one of the above-mentioned formulas⁷⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁸⁹Substituted phenyl, and optionally substituted with 1-3R⁸⁹A substituted benzyl group; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted 6-membered heterocycloalkyl.

Embodiment 884, embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound of any one of the above-mentioned formulas⁷⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, and benzyl; or any two R attached to the same phosphorus atom⁷⁸May form, together with the phosphorus atom to which they are attached, an optionally substituted C of 1 to 3_1-6Alkyl substituted azaphosphinane rings.

Embodiment 885, embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a compound of any one of the above formulas⁷⁸Optionally substituted by 1-3R at each occurrence⁸⁹Substituted C_1-6An alkyl group; or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-3R together with the phosphorus atom to which they are attached⁸⁹Substituted azaphosphine alkane rings.

Embodiment 886, embodiments 1-156, 200-250, 300-371, 400-440. 500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R is a metal oxide or a metal oxide, or a⁷⁸At each occurrence is C_1-6An alkyl group.

Embodiment 900, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R is a compound of any one of the above-mentioned embodiments⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-C(＝O)C(＝O)R¹¹⁰、-C(＝NR¹¹⁵)R¹¹⁰、-C(＝NR¹¹⁵)NR¹¹²R¹¹³、-C(＝NOH)NR¹¹²R¹¹³、-C(＝NOR¹¹⁶)R¹¹⁰、-C(＝NNR¹¹²R¹¹³)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)R¹¹¹)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)OR¹¹¹)R¹¹⁰、-C(＝S)NR¹¹²R¹¹³、-NC、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴NR¹¹²R¹¹³、-N＝NR¹¹⁴、＝NR¹¹⁰、＝NOR¹¹⁰、-NR¹¹⁴OR¹¹⁶、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)OR¹¹⁰、-NR¹¹⁴C(＝NR¹¹⁵)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝S)R¹¹⁰、-NR¹¹⁴C(＝S)OR¹¹⁰、-NR¹¹⁴C(＝S)NR¹¹²R¹¹³、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-NR¹¹⁴P(＝O)R¹¹⁸R¹¹⁸、-NR¹¹⁴P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-NR¹¹⁴P(＝O)(OR¹¹⁰)(OR¹¹⁰)、-NR¹¹⁴P(＝O)(SR¹¹⁰)(SR¹¹⁰)、-OR¹¹⁰、＝O、-OCN、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-OC(＝NR¹¹⁵)NR¹¹²R¹¹³、-OS(＝O)R¹¹⁰、-OS(＝O)₂R¹¹⁰、-OS(＝O)₂OR¹¹⁰、-OS(＝O)₂NR¹¹²R¹¹³、-OP(＝O)R¹¹⁸R¹¹⁸、-OP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-OP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-OP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-Si(R¹¹⁴)₃、-SCN、＝S、–S(＝O)_nR¹¹⁰、-S(＝O)₂OR¹¹⁰、-SO₃R¹¹¹¹、-S(＝O)₂NR¹¹²R¹¹³、-S(＝O)NR¹¹²R¹¹³、-SP(＝O)R¹¹⁸R¹¹⁸、-SP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-SP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-SP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-P(＝O)R¹¹⁸R¹¹⁸、-P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-P(＝O)(OR¹¹⁰)(OR¹¹⁰) and-P (═ O) (SR)¹¹⁰)(SR¹¹⁰)。

Embodiment 901, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R is a compound of any one of the above-mentioned formulas⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹¹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NC、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴NR¹¹²R¹¹³、-NR¹¹⁴OR¹¹⁶、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-OR¹¹⁰、＝O、-OCN、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-Si(R¹¹⁴)₃、-SCN、＝S、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 902, embodiments 1 to 156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹¹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-OR¹¹⁰、＝O、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-Si(R¹¹⁴)₃、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 903, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹¹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹¹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹¹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹¹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-OR¹¹⁰、＝O、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-Si(R¹¹⁴)₃、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 904, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of the formulas⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹¹⁹Substituted phenyl, optionally substituted with 1-3R¹¹⁹Substituted benzyl, optionally substituted with 1-3R¹¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-OR¹¹⁰、＝O、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-Si(R¹¹⁴)₃、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 905, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹¹⁹Substituted phenyl, optionally substituted with 1-3R¹¹⁹Substituted benzyl, optionally substituted with 1-3R¹¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹¹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-OR¹¹⁰、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 906, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴S(＝O)₂R¹¹¹、-OR¹¹⁰、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-S(＝O)_nR¹¹⁰and-S (═ O)₂NR¹¹²R¹¹³。

Embodiment 907, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -CN, -C (═ O) OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-OR¹¹⁰and-S (═ O)_nR¹¹⁰。

Embodiment 908, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R is a compound of any one of the formulas⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹¹⁹Substituted phenyl, optionally substituted with 1-3R¹¹⁹Substituted benzyl, halogen, -CN, -C (═ O) OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-NO₂、-NR¹¹²R¹¹³、-OR¹¹⁰and-S (═ O)_nR¹¹⁰。

Embodiment 909, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of the above-mentioned formulas⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -NR¹¹²R¹¹³and-OR¹¹⁰。

Embodiment 910, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of the formulas⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Is independently selected at each occurrence from C_1-6Alkyl, halogen, -NR¹¹²R¹¹³and-OR¹¹⁰。

Embodiment 911, embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, 700-, 714, 750-, 795, 800-, 817, or 850-886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6Alkyl and halogen.

Embodiment 912, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R is a compound of any one of the above-mentioned embodiments⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹¹⁹Substituted C_1-6An alkyl group.

Embodiment 913, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, or 850-functional 886, wherein R is a compound of any one of⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is C_1-6An alkyl group.

Embodiment 914, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 915, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-6R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹²⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹²⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹²⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹²⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R¹²⁹Substituted 5-10 membered heteroaryl.

Embodiment 916, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹²⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹²⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹²⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹²⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-10 membered heteroaryl.

Embodiment 917, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913, wherein R is a compound of any one of embodiments 1-156, 200-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted phenyl, optionally substituted with 1-3R¹²⁹Substituted benzyl, optionally substituted with 1-3R¹²⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-10 membered heteroaryl.

Embodiment 918, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 919. embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted phenyl, optionally substituted with 1-3R¹²⁹Substituted benzyl, optionally substituted with 1-3R¹²⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-6 membered heteroaryl.

Embodiment 920, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 921. Compound of any of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913, wherein R is a halogen atom¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl、C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 922, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl optionally substituted by 1R¹²⁹Substituted 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 923, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R¹²⁹Substituted C_1-6An alkyl group.

Embodiment 924, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 925, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-913¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷At each occurrenceIs H.

Embodiment 926. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925, wherein R represents a substituent¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-13R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹³⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹³⁹Substituted 6-21 membered heteroarylalkyl; or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁴⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁴⁹Substituted 5-15 membered heteroaryl.

Embodiment 927, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-6R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹³⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹³⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-6R¹³⁹Substituted 6-21 membered heteroarylalkyl; or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R¹⁴⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁴⁹Substituted 5-15 membered heteroaryl.

Embodiment 928, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, optionally substituted with 1-3R¹³⁹Substituted benzyl, optionally substituted with 1-3R¹³⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹³⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹³⁹Substituted 5-10 membered heteroaryl; or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁴⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R¹⁴⁹Substituted 5-15 membered heteroaryl.

Embodiment 929, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, optionally substituted with 1-3R¹³⁹Substituted benzyl, optionally substituted with 1-3R¹³⁹Substituted byC_3-10Cycloalkyl optionally substituted by 1-3R¹³⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹³⁹Substituted 5-10 membered heteroaryl.

Embodiment 930, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, optionally substituted with 1-3R¹³⁹Substituted benzyl, optionally substituted with 1-3R¹³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹³⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R¹³⁹Substituted 5-6 membered heteroaryl; or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁴⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁴⁹Substituted 5-10 membered heteroaryl.

Embodiment 931, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, optionally substituted with 1-3R¹³⁹Substituted benzyl, optionally substituted with 1-3R¹³⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R¹³⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹³⁹Substituted 5-6 membered heteroaryl.

Embodiment 932, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925, wherein R is¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, optionally substituted with 1-3R¹³⁹Substituted benzyl, optionally substituted with 1-3R¹³⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹³⁹Substituted 5-6 membered heteroaryl.

Embodiment 933. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-925, wherein R represents a group¹¹²And R¹¹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 934, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 935, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925, wherein R is a compound of any one of embodiments 1-156, 200-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-3R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹³⁹Substituted phenyl, and optionally substituted with 1-3R¹³⁹A substituted benzyl group.

Embodiment 936, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925 compounds, wherein R represents a substituent¹¹²And R¹¹³Independently at each occurrence, selected from H and optionally substituted with 1-3R¹³⁹Substituted C_1-6An alkyl group.

Embodiment 937, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-925¹¹²And R¹¹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, and benzyl.

Embodiment 938, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-925 compounds, wherein R represents a substituent¹¹²And R¹¹³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 939, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-925¹¹²And R¹¹³At each occurrence is H.

Embodiment 940. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-939, wherein R represents a substituent¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 941. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-939, wherein R is a halogen atom¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹²⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R¹²⁹Substituted 3-15 heterocycloalkyl, optionally substituted with 1-3R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R¹²⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 942, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939, wherein R is a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted1-3R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹²⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹²⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹²⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹²⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-10 membered heteroaryl.

Embodiment 943, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-939, wherein R represents a compound of any one of the above formulas¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹²⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹²⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-10 membered heteroaryl.

Embodiment 944, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939, wherein R is a compound of any one of the above formulas¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted phenyl, optionally substituted with 1-3R¹²⁹Substituted benzyl, optionally substituted with 1-3R¹²⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹²⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R¹²⁹Substituted 5-6 membered heteroaryl.

Embodiment 945, embodiments 1 to 156, 200 and 250, 300 and 371,400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886 or 900-939, wherein R is a compound of any one of¹¹⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 946, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-939, wherein R is a compound of any one of¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, phenyl, and benzyl.

Embodiment 947. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-939, wherein R is a halogen atom¹¹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹²⁹Substituted phenyl, and optionally substituted with 1-3R¹²⁹A substituted benzyl group.

Embodiment 948, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-939, wherein R represents a compound of any one of the above formulas¹¹⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, and benzyl.

Embodiment 949. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-939, wherein R is a halogen atom¹¹⁸Optionally substituted by 1-3R at each occurrence¹²⁹Substituted C_1-6An alkyl group.

Embodiment 950, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939, wherein R is a compound of any one of the formulas¹¹⁸At each occurrence is C_1-6An alkyl group.

Embodiment 951, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950, wherein R is a compound of any one of the above-mentioned embodiments¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁵⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁵⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-C(＝O)C(＝O)R¹⁵⁰、-C(＝NR¹⁵⁵)R¹⁵⁰、-C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-C(＝NOH)NR¹⁵²R¹⁵³、-C(＝NOR¹⁵⁶)R¹⁵⁰、-C(＝NNR¹⁵²R¹⁵³)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)R¹⁵¹)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)OR¹⁵¹)R¹⁵⁰、-C(＝S)NR¹⁵²R¹⁵³、-NC、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴NR¹⁵²R¹⁵³、-N＝NR¹⁵⁴、＝NR¹⁵⁰、＝NOR¹⁵⁰、-NR¹⁵⁴OR¹⁵⁶、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)OR¹⁵⁰、-NR¹⁵⁴C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝S)R¹⁵⁰、-NR¹⁵⁴C(＝S)OR¹⁵⁰、-NR¹⁵⁴C(＝S)NR¹⁵²R¹⁵³、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-NR¹⁵⁴P(＝O)R¹⁵⁸R¹⁵⁸、-NR¹⁵⁴P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-NR¹⁵⁴P(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-NR¹⁵⁴P(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-OR¹⁵⁰、＝O、-OCN、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-OC(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-OS(＝O)R¹⁵⁰、-OS(＝O)₂R¹⁵⁰、-OS(＝O)₂OR¹⁵⁰、-OS(＝O)₂NR¹⁵²R¹⁵³、-OP(＝O)R¹⁵⁸R¹⁵⁸、-OP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-OP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-OP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-Si(R¹⁵⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁵⁰、-S(＝O)₂OR¹⁵⁰、-SO₃R¹⁵¹⁵、-S(＝O)₂NR¹⁵²R¹⁵³、-S(＝O)NR¹⁵²R¹⁵³、-SP(＝O)R¹⁵⁸R¹⁵⁸、-SP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-SP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-SP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-P(＝O)R¹⁵⁸R¹⁵⁸、-P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-P(＝O)(OR¹⁵⁰)(OR¹⁵⁰) and-P (═ O) (SR)¹⁵⁰)(SR¹⁵⁰)。

Embodiment 952, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950, wherein R is a compound of any one of the formulas¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁵⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NC、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴NR¹⁵²R¹⁵³、-NR¹⁵⁴OR¹⁵⁶、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-OR¹⁵⁰、＝O、-OCN、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-Si(R¹⁵⁴)₃、-SCN、＝S、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 953 the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, 800, 817, 850, 886, or 900, 950, wherein R is a compound represented by the formula¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁵⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁵⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-OR¹⁵⁰、＝O、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-Si(R¹⁵⁴)₃、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 954, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a compound of any one of¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁵⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁵⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁵⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁵⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁵⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-OR¹⁵⁰、＝O、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-Si(R¹⁵⁴)₃、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 955 Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a group of the formula¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁵⁹Substituted phenyl, optionally substituted with 1-3R¹⁵⁹Substituted benzyl, optionally substituted with 1-3R¹⁵⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁵⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁵⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-OR¹⁵⁰、＝O、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-Si(R¹⁵⁴)₃、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 956, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950, wherein R is a compound of any one of the above-mentioned embodiments¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁵⁹Substituted phenyl, optionally substituted with 1-3R¹⁵⁹Substituted benzyl, optionally substituted with 1-3R¹⁵⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁵⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁵⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-OR¹⁵⁰、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 957 the compound of any one of embodiments 1 to 156, 200, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, 800, 817, 850, 886, or 900, 950, wherein R is a compound represented by the formula¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-OR¹⁵⁰、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-S(＝O)_nR¹⁵⁰and-S (═ O)₂NR¹⁵²R¹⁵³。

Embodiment 958, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950, wherein R is a compound of any one of the above-mentioned embodiments¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -CN, -C (═ O) OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-OR¹⁵⁰and-S (═ O)_nR¹⁵⁰。

Embodiment 959 the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-950, wherein R represents a group¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁵⁹Substituted phenyl, optionally substituted with 1-3R¹⁵⁹Substituted benzyl, halogen, -CN, -C (═ O) OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-NO₂、-NR¹⁵²R¹⁵³、-OR¹⁵⁰and-S (═ O)_nR¹⁵⁰。

Embodiment 960, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a compound of any one of the above-mentioned embodiments¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -NR¹⁵²R¹⁵³and-OR¹⁵⁰。

Embodiment 961, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 533-, 600-, 668-, 700-, 850-, or 900-950¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Is independently selected at each occurrence from C_1-6Alkyl, halogen, -NR¹⁵²R¹⁵³and-OR¹⁵⁰。

Embodiment 962, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a compound of any one of the above-mentioned embodiments¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6Alkyl and halogen.

Embodiment 963, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-950, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁵⁹Substituted C_1-6An alkyl group.

Embodiment 964 practiceThe compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-, 950, wherein R represents a substituent¹¹⁹、R¹²⁹、R¹³⁹And R¹⁴⁹Independently at each occurrence is C_1-6An alkyl group.

Embodiment 965. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R represents¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 966, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-6R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁶⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁶⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁶⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁶⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R¹⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 967. the compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R represents a substituent¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁶⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁶⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 968, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted phenyl, optionally substituted with 1-3R¹⁶⁹Substituted benzyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 969, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 970, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of embodiments 1-156, 200-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted phenyl, optionally substituted with 1-3R¹⁶⁹Substituted benzyl, optionally substituted with 1-3R¹⁶⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-6 membered heteroaryl.

Embodiment 971, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 972 Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, or 900-964, wherein R is¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 973, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of the above-mentioned embodiments¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl optionally substituted by 1R¹⁶⁹Substituted 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 974, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R¹⁶⁹Substituted C_1-6An alkyl group.

Embodiment 975, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 976, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a metal, such as aluminum, copper, zinc¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵、R¹⁵⁶And R¹⁵⁷At each occurrence is H.

Embodiment 977, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a metal, such as aluminum, copper, zinc¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁷⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁷⁹Substituted 6-21 membered heteroarylalkyl; or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁸⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁸⁹Substituted 5-15 membered heteroaryl.

Embodiment 978, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-976, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally 1-6R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁷⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-6R¹⁷⁹Substituted 6-21 membered heteroarylalkyl; or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R¹⁸⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-6R¹⁸⁹Substituted 5-15 membered heteroaryl.

Embodiment 979, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a metal, such as aluminum, copper, zinc¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, optionally substituted with 1-3R¹⁷⁹Substituted benzyl, optionally substituted with 1-3R¹⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁷⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁷⁹Substituted 5-10 membered heteroaryl; or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁸⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R¹⁸⁹Substituted 5-15 membered heteroaryl.

Embodiment 980, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-,700-714, 750-795, 800-817, 850-886 or 900-976 compounds, wherein R¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, optionally substituted with 1-3R¹⁷⁹Substituted benzyl, optionally substituted with 1-3R¹⁷⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁷⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁷⁹Substituted 5-10 membered heteroaryl.

Embodiment 981, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, optionally substituted with 1-3R¹⁷⁹Substituted benzyl, optionally substituted with 1-3R¹⁷⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁷⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R¹⁷⁹Substituted 5-6 membered heteroaryl; or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R¹⁸⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R¹⁸⁹Substituted 5-10 membered heteroaryl.

Embodiment 982, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, optionally substituted with 1-3R¹⁷⁹Substituted benzyl, optionally substituted with 1-3R¹⁷⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R¹⁷⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹⁷⁹Substituted 5-6 membered heteroaryl.

Embodiment 983, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, optionally substituted with 1-3R¹⁷⁹Substituted benzyl, optionally substituted with 1-3R¹⁷⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R¹⁷⁹Substituted 5-6 membered heteroaryl.

Embodiment 984, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 985, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 986, embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, 700-, 714, 750-795, 800-817, 850-886, or 900-976, wherein R¹⁵²And R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-3R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁷⁹Substituted phenyl, and optionally substituted with 1-3R¹⁷⁹A substituted benzyl group.

Embodiment 987, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence, selected from H and optionally substituted with 1-3R¹⁷⁹Substituted C_1-6An alkyl group.

Embodiment 988, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-976, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, and benzyl.

Embodiment 989, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁵²And R¹⁵³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 990, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976¹⁵²And R¹⁵³At each occurrence is H.

Embodiment 991. embodimentA compound of any one of formulas 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a halogen atom¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 992, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R¹⁶⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 993, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R¹⁶⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁶⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 994, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁶⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-10 membered heteroaryl.

Embodiment 995. Compound of any one of embodiments 1-156, 200-, 250, 300-, 371, 400-, 440, 500-, 533, 600-, 668, 700-, 714, 750-, 795, 800-, 817, 850-, 886, or 900-990, wherein R is¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted phenyl, optionally substituted with 1-3R¹⁶⁹Substituted benzyl, optionally substituted with 1-3R¹⁶⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁶⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R¹⁶⁹Substituted 5-6 membered heteroaryl.

Embodiment 996, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 997, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, phenyl, and benzyl.

Embodiment 998, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned formulas¹⁵⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁶⁹Substituted phenyl, and optionally substituted with 1-3R¹⁶⁹A substituted benzyl group.

Embodiment 999, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R is a compound of any one of the above-mentioned embodiments¹⁵⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, and benzyl.

Embodiment 1000, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-990, wherein R represents a compound of any one of the above-mentioned embodiments¹⁵⁸Optionally substituted by 1-3R at each occurrence¹⁶⁹Substituted C_1-6An alkyl group.

Embodiment 1001, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990, wherein R represents a compound of any one of the above embodiments, R represents a cyclic amino acid¹⁵⁸At each occurrence is C_1-6An alkyl group.

Embodiment 1002, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 850-, or 900-, 1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R¹⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R¹⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R¹⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R¹⁹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-6R¹⁹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-C(＝O)C(＝O)R¹⁹⁰、-C(＝NR¹⁹⁵)R¹⁹⁰、-C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-C(＝NOH)NR¹⁹²R¹⁹³、-C(＝NOR¹⁹⁶)R¹⁹⁰、-C(＝NNR¹⁹²R¹⁹³)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)R¹⁹¹)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)OR¹⁹¹)R¹⁹⁰、-C(＝S)NR¹⁹²R¹⁹³、-NC、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴NR¹⁹²R¹⁹³、-N＝NR¹⁹⁴、＝NR¹⁹⁰、＝NOR¹⁹⁰、-NR¹⁹⁴OR¹⁹⁶、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)OR¹⁹⁰、-NR¹⁹⁴C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝S)R¹⁹⁰、-NR¹⁹⁴C(＝S)OR¹⁹⁰、-NR¹⁹⁴C(＝S)NR¹⁹²R¹⁹³、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-NR¹⁹⁴P(＝O)R¹⁹⁸R¹⁹⁸、-NR¹⁹⁴P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-NR¹⁹⁴P(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-NR¹⁹⁴P(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-OR¹⁹⁰、＝O、-OCN、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-OC(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-OS(＝O)R¹⁹⁰、-OS(＝O)₂R¹⁹⁰、-OS(＝O)₂OR¹⁹⁰、-OS(＝O)₂NR¹⁹²R¹⁹³、-OP(＝O)R¹⁹⁸R¹⁹⁸、-OP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-OP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-OP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-Si(R¹⁹⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁹⁰、-S(＝O)₂OR¹⁹⁰、-SO₃R¹⁹¹⁹、-S(＝O)₂NR¹⁹²R¹⁹³、-S(＝O)NR¹⁹²R¹⁹³、-SP(＝O)R¹⁹⁸R¹⁹⁸、-SP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-SP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-SP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-P(＝O)R¹⁹⁸R¹⁹⁸、-P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-P(＝O)(OR¹⁹⁰)(OR¹⁹⁰) and-P (═ O) (SR)¹⁹⁰)(SR¹⁹⁰)。

Embodiment 1003, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above formulas¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R¹⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NC、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴NR¹⁹²R¹⁹³、-NR¹⁹⁴OR¹⁹⁶、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-OR¹⁹⁰、＝O、-OCN、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-Si(R¹⁹⁴)₃、-SCN、＝S、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Embodiment 1004, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-533, 400-440-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-6R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_6-10Aryl, optionally substituted with 1-6R¹⁹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R¹⁹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R¹⁹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-6R¹⁹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-OR¹⁹⁰、＝O、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-Si(R¹⁹⁴)₃、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Implementation methodFormula 1005, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R is a compound of any one of the formulas¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹⁹Substituted C_6-10Aryl, optionally substituted with 1-3R¹⁹⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R¹⁹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R¹⁹⁹Substituted 3-10 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹⁹Substituted 5-10 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-OR¹⁹⁰、＝O、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-Si(R¹⁹⁴)₃、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Embodiment 1006, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹⁹Substituted benzyl, optionally substituted with 1-3R¹⁹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-OR¹⁹⁰、＝O、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-Si(R¹⁹⁴)₃、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Embodiment 1007, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 533-, 600-, 500-, 668-, 700-, 750-, 795-, 800-, 850-, or 900-, 1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹⁹Substituted benzyl, optionally substituted with 1-3R¹⁹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R¹⁹⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-OR¹⁹⁰、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Embodiment 1008, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 850-, or 900-22-, 1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-OR¹⁹⁰、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-S(＝O)_nR¹⁹⁰and-S (═ O)₂NR¹⁹²R¹⁹³。

Embodiment 1009, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above embodiments¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -CN, -C (═ O) OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-OR¹⁹⁰and-S (═ O)_nR¹⁹⁰。

Embodiment 1010, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹⁹Substituted benzyl, halogen, -CN, -C (═ O) OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-NO₂、-NR¹⁹²R¹⁹³、-OR¹⁹⁰and-S (═ O)_nR¹⁹⁰。

Embodiment 1011, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above-mentioned embodiments¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, halogen, -NR¹⁹²R¹⁹³and-OR¹⁹⁰。

Embodiment 1012, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Is independently selected at each occurrence from C_1-6Alkyl, halogen, -NR¹⁹²R¹⁹³and-OR¹⁹⁰。

Embodiment 1013, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1001, wherein R represents a compound of any one of the above formulas¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6Alkyl and halogen.

Embodiment 1014, embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817. 850-886 or 900-1001, wherein R is¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R¹⁹⁹Substituted C_1-6An alkyl group.

Embodiment 1015, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001, wherein R represents a compound of any one of embodiments 1-156, 200-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001¹⁵⁹、R¹⁶⁹、R¹⁷⁹And R¹⁸⁹Independently at each occurrence is C_1-6An alkyl group.

Embodiment 1016, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015-one of the compounds, wherein R represents¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 1017, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-,800-817, 850-886, or 900-1015, wherein R¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-6R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R²⁰⁹Substituted C_6-10Aryl, optionally substituted with 1-6R²⁰⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-6R²⁰⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-6R²⁰⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-6R²⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 1018. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015, wherein R is a compound of formula II¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R²⁰⁹Substituted C_6-10Aryl, optionally substituted with 1-3R²⁰⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R²⁰⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 1019, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted phenyl, optionally substituted with 1-3R²⁰⁹Substituted benzyl, optionally substituted with 1-3R²⁰⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 1020, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015, wherein R is a compound of any one of embodiments 1-156, 200-371, 400-440, 500-533¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 1021, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a halogen atom¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, optionally substituted with 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted phenyl, optionally substituted with 1-3R²⁰⁹Substituted benzyl, optionally substituted with 1-3R²⁰⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-6 membered heteroaryl.

Embodiment 1022. any of the compounds of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-, 1015,wherein R is¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1023, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015, wherein R represents a compound of any one of the above-mentioned embodiments¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1024. Compounds of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015, wherein R is a halogen atom¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl optionally substituted by 1R²⁰⁹Substituted 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1025, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1015-one of the compounds, wherein R is a halogen atom¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R²⁰⁹Substituted C_1-6An alkyl group.

Embodiment 1026 practiceThe compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-, 1015, wherein R is a halogen atom¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 1027, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015, wherein R is a compound of any one of¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵、R¹⁹⁶And R¹⁹⁷At each occurrence is H.

Embodiment 1028, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, wherein R represents a compound of any one of the above formulas¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-13R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²¹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²¹⁹Substituted 6-21 membered heteroarylalkyl; or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R²²⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R²²⁹Substituted 5-15 membered heteroaromaticsAnd (4) a base.

Embodiment 1029, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027, wherein R is a compound of any one of¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-6R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-6R²¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-6R²¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-6R²¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R²¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R²¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-6R²¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-6R²¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-6R²¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-6R²¹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-6R²¹⁹Substituted 6-21 membered heteroarylalkyl; or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-6R²²⁹Substituted 3-15 membered heterocycloalkyl, or optionally substituted with 1-6R²²⁹Substituted 5-15 membered heteroaryl.

Embodiment 1030, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, wherein R represents a compound of any one of¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, optionally substituted with 1-3R²¹⁹Substituted benzyl, optionally substituted with 1-3R²¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²¹⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²¹⁹Substituted 5-10 membered heteroaryl; or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R²²⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-3R²²⁹Substituted 5-15 membered heteroaryl.

Embodiment 1031. embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027, wherein R is a compound of any one of¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, optionally substituted with 1-3R²¹⁹Substituted benzyl, optionally substituted with 1-3R²¹⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²¹⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²¹⁹Substituted 5-10 membered heteroaryl.

Embodiment 1032, embodiment 250, 300, 371, 400, 440, 500, 533, 600, 668, 700, 714, 750, 795, 800, 817, 850, 886, or 900, 1027, wherein R is a compound of any one of embodiments 1-156, 200, 371, 400, 440, 533, 600, 1027¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, optionally substituted with 1-3R²¹⁹Substituted benzyl, optionally substituted with 1-3R²¹⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R²¹⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R²¹⁹Substituted 5-6 membered heteroaryl; or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3R²²⁹Substituted 3-10 membered heterocycloalkyl or optionally substituted with 1-3R²²⁹Substituted 5-10 membered heteroaryl.

Embodiment 1033. embodiments 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714750-795, 800-817, 850-886 or 900-1027, wherein R is a pharmaceutically acceptable salt thereof¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, optionally substituted with 1-3R²¹⁹Substituted benzyl, optionally substituted with 1-3R²¹⁹Substituted C_5-6Cycloalkyl optionally substituted by 1-3R²¹⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R²¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 1034, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, optionally substituted with 1-3R²¹⁹Substituted benzyl, optionally substituted with 1-3R²¹⁹Substituted 5-6 membered heterocycloalkyl, and optionally substituted 1-3R²¹⁹Substituted 5-6 membered heteroaryl.

Embodiment 1035, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027¹⁹²And R¹⁹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 1036. Compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, whereinR¹⁹²And R¹⁹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, benzyl, C_5-6Cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1037. Compounds of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1027, wherein R is a halogen atom¹⁹²And R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-3R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²¹⁹Substituted phenyl, and optionally substituted with 1-3R²¹⁹A substituted benzyl group.

Embodiment 1038, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1027, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁹²And R¹⁹³Independently at each occurrence, selected from H and optionally substituted with 1-3R²¹⁹Substituted C_1-6An alkyl group.

Embodiment 1039, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom¹⁹²And R¹⁹³Independently at each occurrence selected from H, C_1-6Alkyl, phenyl, and benzyl.

Embodiment 1040, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1027, wherein R represents a compound of any one of the above-mentioned embodiments¹⁹²And R¹⁹³Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment 1041, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027, wherein R represents a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027¹⁹²And R¹⁹³At each occurrence is H.

Embodiment 1042, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1041, wherein R is a compound of any one of the above formulas¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 1043, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-3R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R²⁰⁹SubstitutionC of (A)_3-11Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-3R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-3R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-3R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-3R²⁰⁹Substituted 6-21 membered heteroarylalkyl.

Embodiment 1044 is a compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1041, wherein R is hydrogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R²⁰⁹Substituted C_6-10Aryl, optionally substituted with 1-3R²⁰⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R²⁰⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 1045, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted C_6-10Aryl, optionally substituted with 1-3R²⁰⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R²⁰⁹Substituted C_3-10Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 3-10 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-10 membered heteroaryl.

Embodiment 1046, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted phenyl, optionally substituted with 1-3R²⁰⁹Substituted benzyl, optionally substituted with 1-3R²⁰⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R²⁰⁹Substituted 3-6 membered heterocycloalkyl, and optionally substituted 1-3R²⁰⁹Substituted 5-6 membered heteroaryl.

Embodiment 1047, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1048, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, phenyl, and benzyl.

Embodiment 1049, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of the above-mentioned embodiments, wherein R is a halogen atom¹⁹⁸Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R²⁰⁹Substituted phenyl, and optionally substituted with 1-3R²⁰⁹A substituted benzyl group.

Embodiment 1050, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041, wherein R is a compound of any one of embodiments 1-156, 200-371, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041¹⁹⁸Is independently selected at each occurrence from C_1-6Alkyl, phenyl, and benzyl.

Embodiment 1051, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1041, wherein R is a compound of any one of¹⁹⁸Optionally substituted by 1-3R at each occurrence²⁰⁹Substituted C_1-6An alkyl group.

Embodiment 1052, embodiment 1-156, 200-, 300-, 371, 400-, 440, 500-, 533, 600-, 668, 700-, 714, 750-, 795, 800-, 817, 850-, 886, or 900-1041, wherein R is a compound of any one of embodiments 1-156, 200-, 371, 400-, 440-, 533-, 600-, 668-, 700-, 795-, 800-, 850-, or 1041¹⁹⁸At each occurrence is C_1-6An alkyl group.

Embodiment 1053, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-13 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-11Aryl radical, C_7-16Arylalkyl radical, C_3-11Cycloalkyl radical, C_4-17Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-C(＝O)C(＝O)R²³⁰、-C(＝NR²³⁰)R²³⁰、-C(＝NR²³⁰)NR²³⁰R²³⁰、-C(＝NOH)NR²³⁰R²³⁰、-C(＝NOR²³⁰)R²³⁰、-C(＝NNR²³⁰R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)OR²³⁰)R²³⁰、-C(＝S)NR²³⁰R²³⁰、-NC、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰NR²³⁰R²³⁰、-N＝NR²³⁰、＝NR²³⁰、＝NOR²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)C(＝O)R²³⁰、-NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)C(＝O)OR²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝NR²³⁰)NR²³⁰R²³⁰、-NR²³⁰C(＝O)C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝S)R²³⁰、-NR²³⁰C(＝S)OR²³⁰、-NR²³⁰C(＝S)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-NR²³⁰P(＝O)R²³¹R²³¹、-NR²³⁰P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-NR²³⁰P(＝O)(OR²³⁰)(OR²³⁰)、-NR²³⁰P(＝O)(SR²³⁰)(SR²³⁰)、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-OC(＝O)NR²³⁰R²³⁰、-OC(＝O)OR²³⁰、-OC(＝NR²³⁰)NR²³⁰R²³⁰、-OS(＝O)R²³⁰、-OS(＝O)₂R²³⁰、-OS(＝O)₂OR²³⁰、-OS(＝O)₂NR²³⁰R²³⁰、-OP(＝O)R²³¹R²³¹、-OP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-OP(＝O)(OR²³⁰)(OR²³⁰)、-OP(＝O)(SR²³⁰)(SR²³⁰)、-Si(R²³⁰)₃、-SCN、＝S、–S(＝O)_nR²³⁰、-S(＝O)₂OR²³⁰、-SO₃R²³⁰、-S(＝O)₂NR²³⁰R²³⁰、-S(＝O)NR²³⁰R²³⁰、-SP(＝O)R²³¹R²³¹、-SP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-SP(＝O)(OR²³⁰)(OR²³⁰)、-SP(＝O)(SR²³⁰)(SR²³⁰)、-P(＝O)R²³¹R²³¹、-P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-P(＝O)(OR²³⁰)(OR²³⁰) and-P (═ O) (SR)²³⁰)(SR²³⁰)。

Embodiment 1054, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-6 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-11Aryl radical, C_7-16Arylalkyl radical, C_3-11Cycloalkyl radical, C_4-17Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-15 membered heteroarylalkyl, halo, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-C(＝O)C(＝O)R²³⁰、-NC、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰NR²³⁰R²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)C(＝O)R²³⁰、-NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)C(＝O)OR²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)C(＝O)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-NR²³⁰P(＝O)R²³¹R²³¹、-NR²³⁰P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-NR²³⁰P(＝O)(OR²³⁰)(OR²³⁰)、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-OC(＝O)NR²³⁰R²³⁰、-OC(＝O)OR²³⁰、-OS(＝O)R²³⁰、-OS(＝O)₂R²³⁰、-OS(＝O)₂OR²³⁰、-OS(＝O)₂NR²³⁰R²³⁰、-OP(＝O)R²³¹R²³¹、-OP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-OP(＝O)(OR²³⁰)(OR²³⁰)、-Si(R²³⁰)₃、-SCN、＝S、–S(＝O)_nR²³⁰、-S(＝O)₂OR²³⁰、-SO₃R²³⁰、-S(＝O)₂NR²³⁰R²³⁰、-S(＝O)NR²³⁰R²³⁰、-P(＝O)R²³¹R²³¹、-P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰) and-P (═ O) (OR)²³⁰)(OR²³⁰)。

Embodiment 1055, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-10Cycloalkyl radical, C_4-17Cycloalkyl radicalsAlkyl, 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl alkyl, 5-10 membered heteroaryl, 6-10 membered heteroarylalkyl, halo, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-NC、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-NR²³⁰P(＝O)R²³¹R²³¹、-NR²³⁰P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-NR²³⁰P(＝O)(OR²³⁰)(OR²³⁰)、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-OC(＝O)NR²³⁰R²³⁰、-OS(＝O)₂NR²³⁰R²³⁰、-OP(＝O)R²³¹R²³¹、-OP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-SCN、＝S、–S(＝O)_nR²³⁰、-S(＝O)₂NR²³⁰R²³⁰、-S(＝O)NR²³⁰R²³⁰、-P(＝O)R²³¹R²³¹and-P (═ O) (NR)²³⁰R²³⁰)(NR²³⁰R²³⁰)。

Embodiment 1056, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogenCN、-C(＝O)R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-S(＝O)_nR²³⁰、-S(＝O)₂NR²³⁰R²³⁰and-S (═ O) NR²³⁰R²³⁰。

Embodiment 1057, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-OR²³⁰、＝O、-S(＝O)_nR²³⁰and-S (═ O)₂NR²³⁰R²³⁰。

Embodiment 1058, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-NR²³⁰R²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-OR²³⁰、＝O、-S(＝O)_nR²³⁰and-S (═ O)₂NR²³⁰R²³⁰。

Embodiment 1059, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl, phenyl, benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-NR²³⁰R²³⁰、-OR²³⁰、＝O、-S(＝O)_nR²³⁰and-S (═ O)₂NR²³⁰R²³⁰。

Embodiment 1060, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-3 halogens_1-6Alkyl, halogen, and-NR²³⁰R²³⁰。

Embodiment 1061, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Is independently selected at each occurrence from C_1-6Alkyl, halogen, and-NR²³⁰R²³⁰。

Embodiment 1062, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹Is independently selected at each occurrence from C_1-6Alkyl and-NR²³⁰R²³⁰。

Embodiment 1063, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹At each occurrence is-NR²³⁰R²³⁰。

Embodiment 1064, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹、R²⁰⁹、R²¹⁹And R²²⁹At each occurrence is C_1-6An alkyl group.

Embodiment 1065, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned formulas¹⁹⁹Is independently selected at each occurrence from C_1-6Alkyl and-NR²³⁰R²³⁰；R²⁰⁹、R²¹⁹And R²²⁹At each occurrence is C_1-6An alkyl group.

Embodiment 1066, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments, R is a halogen atom, or a salt thereof¹⁹⁹Is independently selected at each occurrence from C_1-6Alkyl and-NR²³⁰R²³⁰；R²⁰⁹、R²¹⁹And R²²⁹At each occurrence is-NR²³⁰R²³⁰。

Embodiment 1067, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1052, wherein R is a compound of any one of the above-mentioned embodiments¹⁹⁹At each occurrence is-NR²³⁰R²³⁰；R²⁰⁹、R²¹⁹And R²²⁹At each occurrence is C_1-6An alkyl group.

Embodiment 1068, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1067, wherein R is a compound of any one of the formulas²³⁰Independently at each occurrence selected from H, C_1-6Alkyl and C_1-6-haloalkyl.

Embodiment 1069, embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, or 900-1067, wherein R is a compound of any one of the formulas²³⁰Independently at each occurrence selected from H and C_1-6An alkyl group.

Embodiment mode 1070. The compound of any one of embodiments 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1067, wherein R is as defined in the description²³⁰At each occurrence is C_1-6An alkyl group.

Embodiment 1071, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1067, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom²³⁰At each occurrence is H.

Embodiment 1072, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1071, wherein R is a compound of any one of the above-mentioned formulas²³¹Is independently selected at each occurrence from C_1-6Alkyl and C_1-6-haloalkyl.

Embodiment 1073, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1071, wherein R is a compound of any one of the above-mentioned formulas²³¹At each occurrence is C_1-6An alkyl group.

Embodiment 1074, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1071, wherein R represents a compound of any one of the above-mentioned embodiments, wherein R represents a nitrogen atom²³¹At each occurrence is C_1-6-haloalkyl.

Embodiment 1075, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is independently selected at each occurrence from 0, 1, and 2.

Embodiment 1076, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is independently selected from 0 and 2 at each occurrence.

Embodiment 1077, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is independently selected from 1 and 2 at each occurrence.

Embodiment 1078, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is independently selected from 0 and 1 at each occurrence.

Embodiment 1079, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is 0 at each occurrence.

Embodiment 1080, embodiment 1-156, 200-, 250-, 300-, 371-, 400-, 440-, 500-, 533-, 600-, 668-, 700-, 714-, 750-, 795-, 800-, 817-, 850-, 886-, or 900-1074, wherein n is 1 at each occurrence.

Embodiment 1081, embodiment 1-156, 200-250, 300-371, 400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074, wherein n is 2 at each occurrence.

The above embodiments include salts of acidic and basic compounds of formula (I). Preferably, the salt is pharmaceutically acceptable. Pharmaceutically acceptable acid addition salts of basic compounds of formula (I) include, but are not limited to: salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid; and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate salts. See, e.g., Berge et al, "pharmaceutically acceptable Salts", j.of Pharmaceutical Science, 1977; 66:1-19.

Acid addition salts may be prepared by contacting a compound of formula (I) with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base form of the compound of formula (I) may be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.

Pharmaceutically acceptable basic salts of the acidic compounds of formula (I) are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or hydroxides of organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucamine, and procaine. See, e.g., Berge et al, "pharmaceutically acceptable Salts", J.of Pharmaceutical Science, 1977; 66:1-19.

Basic salts can be prepared by contacting a compound of formula (I) with a sufficient amount of the desired base to form a salt in a conventional manner. The acidic form of the compound of formula (I) may be regenerated by contacting the salt form with an acid and isolating the acid in a conventional manner.

Some of the compounds of the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric isomers. Geometric isomers include compounds of the invention having an alkenyl group, which may exist in the E (entgegen) or Z (zusammen) configuration, in which case all geometric forms of the compound, E and Z, cis and trans, and mixtures thereof, are within the scope of the invention. Some compounds of the present invention have a cycloalkyl group, which may be substituted at more than one carbon atom, in which case all geometric forms of the compounds, both cis and trans, and mixtures thereof, are within the scope of the present invention. All of these forms, including (R), (S), epimers, diastereomers, cis, trans, (E), (Z), tautomers, and mixtures thereof, are included in the compounds of the invention.

The compounds of the invention may be in any physical form, including any polymorphic crystalline or amorphous solid in any state of purity. Crystalline polymorphs include unsolvated forms as well as solvated forms, such as hydrated forms.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a compound according to any one of the embodiments above (e.g. a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. For preparing pharmaceutical compositions from the compounds of the invention, the pharmaceutically acceptable excipients may be solid or liquid. An excipient may be one or more substances that may act as, for example, a carrier, diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material. The pharmaceutical composition may comprise two or more compounds of the invention (e.g. two different salt forms of a compound of formula (I) may be used together in the same pharmaceutical composition). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof. In one embodiment, the composition comprises an amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof effective to treat an atypical protein kinase c (apkc) -dependent disorder or condition. Preferably, the compounds of the present invention will result in a reduction of symptoms or disease signs associated with an aPKC-dependent disorder, as measured by quantitative or qualitative means. In addition to the compound of formula (I) or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable excipient, the composition may comprise another therapeutic compound, for example a compound useful in the treatment of cancer.

The compounds of the present invention may be formulated as pharmaceutical compositions in any delivery form, such as syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, troches, aqueous solutions, creams, ointments, lotions, gels, emulsions, and the like. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Preferably, the pharmaceutical composition is a tablet or capsule. In one embodiment, the pharmaceutical composition is a tablet. In another embodiment, the pharmaceutical composition is a capsule.

In powders, the excipient may be a finely divided solid in a mixture with the finely divided active component (i.e. a compound of the invention). In tablets, the active ingredient may be mixed with excipients having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Suitable excipients include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

The pharmaceutical composition preferably comprises 1% to 95% (w/w) of the active compound (i.e. the compound of the invention). More preferably, the pharmaceutical composition comprises 5% to 70% (w/w) of the active compound.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, may be melted and the active ingredient dispersed homogeneously therein by stirring. The molten homogeneous mixture may then be poured into a suitably sized mold and allowed to cool, thereby solidifying.

Liquid form preparations include solutions, suspensions, and emulsions. Formulations suitable for parenteral administration, for example by intravenous, intramuscular, intradermal and subcutaneous routes, include: aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. In the practice of the present invention, the compositions may be administered, for example, by intravenous injection, orally, topically, intraperitoneally, intravesically or intrathecally. The formulations of the compounds may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials. Injectable solutions and suspensions may be prepared as sterile powders, granules and tablets of the type described hereinbefore.

The compounds of the present invention, alone or in combination with other suitable components, can be formulated as aerosols (e.g., they can be "nebulized") for administration by inhalation. The aerosol may be placed in a pressurized acceptable propellant such as dichlorodifluoromethane, propane, nitrogen, and the like.

The pharmaceutically acceptable excipients will be determined in part by the particular composition being administered and by the particular method used to administer the composition. Thus, there are a number of suitable formulations of The pharmaceutical compositions of The present invention (see, for example, Remington: The Science and Practice of Pharmacy, 20 th edition, eds. Gennaro et al, Lippincott Williams and Wilkins, 2000).

The amount of active ingredient in the pharmaceutical composition may vary or be adjusted depending on the particular application and the desired size of the dosage form, for example, from 1mg to 1,000mg, from 5mg to 500mg, from 10mg to 300mg, or from 25mg to 250 mg.

The dose administered to the subject is preferably sufficient to induce a beneficial therapeutic response in the subject over time. The beneficial agent amount varies from subject to subject depending on, for example, the condition, body weight, surface area, and side effect sensitivity of the subject. Administration can be accomplished in a single dose or in divided doses.

Methods of treatment

In another aspect, the present invention provides a method of treating an aPKC-dependent disorder or condition in a subject comprising: administering to the subject a compound of formula (I) as defined in any one of the embodiments above, or a pharmaceutically acceptable salt form thereof. In another aspect, the present invention provides a compound of formula (I) as defined in any one of the embodiments above, or a pharmaceutically acceptable salt form thereof, for use in the treatment of an aPKC-dependent disorder or condition in a subject. In another aspect, the present invention provides a compound of formula (I) as defined in any one of the embodiments above, or a pharmaceutically acceptable salt form thereof, for use in the manufacture of a medicament for treating an aPKC-dependent disorder or condition in a subject. Preferably, the compound is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. Preferably, the compound is administered to the subject in a pharmaceutically acceptable amount. In one embodiment, the aPKC-dependent symptom or disorder is cancer. In another embodiment, the aPKC-dependent symptom is selected from the group consisting of non-small cell lung cancer (NSCLC), squamous cell carcinoma (e.g., esophageal squamous cell carcinoma), leukemia, prostate cancer, non-hodgkin's lymphoma (e.g., follicular lymphoma), endometrial cancer, lung cancer, and breast cancer.

aPKC-dependent conditions or symptoms can be treated prophylactically, acutely, or chronically using compounds of the invention, depending on the nature of the condition or symptom. Typically, the subject in each of the methods is human, although other mammals may also benefit from administration of the compounds of the invention.

In another embodiment, the present invention provides a method of treating a proliferative disorder in a subject, comprising administering to said subject a compound of formula (I) as defined in any one of the embodiments above, or a pharmaceutically acceptable salt form thereof. In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt form thereof, as defined in any one of the embodiments above, for use in the treatment of a proliferative disorder in a subject. In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt form thereof, as defined in any one of the embodiments above, for use in the manufacture of a medicament for treating a proliferative disorder in a subject. Preferably, the compound is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. Preferably, the compound is administered to the subject in a pharmaceutically acceptable amount. In some embodiments, the proliferative disorder is aPKC-dependent. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is selected from non-small cell lung cancer (NSCLC), squamous cell carcinoma (e.g., esophageal squamous cell carcinoma), leukemia, prostate cancer, non-hodgkin's lymphoma (e.g., follicular lymphoma), endometrial cancer, lung cancer, and breast cancer.

The proliferative disorders may be treated prophylactically, acutely or chronically with the compounds of the invention, depending on the nature of the disorder or condition. Typically, the subject in each of the methods is human, although other mammals may also benefit from administration of the compounds of the invention.

In therapeutic applications, the compounds of the present invention may be prepared and administered in a variety of oral and parenteral dosage forms. Thus, the compounds of the present invention may be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal injection. Likewise, the compounds described herein may be administered by inhalation, e.g., intranasally. In addition, the compounds of the present invention may be administered transdermally. In another embodiment, the compounds of the invention are delivered orally. The compounds may also be delivered rectally, buccally or by insufflation.

Determination of an appropriate dosage for a particular situation is within the ability of those skilled in the art. Typically, treatment is initiated at a smaller dose than the optimal dose of the compound. Thereafter, the dose is gradually increased in small increments until the best effect under the circumstances is achieved. For convenience, the total daily dose may be divided and administered in portions throughout the day, if desired. A typical dose is from about 1mg to about 1,000mg per day, for example from about 5mg to about 500mg per day. In some embodiments, the dose is from about 10mg to about 300mg per day, for example from about 25mg to about 250mg per day.

Chemistry of V

Abbreviations

For convenience, the following common abbreviations are used herein:

LCMS means liquid chromatography-mass spectrometry.

HPLC means high pressure liquid chromatography.

NMR denotes nuclear magnetic resonance.

RT denotes the retention time.

MI represents a molecular ion

h represents hour

min represents minutes

AlCl₃Represents aluminum chloride

BBr₃Represents boron tribromide

Boc represents tert-butyloxycarbonyl

cataCXium C represents trans-bis (acetate) bis [ n- (di-o-tolylphosphino) benzyl ] dipalladium (II).

Cs₂CO₃Represents cesium carbonate

CuI represents copper (I) iodide

DAST stands for diethylaminosulfur trifluoride

DBU represents 1, 8-diazabicyclo (5.4.0) undec-7-ene

DMAP for 4- (dimethylamino) pyridine

DCE represents 1, 1-dichloroethane or ethylidene dichloride

DCM represents dichloromethane or methylenedichloride

DEA means diethanolamine

DIPEA stands for N, N-di-isopropylethylamine, Hunig's base

DMA represents N, N-dimethylacetamide

DMF means N, N-dimethylformamide

DMSO represents dimethyl sulfoxide

Et₃N represents triethylamine

EtOH for ethanol

Ex denotes examples

HCl represents hydrochloric acid

H₂SO₄Represents sulfuric acid

Int represents an intermediate

KOH represents potassium hydroxide

MW represents microwave

mCPBA for m-chloroperoxybenzoic acid

MeOH denotes methanol

Mo(CO)₆Represents molybdenum hexacarbonyl

MP-BH₄Represents macroporous methylpolystyrene triethylammonium borohydride

NaOH is sodium hydroxide

Na₂CO₃Represents carbonic acidSodium salt

Na₂SO₄Denotes sodium sulfate

NaOAc represents sodium acetate

NaOtBu represents sodium tert-butoxide

NMP stands for 1-methyl-2-pyrrolidone

NMM stands for N-methylmorpholine

Pd(dba)₂Represents bis (dibenzylideneacetone) palladium

Pd(OAc)₂Represents palladium diacetate

Pd(Ph₃)₄Represents tetrakis (triphenylphosphine) palladium

Pd(PPh₃)₂Cl₂Represents bis (triphenylphosphine) palladium (II) dichloride

POCl₃Represents phosphorus oxychloride

PPh₃Represents triphenylphosphine

PS-TsCl represents polystyrene sulfonyl chloride

PS-PPh₃Pd represents polystyrene triphenylphosphine-Pd (0)

SCX-2 denotes a silica-based adsorbent containing chemically bound propanesulfonic acid functional groups

TBAF means tetra-n-butylammonium fluoride

TBDMS represents tert-butyldimethylsilyl group

TCA represents trichloroacetic acid

TFA represents trifluoroacetic acid

THF represents tetrahydrofuran

TMS Azide stands for trimethylsilyl azide

Xantphos means 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

XPhos represents 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl

LCMS method

The following conditions were used for the samples analyzed by high performance liquid chromatography-mass spectrometry. Method X was used unless otherwise noted.

Method 1

Method 1 used a Gilson 306 pump, a Gilson 811C mixer, a Gilson 806 pressure measurement module, and a Gilson UV/VIS 152 detector at a wavelength of 254 nm. The mass spectrometer was Finnigan AQA, the column used was Waters SunAire, 5 μm pore size, C18 size 50x 4.60mm. The injection volume was 10. mu.l. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. Elution flow rate was 1.5mL/min, using 95% water: 5% acetonitrile, linearly changing to 5% water within 5.5 minutes: 95% acetonitrile, then held under the mixture for 2 minutes.

Method 2

Method 2 used a Waters 515 pump, a Waters 2525 mixer, and a Waters2996 diode array detector. Detection was performed between 210nm and 650 nm. The mass spectrometer was a Waters micromass ZQ, the column used was a Waters SunFire, 5 μm pore size, and the size of C18 was 50 x4.60mm. The injection volume was 10. mu.l. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. Elution flow rate was 1.5mL/min, using 95% water: 5% acetonitrile, linearly changing to 5% water within 5.5 minutes: 95% acetonitrile, then held under the mixture for 2 minutes.

Method 3

Method 3 used a Waters 515 pump, a Waters 2525 mixer and a Waters2487UV detector (single wavelength 254 nm). The mass spectrometer was a Waters micromass ZQ, the column used was Waters SunAire, 5 μm pore size, and the size of C18 was 50 x4.60mm. The injection volume was 10. mu.l. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. Elution flow rate was 1.5mL/min, using 95% water: 5% acetonitrile, linearly changing to 5% water within 5.5 minutes: 95% acetonitrile, then held under the mixture for 2 minutes.

Method 4

Method 4 used a Waters 515 pump, a Waters 2545 mixer with valves directed to different columns and a Waters2996 diode array detector. Detection was performed between 210nm and 650 nm. The mass spectrometer used was a Waters 3100, which detected a mass between 100 and 700 g/mol. The column used was XBridge, 5 micron pore size, C18, 50 × 4.60mm. The injection volume was 10. mu.l solution (approximately 1 mg/ml). The flow rate was 1.5mL/min, and the mobile phase was water pH 100.03% ammonium hydroxide (3mL/10l) and acetonitrile 0.03% ammonium hydroxide (3mL/10 l). Elution started from 95% water: 5% acetonitrile, ramped to 5% water in 5.50 minutes: 95% acetonitrile. The eluent level was returned to the starting condition of 95% water in 6 seconds: 5% acetonitrile. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 5

Method 5 used a Waters 515 pump, a Waters 2525 mixer with valves directed to different columns and a Waters2487UV detector. Detection was performed at 254 nm. The mass spectrometer used was a Waters micromass ZQ, which detected masses between 100 and 700 g/mol. The column used was SunAire, 5 micron pore size, C18 column with a size of 50X4.60mm was used. The injection volume was 10. mu.L of solution (approximately 1 mg/mL). The flow rate was 1.5mL/min, and the mobile phase was water containing 0.1% formic acid and methanol. Elution started from 85% water: 15% methanol, ramped to 15% water in 4.5 minutes: 85% methanol, these conditions were maintained for 1 minute, then the eluent level was returned to the starting conditions of 85% water: 15% methanol. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 6

Method 6 used a Waters 515 pump, a Waters 2545 mixer with valves directed to different columns and a Waters2996 diode array detector. Detection was performed between 210nm and 650 nm. The mass spectrometer used was a Waters 3100, which detected a mass between 100 and 700 g/mol. The column used was XBridge, 5 micron pore size, C18, 50 × 4.60mm. The injection volume was 10. mu.L of solution (approximately 1 mg/mL). The flow rate was 1.5mL/min, and the mobile phase was water, pH 100.03% ammonium hydroxide (3mL/10l) and methanol, 0.03% ammonium hydroxide (3mL/10 l). Elution started from 85% water: 15% methanol, ramped to 15% water in 4.5 minutes: 85% methanol. These conditions were maintained for 1 minute, and then the eluent levels were returned to the starting conditions of 85% water over 6 seconds: 15% methanol. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 7

Method 7 used a Waters 515 pump, a Waters 2545 mixer with valves directed to different columns and a Waters2487UV detector. Detection was performed at 254 nm. The mass spectrometer used was a Waters micromass ZQ, which detected masses between 100 and 700 g/mol. The column used was SunAire, 5 micron pore size, C18 column with a size of 50X4.60mm was used. The injection volume was 10. mu.L of solution (approximately 1 mg/mL). The flow rate was 1.5mL/min, and the mobile phase was water containing 0.1% formic acid and methanol. Elution started from 85% water: 15% methanol, ramped to 15% water in 4.5 minutes: 85% methanol, these conditions were maintained for 1 minute, then the eluent level was returned to the starting conditions of 85% water: 15% methanol. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 8

Method 8 used a Waters 515 pump, a Waters 2525 mixer with valves directed to different columns and a Waters2487UV detector. Detection was performed at 254 nm. The mass spectrometer used was a Waters micromass ZQ, which detected masses between 100 and 700 g/mol. The column used was SunAire, 5 micron pore size, C18 column with a size of 50X4.60mm was used. The injection volume was 10. mu.L of solution (approximately 1 mg/mL). The flow rate was 1.5mL/min, and the mobile phase was water containing 0.1% formic acid and methanol. Elution started from 85% water: 15% methanol, ramped to 15% water over 3 minutes: 85% methanol, these conditions were maintained for 2.5 minutes, then the eluent levels were returned to the starting conditions of 85% water over 6 seconds: 15% methanol. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 9

Method 9 used a Waters 515 pump, a Waters 2545 mixer with valves directed to different columns and a Waters2487UV detector. Detection was performed at 254 nm. The mass spectrometer used was a Waters micromass ZQ, which detected masses between 100 and 700 g/mol. The column used was XBridge, 5 micron pore size, C18, 50 × 4.60mm. The injection volume was 10. mu.L of solution (approximately 1 mg/mL). The flow rate was 1.5mL/min, and the mobile phase was water pH 100.03% ammonium hydroxide (3mL/10l) and methanol 0.03% ammonium hydroxide (3mL/10 l). Elution started from 85% water: 15% methanol, ramped to 15% water in 4.5 minutes: 85% methanol. These conditions were maintained for 1 minute, and then the eluent levels were returned to the starting conditions of 85% water over 6 seconds: 15% methanol. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Method 10

LCMS results were obtained on either instrument. LCMS analysis was performed on a Waters AquityUPLC Performance LC with a 2.1mm x 50mm Waters AquityUPLC BEH C181.7 μm column. The target column temperature was 45 ℃, run time was two (2) minutes, flow rate was 0.600mL/min, solvent mixture was 5% (0.1% formic acid/water): 95% (acetonitrile/0.1% formic acid). Mass spectral data were obtained on a Micromass LC-ZQ 2000 quadrupole mass spectrometer. Alternatively, LCMS analysis was performed on a Bruker Esquire 200 ion trap.

Preparative HPLC method

The following conditions were used for samples purified by mass spectrometry-guided high performance liquid chromatography.

Method A

Method A used a Waters 515 pump, a Waters 2525 mixer, and a Waters2487UV detector (single wavelength 254 nm). The mass spectrometer was a Waters micromass ZQ, the column used was Waters SunAire, 5 μm pore size, and the size of C18 was 50X19 mm. The injection volume is up to 500. mu.L of solution, with a maximum concentration of 50 mg/mL. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The flow rate of the eluent was 25mL/min, and the eluent was linearly changed to 95% acetonitrile and 5% water in 5.3 minutes using 95% water and 5% acetonitrile, and the eluent was maintained for 0.5 minute.

Method B

Method B used a Waters 515 pump, a Waters 2545 mixer with valves directed to different columns, and a Waters2996 diode array detector. Detection was performed between 210nm and 650 nm. The mass spectrometer used was a Waters 3100, which detected a mass between 100 and 700 g/mol. The column used was XBridge, 5 micron pore size, C18, 50x19 mm. The injection volume is selected by the user and can be up to 500. mu.L of solution (50 mg/mL maximum). The flow rate was 25mL/min, and the mobile phase was water, pH 100.03% ammonium hydroxide (3mL/10l) and acetonitrile, 0.03% ammonium hydroxide (3mL/10 l). Elution started from 95% water: 5% acetonitrile, ramped to 5% water in 5.30 minutes: 95% acetonitrile. The eluent level was returned to the starting condition of 95% water over 0.6 min: 5% acetonitrile. These conditions were maintained for 1.4 minutes to allow the column to equilibrate before injecting the next sample. The run lasted 7 minutes in total.

Analytical HPLC method

Method X

Method X used a gradient elution on an Agilent 1100 series HPLC at 2.5ml/min on a 4.6X 75mm (2.5 micron) Zorbax XDB-C8 column over 5 minutes, (0 to 100%) acetonitrile (containing 0.1% trifluoroacetic acid): water (containing 0.1% trifluoroacetic acid).

Synthesis of

Several methods for the chemical synthesis of the 4-substituted-2- (pyridin-4-yl) -azaquinazoline compounds of the present invention (collectively referred to herein as "4 PAZ compounds" for convenience) are described herein. These methods and/or other known methods may be modified and/or adapted in known ways to facilitate the synthesis of other compounds within the scope of the invention.

In one method, the general formula [ F-001]By reacting a compound of formula [ F-002 (wherein a ═ NH or N alkyl) ]4 PAZ]Wherein X is halogen such as chlorine or sulfonate, with a compound of the formula [ F-003 ]]Wherein A is NH or NH₂Z on the terminal nitrogen is H, alkyl or a suitable nitrogen protecting group such as Boc, Alloc, Cbz or Fmoc) in a suitable solvent such as DMF in the presence of a suitable base such as triethylamine. The reaction is suitably carried out at elevated temperature, for example 40 ℃. When Z is a suitable nitrogen protecting group such as Boc, Alloc, Cbz or Fmoc, the formula [ F-001]The compound of (3) is prepared by a suitable deprotection reaction. For example, when Z is a Boc protecting group, it is reacted with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably carried out at ambient temperature. In one method, the formula [ F-001]By reacting a compound of the formula [ F-002] (wherein a ═ O)]Wherein X is halogen such as chlorine or sulfonate, with a compound of the formula [ F-003 ]]Wherein a is OH and Z on the terminal nitrogen is H, alkyl or a suitable nitrogen protecting group such as Boc, Alloc, Cbz or Fmoc in a suitable solvent such as DMA in the presence of a suitable base such as sodium hydride. The reaction is suitably carried out at ambient temperature. When Z is a suitable nitrogen protecting group such as Boc, Alloc, Cbz or Fmoc, the formula [ F-001]The compound of (3) is prepared by a suitable deprotection reaction. For example, when Z is a Boc protecting group, it is reacted with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably carried out at ambient temperature.

In one method, a compound of formula [ F-002] (wherein X is a halogen such as chlorine) is prepared by reacting a compound of formula [ F-004] with a suitable halogenating agent such as phosphorus oxychloride. The reaction is suitably carried out at elevated temperature, for example 125 ℃. The compound of formula [ F-002] (wherein X is a sulfonate) is prepared by reacting a compound of formula [ F-004] with a suitably substituted sulfonyl chloride in a suitable solvent such as DMA in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP. The reaction is suitably carried out at ambient temperature.

In one method, a compound of formula [ F-004] is prepared by reacting a compound of formula [ F-005], wherein Rx is an alkyl group such as methyl or ethyl, with a compound of formula [ F-006] in a suitable solvent in an anhydrous aprotic solvent such as dioxane or THF in the presence of a hindered alkoxide base such as potassium tert-amylate 1.7M or potassium tert-butoxide in toluene. The reaction is suitably carried out at ambient temperature.

In one method, a compound of formula [ F-004] is prepared by reacting a compound of formula [ F-007] with a compound of formula [ F-006] in a suitable solvent in a protic solvent such as methanol in the presence of a base such as sodium methoxide. The reaction is suitably carried out first at ambient temperature and then at reflux overnight.

An example of the method described above is shown in the scheme below.

General Synthesis scheme A1 for 4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-001]

General formula [ F-001]Substituted 2-pyridin-4-yl-pyrido [3,4-d]The pyrimidin-4-ol derivatives are prepared by reacting a compound of the formula [ F-005]]2-amino group of (A)-pyridyl derivatives and compounds of the general formula [ F-006]]In the presence of a base such as sodium methoxide in a polar aprotic solvent such as methanol. The reaction is suitably carried out at elevated temperature to give the general formula [ F-004]Cyclized 2-pyridin-4-yl-pyrido [3,4-d]Pyrimidin-4-ol products. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ F-004]2-pyridin-4-yl-pyrido [3,4-d of]Reaction of the pyrimidin-4-ol derivative with a chlorinating agent such as phosphoryl chloride gives compounds of the general formula [ F-008 [ ]]4-chloro-1-yl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine derivatives in polar aprotic solvents such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature with a compound of the formula [ F-003]By reaction of a primary or secondary amine derivative [ method A ]]. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine derivatives represented by the general formula [ F-004]]2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM with catalytic amounts of DMAP in polar aprotic solvents such as DMA, DMF, NMP [ method B ]]. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2-pyridin-4-yl-thieno [3,2-d]Pyrimidin-4-yl esters with the general formula [ F-003 ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection in a solvent such as DCM, DCE, THF, EtOH or MeOH, and reaction of the crude productThe product was purified by reverse phase preparative HPLC.

Scheme A1

Synthesis method A of 4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [1]

Synthesis of 2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol [ A001]

A mixture of 4-cyanopyridine (8.25g, 79.2mmol), sodium methoxide (891mg, 16.5mmol), and methanol (400mL) was stirred at room temperature for 60 minutes. 3-amino-isonicotinic acid (9.12g, 66.0mmol) was added and the mixture was heated under reflux for 3 days. After cooling to room temperature, the solid precipitate was collected by filtration and then dried in a vacuum oven to give the title compound as an off-white solid (6.02 g): (1H,300MHz, d6-dmso)13.10(1H, br s),9.16(1H, s),8.80(2H, dd),8.70(1H, d),8.10(2H, dd),8.00(1H, dd)

Synthesis of 4-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [ A002]

Adding POCl₃2-pyridin-4-yl-pyrido [3,4-d ] in (50mL, 538mmol)]Pyrimidin-4-ol [ A001](4g, 17.8mmol) was heated to 110 ℃ for 3 hours. The reaction mixture was concentrated in vacuo and taken up with saturated NaHCO₃The solution was quenched, extracted into DCM, washed with water followed by brine, passed through a phase separation cartridge and evaporated to give the title compound [ a002] as a yellow/brown solid](2.6g), used without further purification: LCMS method: 1, RT: 4.09min, MI 243[ M + H ]]。

Synthesis of 1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine [1]

Reacting 4-chloro-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine [ A002]A solution of (100mg, 0.43mmol) piperazine (172mg, 2mmol) in anhydrous DMA (5mL) was stirred at room temperature for 3 days. The reaction mixture was partitioned between NaOH (2M aq) and ethyl acetate. The organic layer was further washed with water, then brine and dried (MgSO)₄) The crude material was purified by preparative HPLC (method a) to give the title compound (1.87 mg). LCMS method 1, RT 3.49min, MI 293[ M + H]；1H-NMR(300MHz；DMSO-d6):9.26(1H,s),8.76(2H,d),8.58(1H,d),8.32(2H,d),8.24(1H,s),7.92(1H,d),3.96(4H,br tr),2.99(4H,br tr)

Synthesis method B of (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine [2]

Synthesis of 5-methoxy-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A003]

To a stirred solution of 2-chloro-4-pyridinecarbonitrile (1g, 9.6mmol) in methanol (20mL) was added 0.5M NaOMe (2mmol, 4mL), followed by 3-amino-5-methoxy-isonicotinic acid (1.35g, 8 mmol). The reaction mass was heated at 75 ℃ overnight. The reaction mass was left to cool to form a solid precipitate which was collected by filtration, washed with cold methanol and dried in a vacuum oven to give the title compound as a light brown solid (610mg, 30% yield). LCMS method 1, RT:3.82min, MI 255.09[ M + H ].

Synthesis of (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine [2]

Reacting 5-methoxy-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine-4- [ A003](0.157mmol, 0.04g), 2,4, 6-triisopropylbenzenesulfonyl chloride (0.173mmol, 0.052 g)) Dissolved in anhydrous DMA (2mL) and Et added sequentially₃N (0.314mmol, 0.045mL) and DMAP (5 mg). The mixture was stirred at room temperature for 1 hour and (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.236mmol, 0.044g) was added. The mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, and the residue was stirred in trifluoroacetic acid (1mL) at room temperature for 3 hours. The solution was poured onto a SCX-2 cartridge (5g), washed with methanol (10mL), then ammonia (2N in methanol, 2.0 mL). The ammonia washes were concentrated in vacuo to a brown residue which was purified by preparative HPLC (method a) to give the title compound (0.016 g). LCMS method 1, RT 1.47min, MI 323[ M + H ]]；1H-NMR 300MHz(1H d6-dmso)8.81(1H,s),8.76(2H,dd),8.35(1H,s),8.32(2H,dd),8.23(1H,d),6.42(1H,s),4.98(1H,m),4.14(3H,s),3.19-3.07(2H,m),2.41-2.29(2H,m),2.07-1.95(2H,m)。

Synthesis of 2- (3-fluoro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ A004]

2- (3-fluoro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ A004]

3-amino-2-chloro-isonicotinamide (0.5g, 3.64mmol), 3-fluoroisonicotinal (0.54g, 4.37mmol) and NaHSO₃(0.75g, 7.29mmol) and DMA (5mL) were added sequentially to the microwave vial. The vial was sealed and then heated at 160 ℃ for 6 minutes. Water (10mL) was added, filtered and the resulting solid used without further purification. LCMS method 1, RT 3.07min, MI 243[ M + H ]]

Synthesis of 8-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A005]

8-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A005]

A solution of 3-amino-2-chloro-isonicotinamide (0.5g, 2.91mmol) and 4-pyridinecarboxaldehyde (0.35g, 3.32mmol) in DMA (10mL) was heated under microwave (100 ℃,2 h). Sodium bisulfite (0.606g, 5.83mmol) was then added and the mixture was heated under microwave (150 ℃,1 h). Then water was added to the mixture and the resulting solid (0.34g, 45%) was collected, washed with water and then with methanol. LCMS method 1, RT 3.89min, MI 258[ M + H ]

Synthesis of 8-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A005]

Synthesis of 2-chloro-3- [ (pyridine-4-carbonyl) -amino ] -isonicotinamide [ A006]

To 3-amino-2-chloro-isonicotinamide (0.5g, 2.913mmol) and K₂CO₃(1g, 7.28mmol) in refluxing Et₂To the suspension in O (25mL) was added isonicotinoyl chloride hydrochloride (0.622g, 3.5mmol) portionwise. The mixture was stirred at reflux for 4 hours. The solvent was removed under reduced pressure and water (50mL) was added. Filtering the resulting solid with H₂O was washed and then collected and dried over an azeotrope containing toluene to give the title compound (0.78g, 96%) which was used without further purification. LCMS method 1, RT:2.55min, MI 277[ M + H ]]

Synthesis of 8-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A004]

To 2-chloro-3- [ (pyridine-4-carbonyl) -amino group]-isonicotinamide [ A006](0.2g, 0.723mmol) in methanol (20mL) was added cesium carbonate (0.47g, 1.44mmol) in H₂Solution in O (2 mL). The mixture was stirred at room temperature overnight. Methanol was removed under reduced pressure and water (10mL) was added. Slowly adding acetic acid, and collecting the resultantThe solid was dried over toluene azeotrope to give the title compound, which was used without further purification. LCMS method 1, RT 3.43min, MI 259[ M + H]

Synthesis of 6-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A007]

6-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A007]

A solution of dipotassium pentoxide (2.6mL, 5.1mmol, 25% solution in toluene) was added dropwise (. about.0.5 mL/min) to a solution of ethyl 5-amino-2-chloro-isonicotinate (0.4g, 2mmol) and 4-cyanopyridine (0.25g, 2.4mmol) in anhydrous THF (5mL) cooled in an ice bath. The reaction was allowed to warm to room temperature and left to stir at room temperature overnight. Water (9mL) was added and the mixture was stirred at room temperature for 20 minutes. Acetic acid (1mL) was then added, the mixture was left to stir at room temperature, the resulting yellow precipitate was filtered and the solid was washed with deionized water (2x3mL) to give the title compound (0.43g, 83% yield). LCMS method 1, RT 2.21min, MI 259[ M + H ]

Synthesis of 2- (3-fluoro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol [ A008]

2- (3-fluoro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol [ A008]

To a stirred solution of 3-fluoroisonicotinitrile (0.088g, 0.71mmol) in methanol (5mL) was added NaOMe (0.008g, 0.15 mmol). After 1h 3-amino-5-methoxy-isonicotinic acid (0.1g, 0.54mmol) was added and the reaction mass was heated to 85 ℃ for 18 h. The solution turned yellow in color. The reaction mixture was cooled to room temperature, and a white solid was collected by filtration and washed with methanol to give the title compound (0.07g, 43% yield). LCMS method 1, RT 1.19min, MI 271.24[ M + H ]

The following compounds were synthesized following the general synthesis shown in scheme [ a1 ]:

(S)-N²,N²-dimethyl-3-phenyl-propane-1, 2-diamine [ A009]Synthesis of (2)

[ (S) -1- (1, 3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl) -2-phenyl-ethyl]-carbamic acid tert-butyl ester [ A010]A mixture of Boc-L-phenylalaninol (25g, 99.5mmol), triphenylphosphine (31.3g, 119.4mmol), phthalimide (16.1mg, 109.5mmol) and THF (300mL) was cooled to 0 ℃. A solution of diisopropyl azodicarboxylate (19.5mL, 99.5mmol) in THF (100mL) was added over 15 minutes. The resulting pale yellow solution was allowed to return to room temperature overnight. The reaction mixture was concentrated to about 100mL and then partitioned between ethyl acetate and water. A white precipitate formed, which was collected by filtration. The organic layer was washed with more water (x1), then brine (x1), dried (MgSO 1)₄) Filtered and evaporated to give the title compound as a second white solid, which was used without further analysis in the next reaction.

((S) -1-aminomethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A011)](ii) stirring [ (S) -1- (1, 3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl) -2-phenyl-ethyl at room temperature]-carbamic acid tert-butyl ester [ A010](2g, 5.25mmol), 4M HCl in dioxane (5mL, 20mmol), and methanol (50 mL). The reaction mixture was loaded directly onto an SCX-2 cartridge under methanol conditions. The cartridge was washed with methanol (2col cols) and then eluted with 2N ammonia in methanol (2 CV). LCMS analysis showed that the target material was predominantly in the methanol wash, but also partially in the NH₃In the eluate. The collected fractions were left for 3 days. After this time, needle-like crystals began to form in the methanol fraction. The crystals were collected by filtration and dried in a vacuum oven to obtain the title compound [ A011 ]](400 mg): NMR (1H,300MHz, d6-DMSO)8.08(2H, br s),7.04(4H, s),7.35-7.29(4H, m),7.26-7.17(1H, m),3.83-3.66(2H, m),3.61(1H, dd),3.06(1H, dd),2.86(1H, dd); LCMS method 1, RT:2.50min, MI 281[ M + H]

Synthesis of 2- ((S) -2-dimethylamino-3-phenyl-propyl) -isoindole-1, 3-dione [ A012]

2- ((S) -2-amino-3-phenyl-propyl) -isoindole-1, 3-dione [ A0 ]11]A mixture of (200mg, 0.71mmol), formaldehyde (2mL, xs) and formic acid (2mL, xs) was heated to 100 ℃ for 2 hours. The reaction mixture was concentrated under vacuum and then at 2M K₂CO₃And DCM. The organic layer was washed with water, then brine, passed through a phase separator and evaporated to give the title compound [ A012]](200mg), used without further purification: LCMS method: 1, RT: 2.42min, MI309[ M + H ]]

(S)-N²,N²-dimethyl-3-phenyl-propane-1, 2-diamine [ A009]Synthesis of (2)

A solution of 2- ((S) -2-dimethylamino-3-phenyl-propyl) -isoindole-1, 3-dione [ A012] (350mg), hydrazine monohydrate (66.1ul, 1.36mmol) and methanol (50mL) was stirred at room temperature for 20 hours. The solvent was removed under vacuum to give a white solid. It was then partitioned between 10% citric acid and isopropanol. The aqueous layer was filtered, basified with 2M NaOH, extracted into isopropanol, washed with brine, passed through a phase separator and evaporated to give the title compound [ a009] (93 mg): LCMS method: 1, RT: 0.53min, MI179[ M + H ]

Synthesis of ((S) -1-methylaminomethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A013]

Synthesis of (S) -2-tert-butoxycarbonylamino-3-phenyl-propyl toluene-4-sulfonate [ A014]

To a solution of Boc-L-phenylalaninol (0.5g, 1.989mmol) in DCM (10mL) was added triethylamine (0.83mL, 5.968mmol) at 0 ℃. The reaction mixture was stirred at this temperature for 5 minutes. P-toluenesulfonyl chloride (2.188mmol, 0.42g) was added dropwise as a solution in DCM (5mL) and the reaction mixture was slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (20mL) and washed with water. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate. DCM was evaporated to dryness under reduced pressure to give the title compound [ a014] (0.8g) as a clear oil. The crude product was used immediately in the next step without further purification.

Synthesis of ((S) -1-methylaminomethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A013]

Toluene-4-sulfonic acid (S) -2-tert-butoxycarbonylamino-3-phenyl-propyl ester [ A014] (0.80g, 1.973mmol) was dissolved in THF (10mL) and methylamine (2N in THF, 10mL) was added in one portion. The reaction mixture was stirred at 60 ℃ overnight. The mixture was diluted with ethyl acetate and washed with brine. The layers were separated and ethyl acetate was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound [ a013] as a clear oil. No further purification was performed at this stage. The crude material was used in the subsequent reaction without further purification.

Synthesis of (2S,4S) -4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester [ A015]

Synthesis of (2S,4R) -4-methanesulfonyloxy-pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ A016]

N-Boc-trans-4-hydroxy-L-proline methyl ester (12.28mmol, 3g) was dissolved in DCM (30mL) and triethylamine (13.45mmol, 1.87mL) was added. The reaction was cooled to 0 ℃ and methanesulfonyl chloride (24.46mmol, 1.89mL) was added dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 45 minutes and then warmed to room temperature for 2 hours. Brine was added, the layers were separated and the aqueous phase was extracted with dichloromethane (× 2). The organic phase was washed with brine (× 1) and MgSO₄Dried, filtered and evaporated to give the title compound as a clear oil (3.95 g): NMR (1H,300MHz, CDCl)₃):5.22(m,1H),4.39(m,1H),3.74(s,3H),3.73(m,2H),3.65(s,3H),3.07(s,3H),2.51(m,1H),2.22(m,2H),1.41(d,9H)

Step 2: synthesis of (2S,4S) -4-azido-pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ A017]

The (2S,4R) -4-methanesulfonyloxy-pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ A016](12.28mmol, 3.95g) was dissolved in anhydrous DMF (20mL) and sodium azide (61.14mmol, 3.97g) was added in one portion. The reaction was heated to 80 ℃ for 3 hours. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate (× 3). The organic phase was washed with brine, over MgSO₄Dried, filtered and evaporated to a colorless oil. Purification by flash column chromatography using 0 to 40% ethyl acetate/cyclohexane to give the title compound [ A017](2.24g)：NMR(1H,300MHz,CDCl₃):4.36(m,1H),4.13(m,1H),3.74(s,3H),3.67(m,1H),3.48(dt,1H),2.47(m,1H),2.14(m,2H),1.43(d,9H)

Synthesis of (2S,4S) -4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester [ A015]

Water (5mL) was added to (2S,4S) -4-azido-pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ A017] in toluene (40mL)](4.44mmol, 1.2g) and triphenylphosphine (9.32mmol, 2.45g) were added to a stirred solution and the reaction was heated to 60 ℃ overnight. After cooling, water was added and the layers were separated. Basifying the aqueous phase with 2M NaOH, extracting twice with ethyl acetate, combining the organic phases, over anhydrous MgSO₄Dried, filtered and concentrated in vacuo to give the title compound (200mg): NMR (1H,300MHz, CDCl)₃):4.20(m,1H),3.71(s,3H),3.62(m,1H),3.50(m,1H),3.22(m,1H),2.43(m,1H),1.78(m,1H),1.43(d,9H)

Synthesis of (1R,2R) -1-aminomethyl-2-fluoro-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A018]

Synthesis of ((1R,2R) -2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A019]

(1R,2R) - (-) -2-amino-1-phenyl-propane-1, 3-diol (5.98mmol, 1.0g) was dissolved in methanol (10mL) and cooledTo 0 ℃. A solution of di-tert-butyldicarbonate in methanol (4mL) was added and the reaction was allowed to warm to room temperature and stirred for 2 hours. The solvent was removed in vacuo and the product was purified by flash chromatography, eluting with 0 to 70% ethyl acetate/cyclohexane to give the title compound [ A019%](1.20g)：NMR(1H,300MHz,CDCl₃) 7.29(m,5H),5.19(m,1H),4.96(m,1H),3.35(m,1H),2.66(m,1H),1.33(s, 9H); LCMS method 1, RT 4.35min, MI traceless.

Synthesis of ((1R,2R) -2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A020]

Allyl chloroformate (11.222mmol, 1.35g) was added dropwise to ((1R,2R) -2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A019] in DCM (50mL) at 0 deg.C](1.20g, 4.48mmol) and pyridine (15.711mmol, 1.27 mL). The reaction was allowed to warm to room temperature and stirred for 1 hour. Water was added to separate the layers. The aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated under vacuum. The crude product was purified by flash chromatography using 0 to 100% ethyl acetate/cyclohexane to give the title compound [ A020%](0.93g)：NMR(1H,300MHz,CDCl₃):7.28(m,5H),5.91(m,1H),5.34(d,1H),5.27(d,1H),4.99(m,1H),4.84(t,1H),4.61(d,2H),4.27(dd,1H),4.07(dd,1H),4.01(m,1H),3.09(bs,1H),1.33(s,9H)；LCMS:LC-MS17QC 94％352+[M+H]5.17min

Synthesis of allyl carbonate (2R,3R) -2-tert-butoxycarbonylamino-3-phenyl-3- (tetrahydro-pyran-2-yloxy) -propyl ester [ A021]

((1R,2R) -2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl in DCM (20mL)Ester [ A020 [ ]]A solution of (1.42mmol, 0.50g) and DIPEA (4.97mmol, 0.865mL) was added dropwise to a solution of (diethylamino) sulfur trifluoride (DAST) (4.97mmol, 0.610mL) at-78 deg.C under nitrogen. The reaction was slowly warmed to room temperature and stirred for 2 hours. Water was added and then extracted twice with DCM. The combined organic phases were washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated under vacuum to give the title compound [ A021]It was used directly in the next step without further purification: LCMS method: 1, RT:3.27min, MI was not seen.

Synthesis of ((1R,2R) -2-fluoro-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A022]

To allyl carbonate (2R,3R) -2-tert-butoxycarbonylamino-3-fluoro-3-phenyl-propyl ester [ A021] in anhydrous THF (15mL) under nitrogen](2.0mmol, 0.71g) Tetrakis (triphenylphosphine) palladium (0) (0.08mmol, 0.093g) and morpholine (3.014mmol, 0.26mL) were added. The reaction was stirred at room temperature under nitrogen atmosphere for 1 hour. Brine was added and the mixture was extracted twice with ethyl acetate. The organic phases were combined over MgSO₄Dried, filtered and concentrated under vacuum. The product was purified by flash chromatography using 0 to 10% methanol/DCM to give the title compound [ a022](0.19g)：NMR(1H,300MHz,CDCl₃):7.32(m,5H),5.68(d,1H),5.11(m,1H),3.99(m,1H),3.86(m,1H),3.67(m,1H),1.39(s,9H)

Synthesis of [ (1R,2R) -1- (1, 3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl) -2-fluoro-2-phenyl-ethyl ] -carbamic acid tert-butyl ester [ A023]

(1R,2R) -2-fluoro-1-hydroxymethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A022](0.705mmol, 0.19g), triphenylphosphine (0.988mmol, 0.259g) And a solution of phthalimide (0.988mmol, 0.145g) was cooled to 0 deg.C and diisopropyl azodicarboxylate (DIAD) (0.988mmol, 0.193mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed in vacuo and the residue was dissolved in DCM. 2M NaOH (aq) was added and the layers were separated using a phase separator. The organic phase was concentrated in vacuo. The product was purified by flash chromatography using 0 to 30% ethyl acetate/cyclohexane to give the title compound [ A023](0.28g)：1LCMS1；98％,399.15+[M+H]+,5.45min；NMR(1H,300MHz,CDCl₃):7.80(m,2H),7.65(m,2H),7.40(m,4H),7.31(m,1H),5.72(dd,1H),5.06(d,1h),4.47(m,1H),3.83(dd,1H),3.57(dd,1H),1.20(s,9H)

Synthesis of (1R,2R) -1-aminomethyl-2-fluoro-2-phenyl-ethyl) -carbamic acid tert-butyl ester [ A018]

Reacting [ (1R,2R) -1- (1, 3-dioxo-1, 3-dihydro-isoindol-2-ylmethyl) -2-fluoro-2-phenyl-ethyl]-carbamic acid tert-butyl ester [ A023](0.705mmol, 0.28g) was dissolved in methanol (5mL) and hydrazine monohydrate (0.916mmol, 0.045mL) was added. The reaction was stirred at room temperature for 1 hour and then at 60 ℃ overnight. After cooling, the solvent was removed in vacuo and the residue was dissolved in DCM. 2M NaOH (aq) was added and the mixture was extracted twice. The organic phases were combined over anhydrous MgSO₄Dried, filtered and concentrated under vacuum. The product was purified using an SCX-2 cartridge and the crude material was used as a DCM solution, washed with methanol and DCM. The material was then washed off the SCX-2 cartridge by washing with ammonia (2N in methanol), and the ammonia wash was concentrated in vacuo to give the title compound [ a018]](0.12g)：NMR(1H,300MHz,CDCl₃):7.34(m,5H),5.62(d,1H),5.19(d,1H),3.89(m,1H),2.83(m,2H),1.40(s,9H)

Synthesis of 2-fluoromethyl-piperazine [ A024]

(1, 4-dibenzyl-piperazin-2-yl) -methanol [ A026]

1, 4-dibenzyl-piperazine-2-carboxylic acid ethyl ester [ A025 ] in THF (10mL)](3.7g, 10.9mmol) was added dropwise to a suspension of LiAlH4(2.24g, 59mmol) in THF (20mL) at 0 deg.C. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with ether, cooled to 0 ℃ and quenched with water (2.25mL) and 2M NaOH (4.5mL) and water (4.5 mL). The suspension was stirred for 15 minutes and anhydrous MgSO was added₄And stirred for a further 15 minutes. The white solid (celite) was filtered off and the solvent was removed in vacuo. The product was purified by flash chromatography using 0 to 100% ethyl acetate/cyclohexane to give the title compound [ A026](3.03g, 94% yield). LCMS method: 1, RT: 2.16 min, MI 297.23[ M + H]；NMR(1H,300MHz,CDCl₃):3.43(m,3H),2.63(m,3H),2.95(m,1H),3.49(m,3H),3.61(d,1H),4.04(dd,2H),7.31(m,10H)

1, 4-dibenzyl-2-fluoromethyl-piperazine [ A027]

(1, 4-dibenzyl-piperazin-2-yl) -methanol [ A026 in DCM (5mL)](1.09g, 3.6mmol) was added dropwise to a stirred solution of DAST (0.9mL, 7.35mmol) in DCM (10mL) at 0 ℃. The reaction was warmed to room temperature and stirred overnight. 2M aqueous NaOH (10mL) was added and the layers were separated by a phase separator. The solvent was removed in vacuo and the product was purified by flash chromatography using 0 to 30% ethyl acetate/cyclohexane to give the title compound [ A027](0.42g, 38% yield). LCMS method 1, RT 5.88min, MI 299.38[ M + H ]]；NMR(1H,300MHz,CDCl₃):2.28(m,3H),2.50(m,2H),2.70(m,2H),2.83(m,1H),3.49(m,3H),4.11(d,1H),4.53(ddd,1H),4.68(ddd,1H),7.25(m,10H)

2-fluoromethyl-piperazine [ A024]

1, 4-dibenzyl-2-fluoromethyl-piperazine [ A027] (0.32g, 1.07mmol) was dissolved in DCE (10mL), and 1-chloroethyl chloroformate (0.35mL, 3.21mmol) was added. The reaction was heated to reflux overnight. After cooling, the solvent was removed in vacuo and the intermediate dicarbamate was purified by flash chromatography, eluting with 0 to 50% ethyl acetate/cyclohexane. The residue was dissolved in methanol (10mL) and heated under reflux for 1 hour. The solvent was removed in vacuo to give the title compound [ a024] which was used in the next step and was used without further purification.

Synthesis of piperazin-2-yl-acetonitrile [ A028]

(1, 4-dibenzyl-piperazin-2-yl) -acetonitrile [ A029]

(1, 4-dibenzyl-piperazin-2-yl) -methanol [ A026 in DCM (10mL)](1g, 3.37mmol) was added dropwise to a solution of thionyl chloride (0.32mL, 4.4mmol) in DCM (5mL) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo and water was added. The aqueous solution was extracted with ether and then saturated Na₂CO₃Alkalizing. It was extracted twice with DCM over anhydrous MgSO₄Dried, filtered and concentrated in vacuo, the crude was used in the next step and it was used without further purification.

To a refluxing solution of KCN (0.244g, 3.7mmol) in water (10mL) was added dropwise 1, 4-dibenzyl-2-chloromethyl-piperazine (0.91g, 2.9mmol) in ethanol (10 mL). The reaction was heated to reflux for 3 hours. After cooling, the solvent was removed in vacuo, the residue was dissolved in DCM, washed with water and over MgSO₄Dried, filtered and concentrated under vacuum. The product was purified by flash chromatography using 0 to 40% ethyl acetate/cyclohexane to give the title compound [ A029%](0.52g, 59% yield). LCMS method 1, RT:2.87min, MI 306.26[ M + H ]]；NMR(1H,300MHz,CDCl₃):2.43(m,3H),2.58(m,4H),2.87(dd,1H),3.00(m,1H),3.48(m,3H),3.80(d,1H),7.28(m,10H)。

Piperazin-2-yl-acetonitrile [ A028]

(1, 4-dibenzyl-piperazin-2-yl) -acetonitrile [ A029] (0.52g, 1.7mmol) was dissolved in DCE (10mL), and 1-chloroethyl chloroformate (0.55mL, 5.1mmol) was added. The reaction was heated to reflux for 2 days. After cooling, the solvent was removed in vacuo and the intermediate dicarbamate was purified by flash chromatography eluting with 0 to 40% ethyl acetate/cyclohexane. The residue was dissolved in methanol (10mL) and heated under reflux for one hour. The solvent was removed in vacuo to give a clean product. NMR (1H,300MHz, d6-dmso) 3.16(m,3H),3.03(t,1H),3.49(m,4H),3.89(m,1H),10.06(m,2H)

Synthesis of 2-ethynyl-piperazine [ A030]

Synthesis of di-tert-butyl (R) -2-hydroxymethyl-piperazine-1, 4-dicarboxylate [ A031]

To a mixture of dioxane (8ml) and water (2ml) was added (R) -1-Boc-2-hydroxymethyl-piperazine (1g, 4.62mmol) and Na at 0 deg.C₂CO₃(990mg, 9.25mmol) of the stirred solution was added di-tert-butyl dicarbonate and the reaction mixture was warmed to room temperature. After 18h, all solvents were removed in vacuo and the resulting residue partitioned between DCM and water. The DCM phase was passed through a phase separation cartridge and evaporated to afford a white solid. Purification by column chromatography (0-50% ethyl acetate: cyclohexane) gave the title compound [ A031] as a white solid](1.26g，86％)。1H-NMR(1H,300MHz,CDCl₃):4.17(2H,s,br),3.93(1H,s,br),3.84(1H,d,br),3.59(2H,s,br),2.95(3H,s,br),1.46(18H,s)。

Synthesis of di-tert-butyl 2-formyl-piperazine-1, 4-dicarboxylate [ A032]

A solution of oxalyl chloride (165. mu.l, 1.90mmol) in DCM (5ml) was cooled to-78 ℃. DMSO (270. mu.l, 3.79mmol) was added dropwise and the reaction mixture was stirred for 15 min. (R) -2-hydroxymethyl-piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A031] in DCM (1ml) was added dropwise](500mg, 0.58mmol) and the reaction mixture was stirred for 1 hour. Triethylamine (1.1ml, 7.90mmol) was added and the reaction mixture was warmed to room temperature. Adding saturated NaHCO₃The layers are separated, and the film is separated,the organic phases were collected and evaporated to give the title compound [ A032] as a white powder](480mg，97％)。1H-NMR(1H,300MHz,CDCl₃):9.58(1H,s),4.63-4.45(2H,m,br),3.95-3.79(2H,m,br),3.15-3.11(2H,m,br),2.88(1H,d,br),1.44(18H,s)。

Synthesis of di-tert-butyl 2-ethynyl-piperazine-1, 4-dicarboxylate [ A033]

To di-tert-butyl 2-formyl-piperazine-1, 4-dicarboxylate [ A032] in methanol (20ml)](480mg, 0.530mmol) and K₂CO₃(425mg, 3.06mmol) of dimethyl (1-diazo-2-oxopropyl) phosphonate (350mg, 1.83mmol) was added to the stirred solution. After 18h the solvent was removed in vacuo and the resulting residue partitioned (DCM: water). The organic phase was separated and concentrated to give the title compound [ A033] as a white solid](430mg，91％)。1H-NMR(1H,300MHz,CDCl₃):4.88(1H,s,br),4.25-4.01(2H,m,br),3.80(1H,d,br),3.18(1H,t,br),3.02-2.74(2H,m),2.23(1H,d),1.47(18H,s)。

Synthesis of 2-ethynyl-piperazine [ A030]

Di-tert-butyl 2-ethynyl-piperazine-1, 4-dicarboxylate [ A033]](430mg, 1.39mmol) in 4N HCl: dioxane (1ml) was stirred for 4 hours. The light yellow solid (226mg, 89%) was collected by filtration and washed with Et₂O washes and then dried in a vacuum oven at 40 deg.C to give the title compound [ A030]]：1H-NMR(1H,300MHz,d6-dmso):4.57(1H,dt),4.04(1H,d),3.63(1H,dd),3.42-3.23(5H,m)。

Synthesis of 2-benzyl-morpholine [ A034]

Synthesis of 1-chloro-3-phenyl-propan-2-ol [ A035]

At 0 ℃ to Et₂Phenylmagnesium bromide (3M in Et) in O (14mL)₂To O, 4.4ml, 13mmol) was added CuI (210mg, 1.08 mmol). Then added to the Table in diethyl ether (14ml)Chlorohydrin (1g, 10.8mmol), the reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. Adding saturated NH₄Cl, the solution was diluted with water and then extracted with ethyl acetate (× 2). The combined organic phases were washed with brine, over MgSO₄Dried and concentrated. Purification by column chromatography (0-20% diethyl ether: cyclohexane) gave the title compound [ A035] as a colorless oil](1.66g，90％)。1H-NMR(1H,300MHz,CDCl₃):7.36-7.22(5H,m),4.11-4.01(1H,m),3.59(1H,dd),3.50(1H,dd),2.90(2H,d),2.18(1H,d)。

Synthesis of 2-benzyl-morpholine [ A034]

To a stirred solution of NaOH (1.63g, 40.8mmol) in water (3.5ml) was added 1-chloro-3-phenyl-propan-2-ol [ A035] in methanol (7ml)](1.16g, 6.8 mmol). After 5 minutes 2-aminoethane hydrogensulfate (3.84g, 27.2mmol) was added and the reaction mixture was stirred at 40 ℃ for 2 hours. NaOH (as powder, 1.63g, 40.8mmol) and PhMe (18ml) were then added and the reaction heated to 65 ℃ for 18 h. Diluted with water (10ml) followed by extraction with PhMe (x 2). The combined organic phases were washed (water then brine), dried and concentrated. Purification by column chromatography (0-10% methanol: DCM) gave the title compound (360mg, 30%) as a colorless oil. 1H-NMR (1H,300MHz, CDCl)₃):7.31-7.19(5H,m),3.86(1H,dd),3.70-3.54(2H,m),2.92-2.77(4H,m),2.67-2.55(2H,m)。

Synthesis of (R) -2- (fluoro-phenyl-methyl) -piperazine [ A036]

Synthesis of (R) -piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester 2-methyl ester [ A037]

To (R) -1-N-Boc-piperazine-2-carboxylic acid methyl ester hydrochloride (2g, 7.12mmol) and Na in dioxane (16ml) and water (4ml) at 0 deg.C₂CO₃(2.26g, 21.4mmol) to the stirred suspension was added di-tert-butyl-bicarbonate (1.55g, 7.12 mmol). After 18 hours, all solvents were removed in vacuo to yieldThe residue of (a) was partitioned between DCM and water. The organic phase was collected and evaporated to give a colourless oil. Purification by column chromatography (0-30% ethyl acetate: cyclohexane) gave the title compound [ A037] as a white powder](2.33g，95％)。1H-NMR(1H,300MHz,CDCl₃):5.30(1H,s),4.72(1H,s,br),4.54(1H,t,br),4.08-3.80(1H,m),3.73(3H,s),3.27-2.73(3H,m),1.44(18H,s)。

Synthesis of (R) -piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester [ A038]

The (R) -piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester 2-methyl ester [ A037]](2.33g, 6.77mmol) and KOH (1.14g, 20.3mmol) were heated to reflux in EtOH (50ml) for 18 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography (0-10% methanol: DCM; 0.1% TEA) to give the title compound [ A038] as a pale orange foam](2.1g，94％)。1H-NMR(1H,300MHz,CDCl₃):4.66-4.50(2H,m,br),3.96-3.74(2H,m,br),3.47(1H,s),3.23(1H,s,br),2.85(1H,s,br),1.42(18H,s)。

Synthesis of (R) -2- (methoxy-methyl-carbamoyl) -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A039]

The (R) -piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester [ A038]](2.10g, 6.36mmol), O- (7-azaphenprobazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.9g, 7.63mmol), N, O-dimethylhydroxylamine hydrochloride (750mg, 7.63mmol) and TEA (2.2ml, 15.3mmol) were stirred in DMA for 18 h. The reaction mixture was then partitioned between ethyl acetate and NaOH (1M), and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with water and brine₄Dried and concentrated. Purification by column chromatography (0-50% ethyl acetate: cyclohexane) gave the title compound [ A039] as a viscous pale yellow oil](2.15g，91％)。1H-NMR(1H,300MHz,CDCl₃) 5.30(1H, s),4.86-4.71(1H, m),4.47-4.32(1H, m),4.06-3.75(2H, m),3.85(3H, s),3.18(3H, s),3.18-2.85(2H, m),1.45(9H, s),1.42(9H, s). LCMS method 1, RT:3.46min, MI 374.26[ M + H [)]。

Synthesis of di-tert-butyl (R) -2-benzoyl-piperazine-1, 4-dicarboxylate [ A040]

To (R) -2- (methoxy-methyl-carbamoyl) -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A039] in THF at 0 deg.C](500mg, 1.34mmol) of a stirred solution phenylmagnesium chloride solution (3.4ml, 6.7mmol, 2.0M in THF) was added and the reaction mixture was allowed to warm to room temperature. After stirring for 4 hours, the solution was quenched (1N NaOH) and the solvent was removed in vacuo. The residue was partitioned between DCM and Rochelle (Rochelles) salt (10% in water), the organic phase was separated and the aqueous phase re-extracted with DCM. The combined organic phases were then dried (MgSO)₄) And concentrated. Purification by column chromatography (0-50% ethyl acetate: cyclohexane) gave the title compound [ A040] as a white solid](416mg，80％)。1H-NMR(1H,300MHz,CDCl₃) 7.89(2H, s, br),7.57(1H, s, br),7.47(2H, s, br),5.53(0.6H, s, br),5.35(0.4H, s, br),4.53-4.38(1H, m, br),4.06(0.6H, m, br),3.87-3.80(1.4H, m, br),3.67-3.53(1H, m, br),3.41-3.29(1H, m, br),2.94-2.81(1H, m, br),1.55-1.12(19H, m, br); LCMS method 1, RT 3.75min, MI391.32[ M + H ]]

Synthesis of di-tert-butyl (R) -2- (hydroxy-phenyl-methyl) -piperazine-1, 4-dicarboxylate [ A041]

To di-tert-butyl (R) -2-benzoyl-piperazine-1, 4-dicarboxylate [ A040] in methanol (4ml)](220mg, 0.553mmol) was added to the stirred solution sodium borohydride (41mg, 1.11 mmol). After two hours, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated and concentrated in vacuo to give the title compound [ A041 as a white crystalline solid](210mg，97％)。1H-NMR(1H,300MHz,CDCl₃) 7.43-7.26(5H, m),4.74(1H, s, br),4.31-3.65(4H, m),3.25-2.81(3H, m),1.55-1.46(18H, m),1.13(1H, s, br); LCMS method 1, RT 3.86min, MI 393.32[ M + H ] ]

Synthesis of di-tert-butyl (R) -2- (fluoro-phenyl-methyl) -piperazine-1, 4-dicarboxylate [ A042]

At 0 ℃ in CHCl₃(R) -2- (hydroxy-phenyl-methyl) -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A041) in (3ml)](210mg, 0.535mmol) of the stirred solution was added (diethylamino) sulfur trifluoride (330. mu.l, 2.68 mmol). After 2 hours, quench the reaction mixture with ice and NaHCO₃Basified (to pH8), then the product was extracted into DCM, which was evaporated to give a colorless oil. Purification was achieved by column chromatography (0-50% ethyl acetate: cyclohexane) to give the title compound [ A042] as a white solid](85mg，40％)。1H-NMR(1H,300MHz,CDCl₃) 7.34(5H, m, br),5.53(1H, d, br),4.38-3.84(4H, m, br),3.08-2.84(3H, m, br),1.49(9H, s, br),1.25(9H, s, br); LCMS method 1, RT 3.68min, MI 295.21[ M + H ]]

Synthesis of (R) -2- (fluoro-phenyl-methyl) -piperazine [ A036]

Di-tert-butyl (R) -2- (fluoro-phenyl-methyl) -piperazine-1, 4-dicarboxylate [ A042]](85mg, 0.215mmol) in 4N HCl: dioxane (2ml) was stirred. After 2 hours, the solution was dissolved in methanol and loaded into an SCX cartridge, which was washed with methanol followed by 2N NH₃: and (4) washing with methanol. Evaporation gave the title compound [ A036] as a yellow gum](35mg，83％)。1H-NMR(1H,300MHz,d4-MeOH):7.49-7.43(5H,m),5.25(1H,d),3.85(1H,dd),3.79-3.726(1H,m),3.20-3.14(2H,m),3.00-2.82(3H,m)。

Synthesis of (4-fluoro-phenyl) - (R) -piperazin-2-yl-methanol [ A043]

Synthesis of di-tert-butyl (R) -2- (4-fluoro-benzoyl) -piperazine-1, 4-dicarboxylate [ A044]

To (R) -2- (methoxy-methyl-carbamoyl) -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A043] in THF (24ml)](1.15g, 3.08mmol) of the stirred solution was added 4-fluorophenylmagnesium bromide solution (2.0M in Et₂7.7ml, 15.4mmol) of O), the reaction mixture was allowed to warm to room temperature. After stirring for 4 hours, the reaction was quenched (1N NaOH) and the solvent was removed in vacuo. The residue was partitioned between DCM and rochelle salt (10% aqueous solution). The organic phase was separated and the aqueous phase re-extracted with DCM. The combined organic phases were evaporated and subsequently purified by column chromatography (0-50% ethyl acetate: cyclohexane) to give the title compound [ A044] as a pale yellow oil](800mg，64％)。1H-NMR(1H,300MHz,CDCl₃) 7.94(2H, s, br),7.15(2H, s, br),5.47(1H, m, br),4.48-4.32(1H, m, br),4.07-4.03(1H, m, br),3.91-3.76(1H, m, br),3.61-3.51(1H, m, br),3.43-3.31(1H, m, br),3.18-3.24(1H, m, br),1.56-1.17(18H, m, br); LCMS method 1, RT 3.79min, MI 409.32[ M + H]

Synthesis of (R) -2- [ (4-fluoro-phenyl) -hydroxy-methyl ] -piperazine-1, 4-dicarboxylic acid di-tert-butyl ester [ A045]

To (R) -di-tert-butyl 2- (4-fluoro-benzoyl) -piperazine-1, 4-dicarboxylate [ A044] in methanol (8ml) at 0 deg.C](520mg, 1.28mmol) of the stirred solution sodium borohydride was added and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated and concentrated in vacuo to give a pale yellow oil. Purification by column chromatography (0-50% ethyl acetate: cyclohexane) gave the title compound [ A045] as a white crystalline solid](330mg，63％)。1H-NMR(1H,300MHz,CDCl₃):7.41-7.08(5H,m),4.74(1H,m),4.27-3.93(3H,m),3.64(1H,m),3.23-2.84(1H,m),1.45(18H,m),1.18(1H,s,br)。

Synthesis of (4-fluoro-phenyl) - (R) -piperazin-2-yl-methanol [ A043]

Reacting (R) -2- [ (4-fluoro-phenyl) -hydroxy-methyl]Di-tert-butyl (A045) piperazine-1, 4-dicarboxylate](330mg, 0.808mmol) in 4N HCl: dioxane (2ml) was stirred. After 2 hours, the solution was dissolved in methanol and loaded into an SCX cartridge, which was washed with methanol followed by 2N NH₃: and (4) washing with methanol. Evaporation gave the title compound [ A043] as a yellow gum]It was used without further purification (170mg, 100%).

Synthesis of N- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -carboxamide [78]

Reacting (S) -3-phenyl-N¹- (2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -Propane-1, 2-diamine [ 6]]A mixture of (70mg, 0.21mmol) and ethyl formate (1.5mL, 18.6mmol) was heated at 100 ℃ for 1 hour under microwave. The reaction mixture was concentrated in vacuo, redissolved in methanol and loaded onto a SCX-2 cartridge (5g) in methanol. The cartridge was washed with methanol (2Col Vols) and then with 2N NH in methanol₃(2CV) elution. Evaporation of the ammonia wash gave the title compound [78]: LCMS method 1, RT:3.87min, MI 385[ M + H ]]；NMR:(1H,300MHz,d6-dmso)9.17(1H,s),8.90-8.87(1H,br t),8.73(2H,d),8.63(1H,d),8.25(2H,dd),8.14(1H,d),8.04(1H,br d),7.97(1H,br s),7.327.20(5H,m),4.55-4.46(1H,m),3.98-3.90(1H,m),3.70-3.62(1H,m),3.00-2.93(1H,dd),2.85-2.77(1H,dd)

Synthesis of N- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -acetamide [79]

To (S) -3-phenyl-N at room temperature¹- (2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine [ 6]]A stirred solution of (70mg, 0.21mmol), DIPEA (73ul, 0.42mmol) and dry DCM (5mL) was added acetic anhydride (29. mu.l, 0.31 mmol). The reaction mixture was concentrated in vacuo, then redissolved in methanol plus formic acid (2 drops) and loaded onto a SCX-2 cartridge (5g) under methanol. The cartridge was washed with methanol (2CV) and then with 2N NH in methanol₃(2CV) elution. Evaporation of the ammonia wash gave the title compound [79]: LCMS method 1, RT 3.92min, MI 399[ M + H]；NMR:(1H,300MHz,d6-dmso)9.17(1H,s),8.85(1H,br t),8.72(2H,dd),8.63(1H,d),7.85(1H,dd),7.30-7.17(5H,m),4.43-4,33(1H,m),4.01-3.92(1H,m),3.63-3.55(1H,m),2.90(1H,dd),2.80(1H,dd),1.70(3H,s)

Synthesis of methyl [ (2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } prop-2-yl ] amine [80]

A stirred suspension of lithium aluminium hydride (19mg, 0.5mmol) in anhydrous THF (2.5mL) was cooled to 0 deg.C. N- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3, 4-d) in THF (2.5mL) was added over 5 minutes]Pyrimidin-4-ylamino) -ethyl]-carboxamides [78](40mg, 0.1 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. To the reaction mixture was added another portion of lithium aluminum hydride (10.5mg, 0.28mmol) and stirring was continued at room temperature for 18 hours. To the reaction mixture was added another portion of lithium aluminum hydride (30mg, 0.79mmol) and stirring was continued at room temperature for another 18 hours. In the second batch of N- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-ylamino) -ethyl]-carboxamides [78](40mg, 0.234mmol) and the crude reaction mixture was combined and diluted with ether (20mL), cooled to 0 deg.C and quenched by dropwise addition of water (approximately 150. mu.L), NaOH (approximately 300. mu.L of a 2M solution) and water (approximately 300. mu.L of a 2M solution) again. Adding MgSO₄The mixture was filtered and concentrated by rotary evaporation. The crude residue was purified by preparative HPLC (method a). The appropriate fractions were combined, the solvent was evaporated, the residue was dissolved in MeOD to precipitate the impurity, which was removed by filtration to give the title compound [80]](2.5 mg). LCMS method 1, RT:2.39min, MI 371[ M + H ]]。¹H NMR(1H,300MHz,d6-dmso)9.13(1H,s),8.64–8.62(2H,m),8.54(1H,d),8.21–8.19(2H,m),7.99(1H,d),7.32–7.21(5H,m),3.97–3.91(1H,m),3.78–3.71(1H,m),3.29–3.22(1H,m),3.05–2.99(1H,m),2.77–2.70(1H,m)。

(2S) -2-benzyl-4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -1-methylpiperazine; synthesis of formic acid [81]

Preparation is in CH₂Cl₂4- ((S) -3-benzyl-piperazin-1-yl) -5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d) in (2mL)]Pyrimidine [30 ]]Stirring the solution. Adding poly(s)Formaldehyde (55mg), acetic acid (6mL, 0.121mmol) and CNBH₃(180mg MP-CNBH₃The loading was 2mmol/g, 0.360mmol), and the reaction was shaken at room temperature overnight. The resin was filtered off and the product was loaded onto a CSX cartridge, washed with methanol and eluted with ammonia in methanol. The ammonia fraction was concentrated and the residue was purified by preparative LCMS. The appropriate fractions were combined and concentrated to give the title compound [81]]. LCMS method 1, RT:2.74min, MI427.22[ M + H ]]；¹H NMR(1H,300MHz,CDCl₃)8.95(s,1H),8.73–8.71(d,2H),8.29(s,1H),8.13-8.11(d,2H),8.06(s,1H),7.37–7.35(m,3H),7.22–7.19(m,2H),4.28(d,1H),4.07(d,1H),3.82(s,3H),3.72–3.63(m,1H),3.34(dd,1H),3.23–3.15(m,2H),2.76–2.69(m,1H),2.63(s,3H),2.60–2.51(m,2H)。

Synthesis of 2- { [ (2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } prop-2-yl ] amino } acetamide [82]

N- [ (2S) -2-amino-3-phenylpropyl group in DMF (5mL)]-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-amine [ 6]]A mixture of (100mg, 0.28mmol), 2-bromoacetamide (38.5mg, 0.28mmol) and potassium carbonate (77.5mg, 0.56mmol) was stirred at room temperature for 3 days. Another portion of 2-bromoacetamide (38.5mg, 0.28mmol) was added and the reaction mixture was stirred for an additional 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in methanol (2mL), filtered and subsequently purified by preparative HPLC (method B). The appropriate fractions were combined, evaporated, triturated with ether and dried in a vacuum oven to give the title compound [82]]：49min,MI 414[M+H]；¹H NMR(1H,300MHz,d6-dmso)9.16(1H,s),9.00(1H,br m),8.72–8.70(2H,m),8.64–8.62(1H,m),8.23–8.21(1H,m),8.10–8.08(2H,m),7.32–7.26(5H,m),7.03(1H,br s),3.89–3.81(1H,m),3.53–3.45(1H,m)。

Synthesis of N- (1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) methanesulfonamide [83]

At room temperature to CH₂Cl₂N- [ (2S) -2-amino-3-phenylpropyl group in (10mL)]-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-amine [ 6]](100mg, 0.28mmol) and DIPEA (98mL, 0.56mmol) was added methanesulfonyl chloride (22mL, 0.28 mmol). The reaction mixture was stirred at room temperature for 30 minutes, diluted with water and the organic phase was separated, over MgSO₄Drying, purifying by column chromatography on silica with 0-10% methanol in CH₂Cl₂And (4) eluting. The appropriate fractions were combined and concentrated to give the title compound [83]LCMS method 1, RT 4.04min, MI 435[ M + H ]]；¹H NMR(1H,300MHz,d6-dmso)9.18(1H,s),8.92(1H,br t),8.73–8.71(2H,m),8.65(1H,d),8.22–8.20(2H,m),8.16(1H,d),7.39(1H,br s),7.33–7.31(4H,m),7.30–7.24(1H,m),3.93–3.88(2H,m),3.69–3.61(1H,m),2.99–2.92(1H,m),2.83–2.76(1H,m),2.35(3H,s)。

Synthesis of (1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) urea [84]

N- [ (2S) -2-amino-3-phenylpropyl group in water (4mL)]-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-amine [ 6]]A mixture of (100mg, 0.28mmol), potassium cyanate (227mg, 2.8mmol) and acetic acid (4mL) was stirred at 50 ℃ for 3 hours. Another portion of potassium cyanate (227mg, 2.8mmol) was added and the reaction mixture was heated in a closed tube under microwave at 100 ℃ for 30 minutes. The reaction mixture was concentrated under vacuum and then partitioned between ethyl acetate and water. The target substance was found to partially precipitate on the inner surface of the separating funnel. The solid was collected, combined with the organic layer, evaporated to dryness, then dissolved in DMSO/methanol (1mL), the desired material began to precipitate, water (2mL) was added, the solid was collected by filtration, and the mixture was washed with waterDried in a vacuum oven to give the title compound [84]]: LCMS method 1, RT 4.54min, MI 398[ M + H ]]；.¹H NMR(1H,300MHz,d6-dmso)9.18(1H,s),8.99(1H,br t),8.74–8.72(2H,m),8.64(1H,d),8.28–8.25(2H,m),8.12(1H,d),7.32–7.19(5H,m),6.05(1H,d),5.48(2H,s),4.29–4.23(1H,m),3.88–3.80(1H,m),3.69–3.60(1H,m),2.94–2.88(1H,m),2.83–2.76(1H,m)。

Synthesis of 3-ethyl-1- (1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) urea [85]

Will be in CH₂Cl₂N- [ (2S) -2-amino-3-phenylpropyl group in (5mL)]-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-amine [ 6]]A solution of (100mg, 0.28mmol) and ethyl isocyanate (19mg, 0.27mmol) was stirred at room temperature for 1 hour. Concentrating the reaction mixture by rotary evaporation, purifying by column chromatography on silica with 0-10% methanol in CH₂Cl₂The residue was purified by elution. The appropriate fractions were combined, evaporated and the residue triturated with ether and then dried in a vacuum oven to give the title compound [85]]. LCMS method 1, RT 4.20min, MI 428[ M + H]；¹H NMR(1H,300MHz,d6-dmso)9.17(1H,s),8.94(1H,br t),8.74–8.72(2H,m),8.64(1H,d),8.28–8.24(2H,m),8.13(1H,d),7.32–7.20(5H,m),5.86(1H,d),5.79(1H,t),4.29–4.22(1H,m),3.90–3.83(1H,m),3.70–3.61(1H,m),2.94–2.77(2H,m),0.84(3H,t)。

(3aR) -5- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-1H- [1,3]Azolo [3,4-a ] s]Piperazin-1-one [86]Synthesis of (2)

(R) -2-benzyl-4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A046]

To 2-pyridin-4-yl-pyrido [2,3-d ] in DMA (93mL)]Pyrimidin-4-ol [ A003 ]](0.2g, 0.78mmol) was added sequentially to 2,4, 6-triisopropylbenzenesulfonyl chloride (0.26g, 0.86mmol), Et₃N (0.22mL, 1.57mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 2 hours, and (R) -2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.2g, 0.94mmol) was added. The reaction was stirred overnight and the solvent was removed under reduced pressure. The product was purified by flash chromatography using 0 to 8% methanol/DCM to give the title compound [ a046]](0.14g, 39% yield). LCMS method 1, RT 4.41min, MI 453.27[ M + H ]]。

(3aR) -5- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-1H- [1,3]Azolo [3,4-a ] s]Piperazin-1-one [86]

At 0 deg.C, will be in CH₂Cl₂(R) -2-hydroxymethyl-4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] of (A)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A046](20mg, 0.044mmol) was added dropwise to CH₂Cl₂(3mL) in a stirred solution of DAST (11mL, 0.088 mmol). The reaction mixture was warmed to room temperature and stirred overnight. Adding NaHCO₃Aqueous solution, organic phase separated, loaded on SCX cartridge, washed with methanol and eluted with ammonia in methanol. The product was purified by preparative HPLC (method a). The appropriate fractions were combined and concentrated to give the title compound [86]LCMS method 1, RT 2.95min, MI 379[ M + H ]]；¹H,NMR(1H,300MHz,CDCl₃):9.03(s,1H),8.60(d,2H),8.29(d,2H),8.24(s,1H),4.50(m,2H),4.18(d,1H),4.09(m,4H),3.97(dd,1H),3.31(td,1H),3.16(td,1H),3.10(dd,1H)。

Example [87] Synthesis of 2- {4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-1-yl } acetonitrile [87]

To 1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d in DMA (2mL)]Pyrimidin-4-yl]Piperazine [31 ]](90mg, 0.28mmol) and NEt₃(78mL, 0.56mmol) of the stirred mixture was added chloroacetonitrile (26mL, 0.42mmol) and the mixture was stirred at room temperature overnight. The crude reaction mixture was diluted with water and CH₂Cl₂(2X5mL) extraction, combine organic extracts and use saturated NaHCO₃(2X10mL), brine (10mL), over MgSO₄Dried, filtered and evaporated to give a brown oil which was purified by SXC-2 ion exchange (1g) to give the title compound as a pale yellow solid (0.085g, 90% yield). LCMS method 1, RT 4.90min, MI 362[ M + H ]]；¹H NMR(1H,300MHz,CDCl₃):9.02(1H,s),8.97–8.77(2H,m),8.36–8.34(2H,m),8.22(s,1H),4.11(3H,s),3.81(4H,brt),3.65(2H,s),2.83(4H,br t)。

General Synthesis scheme A2 for 2-substituted-piperazine derivatives of the general formula [ F-008b ]

By (R) -1, 1-dioxo-tetrahydro-2-oxa 1. lamda⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A049 ]]With phenol in a polar aprotic solvent such as DMF in the presence of a strong base such as sodium hydride or potassium cyanide to give the general formula [ F-008a]2-substituted piperazine derivatives of the general formula [ F-008b ]]The 2-substituted piperazine derivative of (1). Purification by chromatography is followed after work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange trap-release resins. Under acidic conditions with strong acids such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄The compound of formula [ F-008a ] is dissolved in a solvent such as DCM, DCE, THF, EtOH or MeOH]Deprotection of the N-Boc derivative of (a) and purification of the crude reaction product by normal phase silica gel chromatography or reverse phase preparative HPLC to give the general formula [ F-008b ]]The 2-substituted-piperazine derivative of (1).

Scheme A2

Synthesis of (R) -2-phenoxymethyl-piperazine [ A047]

(R) -1-oxo-tetrahydro-2-oxa-1 lambda⁴-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A048]

Preparation is in CH₂Cl₂(330mL) of a solution of (R) -3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (5.00g, 23.118mmol) and cooled to 0 ℃. Imidazole (6.295g, 92.472mmol) and triethylamine (7.06mL, 50.860mmol) were added, followed by dropwise addition over 20 minutes as in CH₂Cl₂Thionyl chloride (1.94mL, 26.586mmol) in solution (20 mL). The reaction mixture was allowed to warm to room temperature (without removing the ice bath) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water (250mL) and the organic phase was separated. By CH₂Cl₂The aqueous phase was extracted (3 × 50mL) and the combined organic fractions were washed over MgSO₄Dried, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica eluting with cyclohexane containing 0-50% ethyl acetate. The appropriate fractions were combined and concentrated to give the title compound as a pale yellow oil which solidified on standing [ A048](5.196g，86％)。¹H NMR(1H,400MHz,d6-dmso)4.81(1H,dd),4.58(1H,dd),4.44(1H,dd),4.28(1H,br d),4.12(1H,br d),4.02(1H,br d),3.93–3.87(2H,m),3.67–3.56(2H,m),3.46–3.34(2H,m),3.14–3.06(1H,d),3.01–2.69(4H,br m),2.55(1H,dt),1.42(s,9H),1.41(s,9H)。

(R) -1, 1-dioxo-tetrahydro-2-oxa-1. lambda⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A049 ]]

Preparation of non-woven fabric under nitrogen(R) -1-oxo-tetrahydro-2-oxa-1. lambda. in Water MeCN (25mL)⁴-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A048](2.99g, 11.409mmol) was stirred and cooled to 0 ℃. Sodium (meta) periodate (2.464g, 11.523mmol) was added followed by ruthenium (III) chloride hydrate (24mg, 0.114mmol) (the reaction mixture turned brown) and water (25 mL). The reaction mixture was stirred at 0 ℃ for 10 minutes, then removed from the ice bath and stirred at room temperature for 10 minutes. TLC showed complete conversion to a new, slightly more polar spot. The reaction mixture was washed with saturated NaHCO₃(aqueous solution) (100mL) diluted and CH₂Cl₂Extraction (3 × 40 mL). The combined organic extracts were dried and concentrated by rotary evaporation. The residue was purified by chromatography on silica eluting with cyclohexane containing 0-50% ethyl acetate to give the title compound [ A049 ] as a pale yellow solid](1.72g，54％)。¹H NMR(1H,500MHz,CDCl₃)4.63(1H, dd,) 4.25-4.07(3H, overlapping t and width m),3.67-3.61(1H, m),3.45(1H, br.d, J ═ 11.2Hz),3.13(1H, br.s),2.98-2.94(2H, br.m),1.47(9H, s).

(R) -3-phenoxymethyl-piperazine-1-carboxylic acid tert-butyl ester [ A050]

Preparation of (R) -1, 1-dioxo-tetrahydro-2-oxa-1. lamda in anhydrous DMF (5mL) under nitrogen⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A049 ]](200mg, 0.719 mmol). Sodium phenolate (88mg, 0.754mmol) was added and the reaction mixture was heated to 50 ℃ overnight. An additional 0.25 equivalents of sodium phenolate was added and heating was continued for an additional 5 hours. The reaction mixture was cooled to room temperature and 2mL of 2M HCl (aq) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was loaded onto a 10g SCX cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia fractions were combined and concentrated under reduced pressure. Purifying the residue by chromatography on silica with CH containing 0-10% methanol₂Cl₂And (4) eluting. The appropriate fractions were combined and concentrated to give the title compound [ a 00?](75mg, 36%). LCMS method 1, RT 2.85min, MI 293[ M + H ]]；¹H NMR(1H,500MHz,CDCl₃)7.31–7.24(2H,m),6.97(1H,t),6.91(2H,d),4.05(1H,br s),3.97–3.95(2H,m),3.88–3.85(1H,m),3.09(1H,br s),3.04–3.01(1H,br m),2.96–2.91(1H,br m),2.83–2.74(1H,br m),2.74(1H,br s),2.14(1H,br s)1.48(9H,s)。

(R) -2-phenoxymethyl-piperazine [ A047]

Preparation of (R) -3-phenoxymethyl-piperazine-1-carboxylic acid tert-butyl ester in Anhydrous dioxane (1mL) [ A050](98mg, 0.332mmol) and 4M HCl in dioxane (5mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated by rotary evaporation to give a pale pink solid. The product was dissolved in methanol and loaded onto an SCX cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia fraction was concentrated by rotary evaporation to give the title compound as an off-white oil which crystallized on standing [ A047](58mg, 91%). LCMS method 1, RT 0.56min, MI 193[ M + H ]]；¹H NMR(1H,500MHz,CDCl₃)7.30–7.27(2H,m),6.97–6.94(1H,m),6.91–6.90(2H,m),3.92–3.90(1H,m),3.83–3.83(1H,m),3.17–3.12(1H,m),3.07–3.03(2H,m),2.99–2.96(1H,m),2.92–2.87(1H,m),2.84–2.79(1H,m)2.63(1H,dd)。

Synthesis of (R) -2- (2-fluoro-phenoxymethyl) -piperazine [ A051]

(R) -3- (2-fluoro-phenoxymethyl) -piperazine-1-carboxylic acid tert-butyl ester [ A052]

A suspension of sodium hydride (69mg, 1.726mmol) in anhydrous DMF (5mL) was prepared and 2-fluorophenol (0.15mL, 1.726mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes, then (R) -1, 1-dioxo-tetrahydro-2-oxa-1. lambda. was added⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A051](400mg, 1.438 mmol). The reaction mixture was heated to 50 ℃ overnight. The reaction mixture was cooled to room temperature and 2M HCl (aq) (1.4mL, 2.875mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Loading reaction mixture into SCX cartridgesAbove, it was washed with methanol and eluted with 7N ammonia in methanol. The ammonia fractions were combined and concentrated by rotary evaporation. Purifying the residue by chromatography on silica with CH containing 0-10% methanol₂Cl₂And (4) eluting. The appropriate fractions were combined and concentrated to give the title compound [ A052 as a colorless oil](318mg, 71%). LCMS method 1, RT:2.92min, MI311[ M + H]；¹H NMR(1H,500MHz,CDCl₃) 7.10-7.04 (2H, m), 6.99-6.91 (2H, m), 4.04-3.89 (4H, m and overlapping br s), 3.14-3.11 (1H, m),3.03(1H, br d),2.96(1H, br t), 2.83-2.79 (1H, m),2.75(1H, br s),2.23(1H, br s),1.48(9H, s).

(R) -2- (2-fluoro-phenoxymethyl) -piperazine [ A051]

Following the procedure described in scheme a2, (R) -3- (2-fluoro-phenoxymethyl) -piperazine-1-carboxylic acid tert-butyl ester [ a052 was treated with 4M HCl in dioxane (2mL)](310mg, 1.00mmol) to give the title compound [ A051 as a pale yellow oil](196mg, 93%). LCMS method 1, RT 0.75min, MI 211[ M + H ]](ii) a LCMS method 1LCMS5, RT:0.75min, MI:211[ M + 1]]。¹H NMR(1H,500MHz,CDCl₃)7.10–7.03(2H,m),6.98–6.89(2H,m),4.00–3.97(1H,m),3.91–3.88(1H,m),3.23–3.18(1H,m),3.08–3.03(2H,m),3.00–2.98(1H,m),2.94–2.89(1H,m),2.85–2.80(1H,m),2.66–2.61(1H,m)。

Synthesis of (R) -2- (4-fluoro-phenoxymethyl) -piperazine [ A053]

(R) -3- (4-fluoro-phenoxymethyl) -piperazine-1-carboxylic acid tert-butyl ester [ A054]

Following the procedure described in scheme A2, step 1, (R) -1, 1-dioxo-tetrahydro-2-oxa-1. lamda. (R-O-O⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A048](400mg, 1.438mmol) was reacted with 4-fluorophenol (193mg, 1.726mmol) to give the title compound [ A054] as a colorless oil](100mg, 22%). LCMS method 1, RT 3.00min, MI311[ M + H]；.¹H NMR(1H,500MHz,CDCl₃)6.99–6.96(2H,m),6.85–6.83(2H,m),4.06(1H,brs),3.95(1H,br s),3.95–3.90(1H,m),3.84–3.80(1H,m),3.10–3.05(1H,m),3.03(1H,brd),2.93(1H,br t),2.83–2.78(1H,m),2.72(1H,br s),2.10(1H,br s),1.48(9H,s)。

(R) -2- (4-fluoro-phenoxymethyl) -piperazine [ A053]

(R) -3- (4-fluoro-phenoxymethyl) -piperazine-1-carboxylic acid tert-butyl ester [ A054] was treated with 4M HCl in dioxane (2mL) following the procedure described in example A2 step 4](100mg, 0.322mmol) to give the title compound [ A053] as a colorless oil which solidified on standing](68mg, 100%). LCMS method 1, RT 0.59min, MI 211[ M + H ]]；¹HNMR(1H,500MHz,CDCl₃)6.99–6.95(2H,m),6.85–6.82(2H,m),3.88–3.86(1H,m),3.81–3.78(1H,m),3.15–3.10(1H,m),3.05–3.02(2H,m),2.98–2.96(1H,m),2.91–2.86(1H,m),2.83–2.78(1H,m),2.63–2.58(1H,m)。

Synthesis of (S) -piperazin-2-yl-acetonitrile [ A055]

(S) -3-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester [ A056]

Following the procedure described in scheme A1, step 3, (R) -1, 1-dioxo-tetrahydro-2-oxa-1. lamda. (R-O-O⁶-thia-5, 7 a-diaza-indene-5-carboxylic acid tert-butyl ester [ A048](1.52g, 5.46mmol) was reacted with KCN (356mg, 5.46mmol) to give the title compound [ A056]](850mg，69％)。¹H NMR(1H,500MHz,CDCl₃)3.95(1H, br s),3.84(1H, br d), 3.03-2.92 (3H, m), 2.82-2.75 (1H, m),2.70(1H, br s), 2.51-2.41 (2H, m),1.49(9H, s). LCMS method 1, RT 1.39min, MI 226[ M + H]。

(S) -piperazin-2-yl-acetonitrile [ A055]

Following the procedure described in exemplary scheme A2, step 4, (S) -3-cyanomethyl-piperazine-1-carboxylic acid was treated with 4M HCl in dioxaneTert-butyl ester [ A056]](800mg, 3.55mmol) to give the title compound [ A055 as a pale orange solid](434mg, 98%). LCMS method 1, RT 0.49min, MI 126[ M + H ]]；¹H NMR(1H,500MHz,CDCl₃)3.06–2.99(3H,m),2.93–2.90(1H,m),2.87–2.82(1H,m),2.77–2.72(1H,m),2.56–2.51(1H,m),2.44–2.42(2H,m)。

Synthesis of phenyl- (S) -piperidin-3-yl-amines [ A057]

(S) -3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester [ A058]

Preparation of (S) -3-amino-piperidine-1-carboxylic acid tert-butyl ester (500mg, 2.497mmol), Pd in toluene (5mL) under nitrogen₂(dba)₃(95mg, 0.104mmol) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (61mg, 0.156 mmol). The solvent was degassed and sodium tert-butoxide (280mg, 2.912mmol) was added followed by bromobenzene (0.22mL, 2.080 mmol). The reaction mixture was heated to 100 ℃ for 24 hours. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. The residue was filtered through a silica plug and CH was used₂Cl₂And (4) eluting. The eluate was concentrated by rotary evaporation. The crude residue was purified by chromatography on silica eluting with 5-50% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated to give the title compound as a pale yellow oil which solidified on standing [ A058](535mg, 78%). LCMS method 1, RT 5.51min, MI 227[ M + H ]]；¹H NMR(1H,500MHz,CDCl₃)7.20–7.17(2H,m),6.71(1H,t),6.64(2H,d),4.02(1H,br s),3.74–3.70(1H,m),3.63(1H,br s),3.39(1H,br m),3.09(1H,br m),2.89(1H,br s),2.02–1.99(1H,m),1.78–1.73(1H,m),1.59–1.51(2H,m),1.46(9H,s)。

Phenyl- (S) -piperidin-3-yl-amines [ A057]

(S) -3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester [ A058] (138mg, 0.5mmol) was treated with 4M HCl in dioxane (2mL) according to the procedure described in scheme A2 step 4 to give the title compound [ A057] (85mg, 97%) as a pale yellow oil. LCMS method 1, RT:0.96min, MI 177[ M + H ].

General Synthesis scheme A3 for 8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-011]

General formula [ F-010]4-substituted 8-chloro-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ F-009]8-chloro-2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP in a polar aprotic solvent such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -8-chloro-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidin-4-yl esters with the general formula [ F-003 ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the crude reaction product is purified by normal phase chromatography or reverse phase preparative HPLC. By the general formula [ F-012 ]]With suitable boric acid or borate, palladium catalysts such as Pd (PPh)₃)₄Or Pd (PPh)₃)₂Cl₂Bases such as Et₃N、KOH、Na₂CO₃Or NaOH in a polar solvent such as EtOH, THF, DMA or dioxane, at elevated temperatures obtained by heating or using a microwave reactor]4-substituted 8-chloro-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivatives are reacted in a reaction of the Suzuki type. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase chromatography or reverse phase preparative HPLC.

Scheme A3

Synthesis of N- {3- [4- ((S) -2-amino-3-phenyl-propylamino) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-8-yl ] -phenyl } -methanesulfonamide [88]

[ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -carbamic acid tert-butyl ester [ A059]

To 2-pyridin-4-yl-pyrido [2,3-d ] in DMA (15mL)]Pyrimidin-4-ol [ A005 ]](1g, 3.8mmol) solution was added sequentially 2,4, 6-triisopropylbenzenesulfonyl chloride (1.3g, 4.25mmol), Et₃N (1.1mL, 7.73mmol) and DMAP (0.1 g). The mixture was stirred at room temperature for 1 hour, then ((S) -2-amino-1-benzyl-ethyl) -carbamic acid tert-butyl ester (1.16g, 4.64mmol) was added. The reaction was stirred overnight, the solvent was removed under reduced pressure, and the crude mixture was purified by flash chromatography (SP1[ eluent: DCM/methanol: 1/0 then 95/5 then 9/1 ]]) To obtain the title compound: LCMS method 1, RT 5.76min, MI 492[ M + H ]]

N- {3- [4- ((S) -2-amino-3-phenyl-propylamino) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-8-yl ] -phenyl } -methanesulfonamide [88]

Microwave vials were loaded with [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.07g, 0.142mmol), 3- (Methanesulfonylamino) phenylboronic acid pinacol ester (0.06g, 0.2mmol), Pd (Ph)₃P)₄(0.017g，0.014mmol)、K₃PO₄Aqueous solution (0.5M, 0.57mL, 0.28mmol) and DMA (1 mL). The vial was heated under microwave irradiation (150 ℃,10 minutes). The solvent was removed under reduced pressure. The crude product is purified by column chromatography (eluent: DCM/methanol: 1:0 to 9/1)And (5) preparing the product. The purified compound was dissolved in DCM (2mL) and TFA (0.5mL) was added. The solution was stirred for 3 hours and then poured onto a SCX2 column, washed with methanol using the solution methanol/NH₃2M released the expected product, which was used without further purification, to give the title compound [88]: LCMS method 1, RT 3.01min, MI526[ M + H ]]；NMR 1H(1H,300MHz,d6-dmso)8.70(d,2H),8.68(d,1H),8.25(d,2H),8.14(d,1H),8.04(d,2H),7.37-7.24(m,7H),3.91-3.86(m,1H),3.46-3.33(m,2H),3.10(s,3H),2.77-2.69(m,2H)。

The following compounds were synthesized following the general synthesis shown in scheme [ a3 ]:

general Synthesis scheme A4 for 8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4d ] pyrimidine derivatives of general formula [ F011]

In Stille type reactions, the general formula [ F013 ] is utilized]Suitable stannane, palladium catalysts such as Pd (PPh)₃)₄Or Pd (PPh)₃)₂Cl₂Bases such as K₃PO₄In polar solvents such as DMA or dioxane, at elevated temperatures obtained by heating or using microwave reactorsBy the general formula [ F-010]4-substituted 8-chloro-2-pyridin-4-yl-pyrido [3,4-d]Reaction of pyrimidine derivatives to prepare compounds of the general formula [ F011]]8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]A pyrimidine derivative. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC.

Scheme A4

(R) -3-phenyl-N¹- (2-pyridin-4-yl-8-pyridin-2-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine [122]Synthesis of (2)

(R) -3-phenyl-N¹- (2-pyridin-4-yl-8-pyridin-2-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine [122]

Microwave vials were loaded with [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.07g, 0.142mmol), 2- (tributylstannyl) pyridine (0.068g, 0.185mmol), Pd (Ph)₃P)₄(0.016g, 0.014mmol), LiCl (0.018g, 0.428mmol) and DMA (1.5 mL). The mixture was heated under microwave irradiation (150 ℃ C., 10 minutes) and the solvent was removed under reduced pressure. The crude product is purified by column chromatography (eluent: DCM/methanol: 1:0 to 9: 1). The purified compound was dissolved in DCM and 0.5mL of TFA was added. The solution was stirred for 3 hours and then poured onto an SCX column, washed with methanol using methanol/NH₃2M solution releases the expected product, the base is concentrated under reduced pressureAn organic solvent to give the title compound as a yellow solid, which was used without further purification: LCMS method 1, RT:2.34min, MI 434[ M + H]；¹H NMR(1H,500MHz,CDCl₃)；8.70-8.76(m,2H),8.63(d,2H),8.42(brs,1H),8.27(d,1H),7.96(dd,1H),7.93(m,1H),7.81(d,2H),7.50(td,1H),7.32-7.52(m,5H),4.00(d,1H),3.51-3.60(m,2H),3.01(dd,1H),2.83(dd,1H)。

General Synthesis scheme A5 for 8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-014]

In a Buchwald type reaction, the general formula [ F-015] is utilized]Suitable amine, palladium catalysts such as Pd (dba)₂Or Pd (OAc)₂Ligands such as Xantphos and bases such as NaOtBu or Cs₂CO₃In a polar solvent such as dioxane or a combination of dioxane and DMA, at elevated temperatures obtained by heating or using a microwave reactor, by the general formula [ F-010]4-substituted 8-chloro-2-pyridin-4-yl-pyrido [3,4-d]Reaction of pyrimidine derivatives to prepare [014 ]]8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]A pyrimidine derivative. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography and deprotection of the N-Boc derivative with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1, 4-dioxane under acidic conditions, or by capture and release of a sulfonic acid resin such as polymer-supported toluenesulfonic acid, the crude reaction product is purified by normal phase chromatography or reverse phase preparative HPLC.

N⁴- ((R) -2-amino-3-phenyl-propyl) -N⁸-phenyl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamines [123 ]]Synthesis of (2)

N⁴- ((R) -2-amino-3-phenyl-propyl) -N⁸-phenyl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamines [123 ]]

Sequential addition of [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ] in a microwave vial]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.05g, 0.1mmol), aniline (0.015g, 0.15mmol), Pd (dba)₂(0.003g, 0.005mmol), Xantphos (0.006g, 0.01mmol), sodium tert-butoxide (0.02g, 0.2mmol) and dioxane (1.3 mL). The microwave vial was heated under microwave (150 ℃,10 minutes). The solvent was then removed under reduced pressure, DCM (2mL) and TFA (0.5mL) were added sequentially, and the solution was stirred for 3 hours. The solution was poured onto a SCX2 column and washed with methanol. Using 2M NH₃The methanol solution released the compound, which was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (method a) to give the title compound [123 []: LCMS method 1, RT:3.53min, MI 448[ M + H ]](ii) a NMR (1H,300MHz, d6-dmso) peaks may be below the solvent peaks at 2.5 and 3.3 ppm. 9.35(s,1H),8.71(d,2H),8.35(d,2H),8.03-8.08(m,3H),7.46(d,1H),7.27-7.38(m,7H),7.02(t,1H),3.86(d,1H),2.70-2.78(m, 2H).

The following compounds were synthesized following the general synthesis shown in scheme [ a5 ]:

general Synthesis scheme A6 for 8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-014]

8-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of the general formula [ F-014] are prepared by reaction of 4-substituted 8-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of the general formula [ F-010] in a polar aprotic solvent such as DMA or DMF at elevated temperature obtained by heating or using a microwave reactor using a suitable amine [ method A ], thiol [ method B ] or phenol of the general formula [ F-015] method C ], and a base such as NaH in a nucleophilic aromatic substitution type reaction. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography and deprotection of the N-Boc derivative with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1, 4-dioxane under acidic conditions, or by capture and release of a sulfonic acid resin such as polymer-supported toluenesulfonic acid, the crude reaction product is purified by normal phase chromatography or reverse phase preparative HPLC.

Scheme A6

(R)-N¹- [8- (4-methyl-piperazin-1-yl) -2-pyridin-4-yl-pyrido [3,4-d]Pyrimidin-4-yl]-3-phenyl-propane-1, 2-diamine [127 ]]Synthesis of (2)

(R)-N¹- [8- (4-methyl-piperazin-1-yl) -2-pyridin-4-yl-pyrido [3,4-d]Pyrimidin-4-yl]-3-phenyl-propane-1, 2-diamine [127 ]]

Microwave vials were loaded with [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.07g, 0.142mmol), N-methylpiperazine (0.031mL, 0.285mmol) and DMA (2 mL). The solution was heated under microwave (150 ℃,10 minutes). An additional 2 equivalents of N-methylpiperazine (0.031mL, 0.285mmol) were added and the vial was again heated under microwave (150 ℃ C., 10 min). The solvent was removed under reduced pressure and DCM (2mL) and TFA (0.5mL) were added sequentially. The solution was stirred for 3 hours and then poured onto a SCX-2 column, washed with methanol using the solution methanol/NH₃2M released the expected product. The crude product was then purified by preparative HPLC (method A) to give the title compound [127 ]]: LCMS method 1, RT 1.55min,MI 455[M+H]；NMR(1H,300MHz,d6-dmso):9.17(brs,1H),8.86(d,2H),8.30(s,3H),8.10(d,1H),7.86(d,2H),7.48(d,1H),7.35-7.41(m,5H),3.83-4.04(m,5H),3.66-3.76(m,1H),3.54-3.64(m,1H),3.12(dd,1H),2.86(dd,1H),2.67-2.72(m,4H),2.53(s,3H)。

(R) -3-phenyl-N¹- (8-phenylthio-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine [128 ]]Synthesis of (2)

(R) -3-phenyl-N¹- (8-phenylthio-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine [128 ]]

To a suspension of NaH (60% in mineral oil, 0.008g, 0.2mmol) in DMF (2mL) was added thiophenol (0.02g, 0.185 mmol). The mixture was stirred for 1 hour and [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ] was added]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.07g, 0.142 mmol). The mixture was stirred overnight and water (0.3mL) was added. The solvent was removed under reduced pressure and DCM (2mL) and TFA (0.5mL) were added sequentially. The solution was stirred for 3 hours and then poured onto a SCX-2 column, washed with methanol using the solution methanol/NH₃2M released the expected product. The crude product was then purified by preparative HPLC (method a) to give the title compound [128]: LCMS method 1, RT 4.06min, MI465[ M + H ]]；NMR(1H,300MHz,d6-dmso):9.38(brs,1H),8.72(d,2H),8.23(s,3H),8.03(d,2H),7.89(d,1H),7.58-7.61(m,2H),7.36-7.47(m,6H),3.98(d,1H),3.56-3.73(m,2H),3.05(dd,1H),2.87(dd,1H)。

The following compounds were synthesized following the general synthesis shown in scheme [ a6 ]:

synthesis of 4- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) -2-methylbut-3-yn-2-ol [ [131]

4- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) -2-methylbut-3-yn-2-ol [ [131]

Microwave vials were loaded with [ (S) -1-benzyl-2- (8-chloro-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ A059](0.05g，0.1mmol)、Pd(PPh₃)₂Cl₂(0.007g, 0.01mmol), CuI (0.002g,0.01mmol), 2-methyl-3-butyn-2-ol (0.035g, 0.037mmol), triphenylphosphine (0.005g, 0.02mmol), triethylamine (0.2mL) and DMF (0.8 mL). The vial was heated under microwave (150 ℃,10 minutes). The solvent was removed under reduced pressure, DCM (2mL) and TFA (1mL) were added, and the mixture was stirred for 3 hours. The solution was poured onto a SCX2 column and washed with methanol. Using 2M NH₃The methanol solution released the compound, which was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (method a) to give the title compound [131]: LCMS method 1, RT 3.12min, MI 439[ M + H]；NMR(1H,300MHz,d6-dmso):8.71(d,2H),8.56(d,1H),8.31(brs,1H),8.15(d,1H),8.08(d,2H),7.41-7.31(m,5H),3.97-3.92(m,1H),3.59-3.50(m,2H),2.99-2.90(m,1H),2.86-2.79(m,1H),1.59(s,6H)。

General Synthesis scheme A7 for substituted 5-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-001]

General formula [ F-004]2-pyridin-4-yl-pyrido [3,4-d of]The pyrimidin-4 alcohol was prepared as follows: a compound of the general formula [ F-016 ] is prepared in a polar aprotic solvent such as DMA or DMF using a suitable coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)]O-halo-isonicotinic acid derivatives of the general formula [ F-018 [ ]]To the appropriately substituted 4-formamidinyl-pyridine. Then the general formula [ F-017]Cyclizing the isonicotinoyl-amidine derivative so as to displace the relevant halogen group, to give the desired general formula[F-004]2-pyridin-4-yl-pyrido [3,4-d of]A pyrimidin-4-ol derivative. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ F-004]2-pyridin-4-yl-pyrido [3,4-d of]Reacting the pyrimidin-4-ol derivative with a chlorinating agent such as phosphoryl chloride, and then reacting the intermediate 4-chloro derivative with the general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature [ method A ]]. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine derivatives represented by the general formula [ F-004 ]]2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM with catalytic amounts of DMAP in polar aprotic solvents such as DMA, DMF, NMP [ method B ]]. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2-pyridin-4-yl-thieno [3,2-d]Pyrimidin-4-yl esters with general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme A7

Synthesis of 5-chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [132]

Synthesis of 3, 5-dichloro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ A060]

3, 5-dichloro-isonicotinic acid (10.4mmol, 1.997g) was dissolved in anhydrous DMF (50mL) at room temperature, HATU (10.4mmol, 3.95g) was added in one portion, and the mixture was stirred for 5 min. DIPEA (28.6mmol, 5.0mL) was then added in one portion and the reaction stirred for 40 min. Pyridine-4-carboxamidine hydrochloride (9.52mmol, 1.5g) was added in one portion and the reaction stirred at room temperature for 18 h.

The reaction mixture was then poured into water (total-250 mL, including the rinse of the reaction vessel) in an Erlenmeyer flask. The resulting mixture was stirred at room temperature for 90 minutes, and the precipitate formed was filtered and washed with water (x2) and diethyl ether (x 2). The solid was then dried in a vacuum oven for 4 hours to give the title compound [ a060] (2.359g) as a pale brown powder. LCMS method 1, RT 3.31min, MI 295[ M + H ].

Synthesis of 5-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A061]

In a 25mL Biotage microwave vessel under nitrogen was added 3, 5-dichloro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ a060] (1.5mmol, 0.443g), cesium carbonate (3.0mmol, 0.978g) and N, N' -dibenzylethylenediamine (0.3mmol, 0.071 mL). The mixture was stirred vigorously in anhydrous DMA (10mL) and iron (III) chloride (0.15mmol, 0.024g) was added in one portion. The mixture was then heated in a microwave at 120 ℃ for 90 minutes. The reaction was allowed to cool to room temperature, acetic acid (12.0mmol, 0.69mL) was added dropwise over about 5 minutes, and the resulting mixture was diluted with methanol (10mL) and stirred at room temperature for 30 minutes. The mixture was added to a 10g SCX-2 cartridge and washed with methanol (. about.25-30 mL). The cartridge was then washed with ammonia (2N in methanol, 40mL) and the ammonia wash was concentrated in vacuo to give 5-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one (130 mg). The non-alkaline methanol wash of the SCX-2 cartridge was allowed to stand overnight to form a precipitate. It was filtered, washed with methanol (x1) and dried in a vacuum oven overnight to give the title compound [ a061] as an off-white solid (13 mg). LCMS method 1, RT 2.12min, MI 259[ M + H ].

Synthesis of 4- (5-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A062]

5-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A061] (0.553mmol, 0.143g) was suspended in anhydrous DCM (14mL) at room temperature under nitrogen, and triethylamine (1.38mmol, 0.193mL), DMAP (about 0.005g), and 2,4, 6-triisopropylbenzenesulfonyl chloride (0.663mmol, 0.201g) were added in that order. The reaction of the off-white suspension was stirred at room temperature for 2 hours. The mixture slowly turned into a pale green suspension which was stirred overnight. Pyridine (4mL) was then added and the reaction vessel was sonicated for 5 minutes in an attempt to improve the solubility which caused the reaction to change from a green to brown suspension. The resulting mixture was stirred at room temperature for 1 hour. Boc-piperazine (0.608mmol, 0.113g) was added in one portion and the mixture was stirred for 18 h.

The reaction was diluted with water and extracted with DCM (× 3). The combined organic phases were washed with brine (× 1) and dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound [ A062]It was used without further purification for the next reaction: LCMS method 1, RT 5.69min, MI427 [ M + H ]]。

Synthesis of 5-chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [132] to a solution of tert-butyl 4- (5-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylate [ a062] (0.47mmol, 0.201g) in anhydrous DCM (8mL) at room temperature was added HCl (4.0N in dioxane, 2mL) to give an orange suspension which was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo, redissolved in DCM/methanol (1:1, ca. 6mL), and added to a cartridge of SCX-210 g. The cartridge was washed with DCM and methanol (ca. 35mL, each at 2: 3). The cartridge was then washed with ammonia in methanol (2N, 40mL) and the ammonia wash was concentrated in vacuo to give 92mg of a brown oil. The crude material was purified by column chromatography (SP 14g VWR column, 15 volumes of 0-20% methanol in DCM) to give the title compound [138] (0.044g) as an orange-yellow foam. LCMS method 1, RT:1.60min, MI 327[ M + H ]; NMR (1H,300MHz, d 6-dmso); 9.15(1H, s),8.77(2H, d),8.61(1H, s),8.29(2H, d),3.69(4H, br s),2.85(4H, br s)

Synthesis of 5, 8-dichloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A063]

2,3, 5-trichloro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ a064] was prepared by reaction of 2,3, 5-trichloro-isonicotinic acid, pyridine-4-formamidine hydrochloride, HATU, DIPEA and DMF at room temperature to give the title compound. LCMS method 1, RT 4.37min, MI 330[ M + H ]; NMR (1H,300MHz, d 6-dmso); 10.24(1H, br s),10.14(1H, br s),8.75(2H, d),8.60(1H, s),7.89(2H, d).

By 2,3, 5-trichloro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ A064]、FeCl₃、Ce₂CO₃HCl (4N in dioxane) and DMA are reacted in a microwave at 120 ℃ for 2 hours to produce 5, 8-dichloro-2-pyridin-4-yl-3H-pyrido [3,4-d]Pyrimidin-4-ones [ A063]. The reaction mixture was cooled, water (0.5mL) was added, followed by methanol (2mL) and HCl (4 eq wrt carbonate, 2.4mmol, 4N HCl in 0.6mL dioxane) and the mixture was stirred for 10 min. The yellow precipitate was collected by filtration and the solid was washed with methanol (2x, 2mL) and then dried in a vacuum oven to give the title compound as a yellow solid (51mg, 56% yield): LCMS method 1, RT 4.80min, MI 293[ M + H]；NMR:(1H,300MHz,d6-dmso)；13.36(1H,br s),8.92(2H,d),8.49(1H,s),8.14(2H,br d)。

Synthesis of 3-bromo-5-fluoro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ A065]

By 3-bromo-4-carboxy-5-fluoro-pyridineReaction of hydrochloride, pyridine-4-carboxamidine hydrochloride, HATU, DIPEA and DMF at room temperature to prepare 2-bromo-5-fluoro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ a066]To give the title compound. LCMS method 1, RT 3.20min, MI 325[ M + H ]]。

Reacting 2-bromo-5-fluoro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ A066](0.05g，0.155mmol)、DMA(0.5mL)、K₂CO₃(0.022g, 0.16mmol), DIPEA (0.28mL, 0.16mmol) and DBA (0.024mL, 0.16mmol) were heated in a microwave at 150 ℃ for 45 minutes. The crude reaction mixture was evaporated under reduced pressure and purified by column chromatography (SP 14 gVWR column in 0.5% Et₃N/DCM/0-20% methanol) to give the title compound as an orange-yellow foam [ a065]](0.044g, 80% yield): LCMS method 1, RT 11.57min, MI 304[ M + H ]]。

The following compounds were synthesized following the general synthesis shown in scheme [ a 7]:

general Synthesis scheme A8 for substituted 5-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-001]

By the general formula [ F-019]Dihalogenated isonicotinic acid derivatives of the general formula [ F-021]In a polar aprotic solvent such as THF or Et₂Reaction in O to prepare [ F-020 [ ] -]O-halo-isonicotinic acid derivatives of (a). General formula [ F-004]2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives are prepared by reacting [ F-020 ] with a suitable coupling agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)]O-halo-isonicotinic acid derivatives of the general formula [ F-018 [ ]]Is prepared by coupling the appropriately substituted 4-carbamimidoyl-pyridine in a polar aprotic solvent such as DMA or DMF. General formula [ F-022]Cyclizing the isonicotinyl-amidine derivative to replace the relevant halogen group to give the desired general formula [ F-004]Is-pyridin-4-yl-pyrido [3,4-d]A pyrimidin-4-ol derivative. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ F-004]2-pyridin-4-yl-pyrido [3,4-d of]Reacting the pyrimidin-4-ol derivative with a chlorinating agent such as phosphoryl chloride, and then reacting the intermediate 4-chloro derivative with the general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature [ method A ]]. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine derivatives represented by the general formula [ F-004 ]]2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and catalytic amounts of DMAPMF, NMP reaction and preparation [ method B]. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2-pyridin-4-yl-thieno [3,2-d]Pyrimidin-4-yl esters with general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme A8

Synthesis of 5-butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [135]

Synthesis of 3-butyl-5-fluoro-isonicotinic acid [ A067]

Under nitrogen, 3, 5-difluoro-isonicotinic acid (0.557g, 3.5mmol) was suspended in anhydrous THF (8mL) at 0 ℃. Butylmagnesium chloride (2.0M in ether, 5.25mL, 10.5mmol) was added dropwise over 10 minutes. The suspension slowly changes form during slow addition, forming a preliminary solid cake, then the solid begins to slowly dissolve, becoming a full solution near the completion of reagent addition. The reaction mixture was allowed to warm to room temperature and stirred for over 72 hours to form a thick yellow suspension. Diluted with water, transferred to a single-necked flask and concentrated in vacuo. The yellow solid was diluted with water (10mL) and ethyl acetate (10 mL). The pH was adjusted to pH 2 by dropwise addition of HCl (conc.) and extracted with ethyl acetate (x 3-part of the yellow color into the organic phase). The combined organic phases were washed with brine (× 1) and dried (MgSO)₄) And concentrated in vacuo to give the title compound [ A067] as a slow-curing orange gum/solid](0.402 g): NMR (1H,300MHz, d 6-dmso); 8.52(1H, s),8.42(1H, s),2.67(2H, t),1.58-1.48(2H, m),1.35-1.22(2H, m),0.87(3H, t); LCMS method 1, RT 1.22min, MI 198[ M + H]。

Synthesis of 3-butyl-5-fluoro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ A068]

Mixing 3-butyl-5-fluoro-isonicotinic acid [ A067](2.05mmol, 0.402g) was dissolved in anhydrous DMF (8mL), Diisopropylethylamine (DIPEA) (5.95mmol, 1.04mL) was added, and the mixture was stirred at room temperature for 5 min. O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.05mmol, 0.78g) was then added in one portion and the resulting mixture was stirred for 1 hour. Pyridine-4-carboxamidine hydrochloride (1.95mmol, 0.307g) was then added portionwise to the reaction over 5 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was poured into water (85mL) and stirred for 30 min, then extracted with ethyl acetate (x 3). The combined organic phases were washed with water (x4), brine (x1) and dried (MgSO 4)₄) Filtered and concentrated in vacuo to give the title compound as a brown solid [ A068]](480 mg). The material was used as crude for the next reaction: NMR (1H,300MHz, d 6-dmso); 10.28(1H, br s),9.93(1H, br s),8.74(2H, d),8.45(1H, s),8.37(1H, s),7.90(2H, d),2.72-2.66(2H, m),1.58-1.48(2H, m),1.28-1.15(2H, m),0.79(3H, t); LCMS method 1, RT 3.90min, MI 301[ M + H]。

Synthesis of 5-butyl-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A069]

3-butyl-5-fluoro-N- (imino-pyridin-4-yl-methyl) -isonicotinamide [ a068] was charged as a solution in anhydrous DMA (5mL) into a 25mL Biotage microwave vessel and heated in the microwave for 45 minutes at 150 ℃. The reaction mixture was filtered through a SCX-225 g cartridge. The cartridge was washed with methanol (50 mL). The cartridge was then washed with ammonia (2N, 40mL) and the ammonia wash was concentrated in vacuo to give the title compound [ a069] (390mg) as a light brown solid: NMR (1H,300MHz, d 6-dmso); 8.95(1H, s),8.79(2H, dd),8.46(1H, s),8.10(2H, dd),3.21(2H, t),1.63-1.50(2H, m),1.43-1.27(2H, m),0.91(3H, t) -also windows one equivalent of DMA; LCMS method 1, RT 3.29min, MI 281[ M + H ].

Synthesis of 5-butyl-4-chloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [ A070]

Reacting 5-butyl-2-pyridin-4-yl-3H-pyrido [3,4-d]Pyrimidin-4-ones [ A069](1.35mmol, 0.378g) was suspended in anhydrous 1, 2-Dichloroethane (DCE) (10mL) and phosphorus oxychloride (POCl) was added dropwise over 2-3 minutes₃) (1.4mmol, 0.131 mL). Finally DIPEA (2.0mmol, 0.348mL) was added and the mixture was stirred under nitrogen at room temperature overnight. After adding POCl₃The latter brown solid slowly changed appearance, then further darkened upon the addition of DIPEA, to a dark brown appearing solution. The reaction was stirred at room temperature under nitrogen overnight. After 20 hours POCl was added₃(65. mu.L) and stirred at room temperature overnight. The crude mixture was concentrated in vacuo and then azeotroped to dryness with toluene (x 2). The residue was diluted with sodium carbonate (aq, 2N, 20mL) and extracted with DCM (× 2), ethyl acetate (× 1). The combined organic phases were washed with brine (× 1) and dried (MgSO)₄) Filtered through a pad of silica and concentrated in vacuo to give the title compound as a pale brown solid [ A070](180mg), which was used without further purification in the following reaction: LCMS method 1, RT 5.66min, MI 299[ M + H ]]。

Synthesis of 4- (5-butyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A071]

Under nitrogen, at room temperature 5-butyl-4-chloro-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine [ A070]](0.615mmol, 0.180g) was dissolved in anhydrous DCM (5mL) and treated with triethylamine (0.868mmol, 0.121mL) and N-Boc-piperazine (0.682mmol, 0.127g) in one portion. The resulting mixture was stirred at room temperature for 2 hours. Sodium carbonate (1N aq, 20mL) was then added and extracted with DCM (x2) and ethyl acetate (x 1). The combined organic phases were washed with brine (× 1) and dried (MgSO)₄) Filtered and concentrated under vacuum to a dark brown solid,the solid was purified by column chromatography (SP1 on 25g VWR cartridge, 15col vols in 0-10% methanol/DCM) to give the title compound [ A071 as a brown gum]It was used without further purification in the following reaction: NMR (1H,300MHz, d 6-dmso); 9.24(1H, s),8.79(2H, d),8.49(1H, s),8.36(2H, d),3.77-3.48(8H, m),3.19-3.07(2H, m),1.64-1.23(4H, m),1.48(9H, s),0.96-0.87(3H, t)

Synthesis of 5-butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [135]

Tert-butyl 4- (5-butyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylate [ a071] (0.20mmol, 0.09g) was dissolved in anhydrous DCM (4mL), treated with hydrogen chloride (4N in dioxane, 4mL) at room temperature and stirred for 2 hours. The reaction was diluted with methanol and poured onto a SCX-2 cartridge (5g) and washed with methanol/DCM (20 mL). The cartridge was then washed with ammonia (2N, 20mL) and the ammonia wash was concentrated in vacuo to give a brown gum (0.059 g). The residue was purified by column chromatography (SP 14g column in a gradient of 5-20% methanol in DCM, 15col vols) to give the title compound [133] as an orange-brown gum (0.020 g): NMR (1H,300MHz, d 6-dmso); 9.09(1H, s),8.76(2H, d),8.51(1H, s),8.31(2H, d),3.73-3.58(2H, br s),3.50-3.37(2H, br s),3.07(2H, t),2.90-2.79(4H, br s),1.51-1.38(2H, m),1.28-1.15pm (2H, m),0.84(3H, t); LCMS method 1, RT:2.58min, MI349[ M + H ].

The following compounds were synthesized following the general synthesis shown in scheme [ A8 ]:

general Synthesis scheme A9 for substituted 5-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of general formula [ F-001]

General formula [ F-004]5-substituted 2-pyridin-4-yl-pyrido [3,4-d of]The pyrimidin-4-ol derivative is prepared by: in a palladium-catalyzed cross-coupling reaction, the general formula [ F-024]5-halo-substituted 2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-olsDerivatives (prepared in scheme A7) with the general formula [ F-023]In the presence of a palladium catalyst such as Pd (PPh)₃)₄Or Pd (OAc)₂And bases such as K₂CO₃Or Cs₂CO₃Under conditions of (a), by heating or using a microwave reactor in a polar solvent such as dioxane or a combination of dioxane and DMA at elevated temperature, or of the general formula [ F-024]5-halo-substituted 2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives (prepared in scheme A7) with the general formula [ F-025]In the presence of a catalyst such as Pd (PPh)₃)₄Or Pd (OAc)₂Ligands such as RuPhos and bases such as K₂CO₃Or Cs₂CO₃Under conditions of (a), a palladium-catalyzed cross-coupling reaction is carried out at elevated temperature in a polar solvent such as dioxane or a combination of dioxane and DMA by heating or using a microwave reactor. General formula [ F-001]5-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ F-004]5-substituted 2-pyridin-4-yl-pyrido [3,4-d of]Reacting the pyrimidin-4-ol derivative with a chlorinating agent such as phosphoryl chloride, and then reacting the intermediate 4-chloro derivative with the general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature [ method A ]]. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC. General formula [ F-001]4-substituted-1-yl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine derivatives represented by the general formula [ F-004 ]]2-pyridin-4-yl-pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM with catalytic amounts of DMAP in polar aprotic solvents such as DMA, DMF, NMP [ method B ]]. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl) is then reacted with a suitable solventYl-benzenesulfonic acid) -2-pyridin-4-yl-thieno [3,2-d]Pyrimidin-4-yl esters with general formula [ F-015]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme A9

Synthesis of 1- [ 5-cyclopropyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine [139]

5-cyclopropyl-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A060]

5-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A061] (0.670mmol, 0.173g), potassium carbonate (2.01mmol, 0.278g) and cyclopropylboronic acid (1.34mmol, 0.115g) were suspended in anhydrous DMA (3mL) and then vacuum/argon balloon bubbling (x3) was performed. Tetrakis (triphenylphosphine) palladium (0.067mmol, 0.077g) was then added in one portion, the reaction vessel sealed and heated in a microwave at 150 ℃ for 1 hour. The reaction was cooled to room temperature under nitrogen. Potassium carbonate (2.01mmol, 0.278g) and cyclopropylboronic acid (1.34mmol, 0.115g) were added and the reaction mixture was subjected to vacuum/argon balloon bubbling (x 3). Tetrakis (triphenylphosphine) palladium (0.067mmol, 0.077g) was then added in one portion, the reaction vessel sealed and heated in a microwave at 180 ℃ for 1 hour. The reaction was cooled to room temperature under air and left for more than 48 hours. The reaction mixture was then poured onto a SCX-2 cartridge (10g) and washed with methanol (ca. 40 mL). The cartridge was then washed with ammonia (2N in methanol,. about.40 mL) and the ammonia wash was concentrated in vacuo to give the title compound [ a072] as a yellow solid (78mg), which was used in the next reaction without purification.

4- (5-cyclopropyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A073]

Stirring of 5-cyclopropyl-2-pyridin-4-yl-3H-pyrido [3,4-d under nitrogen at room temperature]Pyrimidin-4-one [ A072]A mixture of (0.08g, 0.3mmol), DIPEA (0.16mL, 0.9mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (0.11g, 0.36mmol), DMAP (3mg) and DMA (2mL) was stirred continuously at room temperature for 2 hours. Boc-piperazine (0.062g, 0.33mmol) was added and the mixture was left to stir at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (× 4). The extracts were combined, washed with water (x4), brine, and dried (MgSO)₄) And concentrated in vacuo. The crude reaction product was purified by flash column chromatography (SP1, ethyl acetate: cyclohexane elution) to give the title compound [ A073]]: method 1, RT 5.57min, MI 433[ M + H ]]。

1- [ 5-cyclopropyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine [139]

4- (5-cyclopropyl-2-pyridin-4-yl-pyrido [3,4-d ] in DCM (3mL) and 4N HCl dioxane (1mL)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A073](0.9g, 0.2mmol) of the mixture was stirred at room temperature overnight. The crude reaction mixture was evaporated under reduced pressure, then dissolved in methanol and washed onto a SCX-2(5g) cartridge and washed with methanol/DCM (1:1,. about.4 mL) then MeOH (10 mL). Then eluted with ammonia (2N in methanol, 15 mL). Concentrating the ammonia eluate in vacuo and subjecting to normal phase chromatography (SiO)₂Methanol (0-15%)/CHCl₃Middle SP1) to obtain the title compound [139](30mg, 43% yield): LCMSMethod 1, RT 1.65min, MI 333[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；8.99(1H,s),8.76(2H,dd),8.30(2H,dd),8.09(1H,s),3.87-3.54(4H,m),2.87(4H,br s),2.63-2.57(1H,m),1.24(2H,ddd),1.01(2H,ddd)

Synthesis of 5-benzyloxymethyl-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A074]

5-benzyloxymethyl-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A074]

Reacting 5-chloro-2-pyridin-4-yl-3H-pyrido [3,4-d]Pyrimidin-4-ones [ A061]A mixture of (0.1g, 0.4mmol), potassium benzyloxymethyltrifluoroborate (0.1g, 0.45mmol), cesium carbonate (0.4g, 1.2mmol) and RuPhos (12mg, 0.028mmol) was charged to a Biotage 5mL vessel and suspended in dioxane (1.8mL) and water (0.2 mL). The mixture was bubbled with vacuum/argon (x3) followed by addition of Pd (OAc)₂(3mg, 0.014mmol), the vessel was sealed and heated at 104 ℃ overnight. DMA (1mL) was added and the mixture was heated in a microwave at 150 ℃ for 1 hour. The reaction mass was cooled and acetic acid (0.57mL) was added and the mixture was stirred for 10 minutes. Then rinsed into an SCX-2 cartridge (10g) and washed with methanol (30-40 mL). Then washed with ammonia (2N in methanol, 40 mL). The ammonia wash was concentrated in vacuo to give the title compound [ A074]]Its use without further purification: method 1, RT 3.31min, MI 345[ M + H ]]。

The following compounds were synthesized following the general synthesis shown in scheme [ a9 ]:

synthesis of 5-chloro-4-piperazin-1-yl-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [141]

4- (5, 8-dichloro-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A075]

Reacting 5, 8-dichloro-2-pyridin-4-yl-3H-pyrido [3,4-d ]]Pyrimidin-4-ones [ A063](0.43g，1.47mmol)、Et₃A mixture of N (0.51mL, 3.6mmol), DCM (10mL), pyridine (2mL) was sonicated for 2 min. DMAP (5mg) was then added followed by 2,4, 6-triisopropylbenzenesulfonyl chloride (0.53g, 1.77 mmol). The reaction mixture was kept stirring at room temperature overnight. The dark brown solution was diluted with water and extracted with DCM (x3) and ethyl acetate (x 1). The combined organic phases were washed with brine (x 1). The brine was re-extracted with ethyl acetate (x 1). The combined organic phases were dried (MgSO)₄) Filtered and concentrated under vacuum. By normal phase chromatography (SiO)₂[ SP1(25g vwr cartridge, 0-10% methanol/DCM)]) Purify the crude material to obtain the title compound [ A075]](0.19g, 28% yield): LCMS method 1, RT 4.17min, MI 461[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；8.81(2H,d),8.45(1H,s),8.33(2H,d),3.76(4H,br s),3.33(4H,br s),1.40(9H,br s)。

4- [ 5-chloro-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ A076]

Reacting 4- (5, 8-dichloro-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A075](0.07g, 0.15mmol), tripotassium phosphate [ K ]₃PO₄212.27g/mol, 21.2g in 100mL deionized water]A mixture of (0.3mL, 0.3mmol), tetrakis (triphenylphosphine) palladium (17mg, 0.015mmol), 1H-pyrazole-5-boronic acid (24mg, 0.21mmol) and DMA (1mL) was heated in a microwave at 150 ℃ for 30 minutes. Acetic acid (0.52mL) was added and the mixture was stirred at room temperature for 20 minutes, then the crude product was loaded onto an SCX cartridge, the cartridge was washed with methanol, and the product was then eluted with 2M ammonia/methanol. Concentrating the eluate under reduced pressure, and performing normal phase chromatography (SiO)₂Ethyl acetate: cyclohexane elution) to obtain the title compound [ a076]]: LCMS method 1, RT 5.62min, MI 493[ M + H ]]。

Chloro-4-piperazin-1-yl-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [141]

A mixture of 4- [ 5-chloro-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ a076] and HCl dioxane (4N, 1mL) was stirred at room temperature for 48 hours. The crude reaction mixture was evaporated under reduced pressure and the crude product was loaded onto an SCX-2 cartridge (1g) and washed with methanol. The product was released from the cartridge using a 2M ammonia/methanol solution. The ammonia/methanol eluate was concentrated under reduced pressure and the crude product was purified by preparative HPLC (method a) to give the title compound: LCMS method 1, RT 1.98min, MI 393[ M + H ]; NMR (1H,300MHz, d 6-dmso); 8.76-8.75(3H, m),8.50(1H, s),8.17(2H, dd),7.90(1H, d),6.67pm (1H, dd),3.76(4H, brs),2.93(2H, brs), 2.80(2H, brs)

Synthesis of 5-chloro-N, N-dimethyl-4- (piperazin-1-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-amine [142]

4- (5-chloro-8-dimethylamino-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A077]

Tert-butyl 4- [ 5-chloro-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylate [ a075] (0.046g, 0.1mmol) in ethanol (0.5mL), DMF (2mL) and dimethylamine were warmed to 50 ℃ in a sealed vessel and stirring was continued for 24 hours. The crude reaction mixture was evaporated under reduced pressure to give the title compound [ a077], which was used in the next step without further purification: LCMS, method 1, RT 4.41min, MI 470[ M + H ].

5-chloro-N, N-dimethyl-4- (piperazin-1-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-amine [142]

Reacting 4- (5-chloro-8-dimethylamino-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester[A077]A mixture of (0.1g, 0.22mmol), DCM (3mL), and HCl (1mL of a 4N solution in dioxane) was stirred at room temperature for 2 hours. The crude reaction mixture was evaporated under reduced pressure, then the crude product was loaded onto an SCX cartridge, which was washed with methanol, then the product was eluted with 2M ammonia/methanol. Concentrating the eluate under reduced pressure, and performing normal phase chromatography (SiO)₂SP1 on a 4g cartridge, 0-15% methanol/DCM) to give the title compound: LCMS method 1, RT 5.40min, MI 370[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；8.73(2H,dd),8.22(2H,dd),7.97(1H,s),3.76-3.68(2H,m),3.56-3.49(2H,m),3.16(3H,s),3.15(3H,s),2.95-2.87(2H,m),2.86.2-77(2H,m)

Synthesis of 5-isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [143]

Step 1: synthesis of 4- (5-bromo-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A078]

A mixture of 5-bromo-2-pyridin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ A065] (0.74g, 2.45mmol), DIPEA (1.3mL, 7.3mmol), and DMAP (5mg) in DMF (15mL) was stirred at room temperature for 10 min. 2,4, 6-triisopropylbenzenesulfonyl chloride (0.89g, 2.94mmol) was added and the mixture was stirred at room temperature for 80 minutes, then boc-piperazine (0.5g, 2.94mmol) was added in one portion and the reaction mass was stirred at room temperature overnight. Water (30mL) was added, and the mixture was stirred at room temperature for 20 minutes. The resulting solid was collected by filtration and the crude product was purified by column chromatography (SP1(25g cartridge), 0-10% methanol/DCM (-20 volumes, 4 volumes at 10% methanol/DCM)) to give the title compound [ a078] (0.69g, 60% yield): LCMS method 1, RT 5.83min, MI 473[ M + H ]; NMR (1H,300MHz, d 6-dmso); 9.22(1H, s),8.78(3H, m),8.32(2H, d),3.79(4H, br s),3.61(4H, br s),1.41(9H, br s).

Step 2: synthesis of 4- (5-isopropenyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A079]

Under nitrogen, 4- (5-bromo-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A078](0.2mmol, 0.094g), potassium phosphate (tribasic) (0.60mmol, 0.127g) and isopropenylboronic acid pinacol ester (0.30mmol, 0.057mL) were suspended in anhydrous dioxane (2mL) in a 5mL Biotage vessel. The vessel was vacuum/argon (balloon) bubbled (x3) and then dichloro [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) dichloromethane adduct (0.01mmol, 0.008g), the reaction was sealed and warmed to 96 ℃ for 18 hours. The reaction mixture was cooled to room temperature under air, silica (1g) was added for chromatography, and the mixture was concentrated in vacuo to a brown powder. It was dry loaded onto a silica cartridge and purified by chromatography (SP1, 0-10% methanol/DCM, 15col vols) to give 85mg of 4- (5-isopropenyl-2-pyridin-4-yl-pyrido [3,4-d ] as a brown glass]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A079](85mg)：NMR:(1H,500MHz,CDCl₃) (ii) a 9.31(1H, s),8.79(2H, d),8.50(1H, s),8.36(2H, d),5.40(1H, s),5.32(1H, s),3.58(8H, br s),2.21(3H, s),1.24(9H, s); LCMS method 1, RT 5.66min, MI 433[ M + H ]]。

And step 3: synthesis of 5-isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [143] to a solution of tert-butyl 4- (5-isopropenyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylate [ a079] (0.105mmol, 0.045g) in DCM (2mL) was added hydrogen chloride (4N, 1mL in dioxane) at room temperature to give a thick yellow-brown suspension which was stirred overnight. The reaction mixture was then concentrated in vacuo and the residue was redissolved in methanol and washed onto an SCX-2 cartridge. The cartridge was washed with DCM and methanol (1:1, 20mL total). SCX-2 was then washed with ammonia (2N in methanol, 15 mL). The combined ammonia washes were concentrated to an orange-brown solid and purified by column chromatography (SP1, 4g cartridge, 0-20% methanol/DCM, 15col vols) to give 5-isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine [143] (0.011g) as a yellow glass: NMR (1H,500MHz, d4-MeOH)9.15(1H, s),8.76(2H, dd),8.49(1H, s),8.31(2H, dd),5.40(1H, s),5.20(1H, s),3.56(4H, br s),2.79(4H, t),2.17(3H, s); LCMS, method 1, RT 1.88min, MI 333[ M + H ]. LC-MS.

Example 151.5-methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine

151a) 3-tert-Butoxycarbonylamino-pyrrolidine-1, 3-dicarboxylic acid 1- (9H-fluoren-9-ylmethyl) ester: 3-tert-Butoxycarbonylamino-pyrrolidine-3-carboxylic acid (1.50g, 6.50mmol) was added to a solution of sodium carbonate (1.65g, 15.6mmol) in water (16.7mL, 926mmol) and 1, 4-dioxane (9mL, 100 mmol). The resulting solution was stirred and cooled on an ice bath. To the stirred reaction solution was added chloroformate-9-fluorenylmethyl ester (1.76g, 6.82mmol) in 1, 4-dioxane (13mL, 160 mmol). The mixture was stirred at room temperature for 2 hours, poured into water (300mL) and extracted twice with ether. The aqueous phase was cooled in an ice bath and slowly treated with 3M hydrogen chloride in water (7.80mL, 23.4mmol) to neutralize. The resulting mixture was extracted with ethyl acetate (2 ×), and the combined organic phases were purified over Na₂SO₄Dried, filtered and concentrated. The residue was pumped under high vacuum for 4 hours, leaving 3.12g (106%) of foam, which was used in the next step without further treatment.

151b) 3-tert-butoxycarbonylamino-3-carbamoyl-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester: di-tert-butyl dicarbonate (655mg, 3.00mmol) was added to a mixture of 1- (9H-fluoren-9-ylmethyl) 3-tert-butoxycarbonylamino-pyrrolidine-1, 3-dicarboxylic acid 1- (905mg, 2.00mmol) and pyridine (0.324mL, 4.00mmol) in 1, 4-dioxane (5mL, 60mmol) at room temperature. After 15 min, ammonium bicarbonate (0.474g, 6.00mmol) was added and the reaction mixture was stirred for 72 h. Water (10mL) was added to the resulting solid mass and vortexed. The solid was filtered off and rinsed extensively with water. After air drying, the resulting solid was dried under high vacuum at room temperature. This gave 1.12g (124%) of a dark brown solid. The dark brown solid was used continuously without further treatment for the subsequent steps.

151c) (3-carbamoyl-pyrrolidin-3-yl) -carbamic acid tert-butyl ester 9H-fluoren-9-ylmethyl 3-tert-butoxycarbonylamino-3-carbamoyl-pyrrolidine-1-carboxylate (410mg, 0.91mmol) was suspended in methanol (5mL, 100mmol) and pure piperidine (1mL, 10mmol) was added at room temperature. After 16 h the reaction was concentrated under reduced pressure and the residue was then pumped under high vacuum overnight (to remove as much piperidine as possible) and the crude product was used directly for the next reaction.

151d) The method comprises the following steps 5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol (127mg, 0.501mmol), triethylamine (216uL, 1.55mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (167mg, 0.552mmol), and 4-dimethylaminopyridine (6.9mg, 0.057mmol) in N, N-dimethylformamide (2.0mL, 26mmol) were stirred at room temperature for 1 hour. Gradual dissolution of the starting material was observed, and the intermediate sulfonate was observed by HPLC. (3-carbamoyl-pyrrolidin-3-yl) -carbamic acid tert-butyl ester (126mg, 0.550mmol) was then added as a solution in N, N-dimethylformamide and the reaction stirred at room temperature. After 45min, the reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase is removed and washed with 3mL of 1N HCl. The aqueous solution was removed, a small amount of DMSO was added and purified by running two times with preparative reverse phase HPLC. The purest fractions of each major product were pooled and lyophilized. 32mg (14%) of the preceding run of tert-butyl [ 3-carbamoyl-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-yl ] -carbamate (LC/MS: M + H466.2) were obtained as a yellow lyophilizate. 35mg (22%) of by-product 5-methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine (LC/MS: M + H ═ 322.1) were also obtained, which was formed from pyridine left when preparing the starting material (3-carbamoyl-pyrrolidin-3-yl) -carbamic acid tert-butyl ester. Tert-butyl [ 3-carbamoyl-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-yl ] -carbamate is used without further treatment for further reactions.

Example 152.3-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidine-3-carboxylic acid amide

A solution of methylene chloride (2mL, 30mmol) in trifluoroacetic acid (1mL, 10mmol) was added to [ 3-carbamoyl-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-yl ] -carbamic acid tert-butyl ester (30mg, 0.06mmol) at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure, and then the residue was triturated with ether to obtain a solid. The solid was filtered and washed extensively with diethyl ether. 17mg of the title compound are obtained as a solid (LC/MS: M + H366.1).

Example 153.3-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidine-3-carboxylic acid benzamide

153a) 3-tert-butoxycarbonylamino-3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid-9H-fluoren-9-ylmethyl ester: n- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (575mg, 3.00mmol) was added to a mixture of 3-tert-butoxycarbonylamino-pyrrolidine-1, 3-dicarboxylic acid 1- (9H-fluoren-9-ylmethyl) ester (905mg, 2.00mmol), 1-hydroxybenzotriazole (2.70E2mg, 2.00mmol) and aniline (228uL, 2.50mmol) in tetrahydrofuran (25mL, 310 mmol). After 10 minutes, N-dimethylformamide (10mL, 100mmol) was added to facilitate dissolution. After 1.5h the reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (2X) and saturated NaHCO₃The aqueous solution was partitioned. The combined organic phases were washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure to give 0.97g (92%) of a foam (LC/MS: M + H528.1) which was used in the next step without further treatment.

153b) (3-phenylcarbamoyl-pyrrolidin-3-yl) -carbamic acid tert-butyl ester: 3-tert-Butoxycarbonylamino-3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (960mg, 1.8mmol) was combined with methanol (10mL, 200mmol), followed by addition of pure piperidine (2mL, 20mmol) at room temperature and stirring of the reaction for 72H. The reaction mixture was concentrated under reduced pressure and a solid material was obtained. The whole sample was triturated with ether, filtered and the solid was rinsed extensively with ether. After air drying 0.55g (99%) of a dark brown solid remained. The material continues to be used in subsequent reactions without further treatment.

153c) [1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -3-phenylcarbamoyl-pyrrolidin-3-yl]-tert-butyl carbamate: 5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] in N, N-dimethylformamide (4.0mL, 52mmol)]Pyrimidin-4-ol (254mg, 1.00mmol), triethylamine (431uL, 3.10mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (334mg, 1.10mmol) and 4-dimethylaminopyridine (14mg, 0.11mmol) were stirred at room temperature for 1 hour. Pure (3-phenylcarbamoyl-pyrrolidin-3-yl) -carbamic acid tert-butyl ester (335mg, 1.10mmol) was added and the reaction stirred at room temperature overnight. The reaction was then concentrated under reduced pressure and partitioned between ethyl acetate and water. It must be filtered before the layers are separated because the precipitated solids can cause problems between the layers. The organic phase is washed with Na₂SO₄Dried above, filtered and concentrated under reduced pressure to give 500mg of crude product. The crude product was dissolved in DMSO (3.6mL), filtered, and purified by preparative reverse phase HPLC. The purest fraction was removed and replaced with saturated NaHCO₃The aqueous solution is alkalized. The solid that had settled out of the solution was filtered and rinsed with water. After air drying, 50mg (9%) of an off-white solid remained. (LC/MS: M + H-542.1). The material is used continuously for subsequent steps without further treatment.

153d) [1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -3-phenylcarbamoyl-pyrrolidin-3-yl ] -carbamic acid tert-butyl ester (50.0mg, 0.0923mmol) was dissolved in methylene dichloride (2.0mL, 31mmol) at room temperature, followed by the addition of neat trifluoroacetic acid (1.0mL, 13 mmol). After 2.5 h the reaction was concentrated under reduced pressure and the residue was dissolved in 0.80mL DMSO, filtered and purified by preparative reverse phase HPLC. The purest fractions were combined and lyophilized. 32mg (78%) of the title compound (LC/MS: M + H442.1) of a yellow lyophilisate are obtained.

Example 154.4-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-4-carboxylic acid [ (S) -1- (4-chloro-phenyl) -3-hydroxy-propyl ] -amide

154a) 4-Boc-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperidine-4-carboxylic acid methyl ester: combine 5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] in N, N-dimethylformamide (2.0mL, 26mmol)]Pyrimidin-4-ol (254mg, 1.00mmol), triethylamine (0.432mL, 3.10mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (334mg, 1.10mmol), and 4-dimethylaminopyridine (14mg, 0.11mmol) and stirred at room temperature. After 45min pure methyl 4-tert-butoxycarbonylamino-piperidine-4-carboxylate (284mg, 1.10 mmol; supplier ═ Oakwood) was added and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was in CH₂Cl₂And water. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. 380mg (77%) of the residue formed were used in the subsequent steps without further treatment.

154b) 4-tert-butoxycarbonylamino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-4-carboxylic acid: a solution of lithium hydroxide (180mg, 7.5mmol) in water (3mL, 200mmol) and a solution of 4-tert-butoxycarbonylamino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-4-carboxylic acid methyl ester (370mg, 0.75mmol) in methanol (10mL, 200mmol) were combined at room temperature and the homogeneous solution was stirred at room temperature for 16 h. After cooling, the reaction mixture was treated with 1M hydrogen chloride in water (7.5mL, 7.5mmol) and then concentrated to remove most of the methanol, leaving a predominantly aqueous solvent. The resulting solid was filtered, and then an aqueous filtrate solution was taken out and concentrated. 292mg were obtained. 2.5mL of DMSO was added, filtered, then purified by preparative reverse phase HPLC and the purest fractions were lyophilized to give 45mg (12%) of the desired product as a yellow lyophile, which was used in the next step without further processing.

154c) [4- [ (S) -1- (4-chloro-phenyl) -3-hydroxy-propylcarbamoyl]-1- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperidin-4-yl]-tert-butyl carbamate: 4-tert-Butoxycarbonylamino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperidine-4-carboxylic acid (30.0mg, 0.0624mmol) with N, N-dimethylformamide (1mL, 10mmol) was combined, then 1-hydroxybenzotriazole (8.44mg, 0.0624mmol) and (S) -3-amino-3- (4-chloro-phenyl) -propan-1-ol hydrochloride (27.7mg, 0.125 mmol; supplier ═ Oakwood) were added, then N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (35.9mg, 0.187mmol) were added. After 3 hours, the reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. Then saturated NaHCO₃The organic phase was washed with aqueous solution over Na₂SO₄Dried, filtered and concentrated. The crude residue was used in the next step without further treatment.

154d) [4- [ (S) -1- (4-chloro-phenyl) -3-hydroxy-propylcarbamoyl ] -1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidin-4-yl ] -carbamic acid tert-butyl ester (70mg, 0.1mmol) was dissolved in methylene chloride (2.0mL) at room temperature, followed by addition of pure trifluoroacetic acid (1.0mL, 13 mmol). After 2h, the reaction was concentrated under reduced pressure, the residue was dissolved in 1mL DMSO, filtered and purified by preparative reverse phase HPLC. The purest fractions were combined and lyophilized overnight. 15mg (20%) of the title compound (LC/MS: M + H. RTM. 548.1) of a yellow lyophilisate are obtained.

Example 155.4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid methyl ester

155a)4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: 5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol (508mg, 2.00mmol), triethylamine (863uL, 6.19mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (668mg, 2.20mmol), and 4-dimethylaminopyridine (28mg, 0.23mmol) in N, N-dimethylformamide (10mL) were stirred at room temperature for 2 hours. Gradual dissolution of the starting material was observed and the solution color was noticeably darker. Piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (536mg, 2.20mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added and the resulting solid product was collected by filtration, washed with water and dried. 448mg (47%) of a dark brown solid product were obtained, which was used in the subsequent steps without further treatment.

155b) 4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (50mg, 0.1mmol) was dissolved in methylene dichloride (2.0mL) at room temperature, followed by the addition of pure trifluoroacetic acid (1.0mL, 13 mmol). After 2.5 h the reaction solution was concentrated under reduced pressure, then the residue was dissolved in 1mL DMSO and the combined desired fractions were purified by preparative reverse phase HPLC and lyophilized overnight. 23mg (60%) of the title compound (LC/MS: M + H. RTM. 381.1) of yellow lyophilisate were obtained.

Example 156.4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid phenylamide

156a)4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -2-phenylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester: 4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d) at room temperature]Pyrimidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester (77.0mg, 0.165mmol) was combined with N, N-dimethylformamide (3mL), followed by the addition of 1-hydroxybenzotriazole (22.3mg, 0.165mmol), 4-methylmorpholine (36.3uL, 0.330mmol) and aniline (22.6uL, 0.247mmol), followed by the addition of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (94.9mg, 0.495 mmol). After 2 hours the reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in ethyl acetate and saturated NaHCO₃The aqueous solution was partitioned. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated. The crude residue was dissolved in 0.95mL DMSO, filtered and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give 42mg (47%) of the desired product as a yellow lyophilizate (LC/MS: M + H542.2).

156b) Trifluoroacetic acid (1mL, 10mmol) and methylenedichloride (2mL, 30mmol) were combined with 4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -2-phenylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (42.0mg, 0.0775mmol) at room temperature. After 1.5 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 1.3mL of DMSO, filtered, and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized overnight to give 29mg (85%) of the title compound as a yellow lyophilizate (LC/MS: M + H442.1).

Example 157.4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid benzamide

157a) 2-benzylcarbamoyl-4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester: 4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d) at room temperature]Pyrimidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester (77.0mg, 0.165mmol) was combined with N, N-dimethylformamide (3mL), followed by the addition of 1-hydroxybenzotriazole (22.3mg, 0.165mmol), 4-methylmorpholine (36.3uL, 0.330mmol) and benzylamine (27.0uL, 0.247mmol), followed by the addition of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (94.9mg, 0.495 mmol). After 1.5h the reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in ethyl acetate and saturated NaHCO₃The aqueous solution was partitioned. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated. The crude residue was dissolved in 0.85ml of ldmso, filtered and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give 48mg (52%) of the desired product as a yellow lyophile (LC/MS: M + H ═ 556.2).

157b) A solution of trifluoroacetic acid (1mL, 10mmol) and methylenedichloride (2mL, 30mmol) was combined with tert-butyl 2-benzylcarbamoyl-4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylate (47.0mg, 0.0846mmol) at room temperature. After 1.5h the mixture was concentrated under reduced pressure and the residue was dissolved in 1.15ml of ldmso, filtered and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give 38mg (99%) of the title compound as a yellow lyophilizate (LC/MS: M + H ═ 456.1).

Example 158.4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid phenethyl-amide

158a)4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -2-phenethylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester: 4- (5-methoxy-2-pyridin-4-yl-pyrido [3, 4-d) at room temperature]Pyrimidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester (77.0mg, 0.165mmol) was combined with N, N-dimethylformamide (3mL,30mmol), followed by the addition of 1-hydroxybenzotriazole (22.3mg, 0.165mmol), 4-methylmorpholine (36.3uL, 0.330mmol) and phenethylamine (31.1uL, 0.248mmol), followed by the addition of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (94.9mg, 0.495 mmol). After 16 h the reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in ethyl acetate and saturated NaHCO₃The aqueous solution was partitioned. The organic phase is washed with Na₂SO₄Dried, filtered and concentrated. The crude residue was dissolved in 0.9ml of ldmso, filtered and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give 53mg (56%) of the desired product as a yellow lyophile (LC/MS: M + H ═ 570.2).

158b) A solution of trifluoroacetic acid (1mL, 10mmol) and methylenedichloride (2mL) was combined with 4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -2-phenethylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (48.2mg, 0.0846mmol) at room temperature. After 1.5h the mixture was concentrated under reduced pressure, then the residue was dissolved in 1.2mL DMSO, filtered and purified by preparative reverse phase HPLC. The desired fractions were combined and lyophilized to give 38mg (96%) of the title compound as a yellow lyophilizate (LC/MS: M + H470.2).

Synthesis of 4- (2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A080]

Stirring 2-pyridin-4-yl-3H-pyrido [3,4-d at room temperature under nitrogen]Pyrimidin-4-one [ A001](1.0g, 4.5mmol), DMF (30mL) and DIPEA (2.35mL, 13.5 mmol).DMAP (5mg) was added followed by 2,4, 6-triisopropylbenzenesulfonyl chloride (1.64g, 5.4mmol) and the mixture was stirred for 2 hours. 1-Boc piperazine (0.83g, 4.5mmol) was added and the mixture was stirred at room temperature overnight. Water (50mL) was added and the mixture was stirred for 20 minutes, filtered and washed with water (x 3). The solid was dissolved in DCM (50mL) and dried (MgSO)₄) Filtered and evaporated under reduced pressure to give the title compound (1.2g, 68% yield) which was used as crude without further treatment in the next step.

Synthesis of 4- (8-propyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A081] and 4- (8-methyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A082]

To 4- (2-pyridin-4-yl-pyrido [3, 4-d) in DMSO (5mL)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ A080]A solution of (0.196g, 0.5mmol), butyraldehyde (0.090mL, 1.0mmol), concentrated sulfuric acid (0.054mL, 1.0mmol), and iron sulfate heptahydrate (0.04g, 0.15mmol) was added dropwise over 2 minutes to hydrogen peroxide (35% aqueous solution, 0.146mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight, then water (5mL) was added and the mixture was basified to pH-7-8 by dropwise addition of NaOH (1N). The mixture was then extracted with DCM (x3), the organic phases combined and washed with water (x1), brine (x1), dried (MgSO)₄) Filtered and evaporated under reduced pressure. By column chromatography (SiO)₂Column, eluting with 50-90% ethyl acetate/cHex ISCO on 120g column) to give: 4- (8-propyl-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester (46 mg): LCMS method 5, RT 5.79min, MI 435[ M + H ]]；¹H NMR (1H, CDCl3,500MHz),8.77(2H, dd),8.50(1H, d),8.38(2H, dd),7.46(1H, d),3.91-3.89(4H, m),3.71-3.69(4H, m),3.49(2H, dd),2.00-1.92(2H, dq),1.51(9H, s),1.09(3H, t) and colorless glassy 4- (8-methyl-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -piperazine-1-carboxylic acidTert-butyl ester (44 mg): LCMS method 5, RT 5.11min, MI 407[ M + H ]]；¹H NMR(CDCl3,500MHz)8.78(2H,dd),8.46(1H,d),8.39(2H,dd),7.47(1H,d),3.91-3.89(4H,m),3.71-3.69(4H,m),3.09(3H,s),1.51(9H,s)。

Example 159.4-piperazin-1-yl-8-propyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine

Reacting 4- (8-propyl-2-pyridine-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -piperazine-1-carboxylic acid [ A081]A mixture of (0.046g, 0.105mmol), DCM (3mL), and HCl (4N in dioxane, 1mL) was stirred at room temperature for 90 minutes. The mixture was evaporated under reduced pressure, then the crude product was dissolved in methanol and added to a SCX-2 cartridge (10g), washed with DCM/methanol (1:110mL) and methanol (20mL), then eluted with ammonia (7N in methanol, 30 mL). The ammonia wash was evaporated under reduced pressure to give the title compound as a yellow solid (34mg, 75% yield): LCMS method 5, RT 2.0min, MI 335[ M + H ]]；¹HNMR(d6-dmso,500MHz),8.76(2H,dd),8.45(1H,d),8.32(2H,dd),7.71(1H,d),3.89(4H,t),3.37(2H,t),2.95(4H,t),1.86(2H,dq),0.99(3H,t)。

Example 160.8-methyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine

Reacting 4- (8-methyl-2-pyridin-4-yl-pyrido [3,4-d ]]Pyrimidin-4-yl) -piperazine-1-carboxylic acid [ A082]A mixture of (0.045g, 0.11mmol), DCM (3mL), and HCl (4N in dioxane, 1mL) was stirred at room temperature for 90 minutes. The mixture was evaporated under reduced pressure, then the crude product was dissolved in methanol and added to a SCX-2 cartridge (10g), washed with DCM/methanol (1:110mL) and methanol (20mL), then eluted with ammonia (7N in methanol, 30 mL). The ammonia wash was evaporated under reduced pressure to give the title compound as a brown gum (29mg, 75% yield): LCMS method 5, RT 2.17min, MI 307[ M + H ]]；¹HNMR(d6-dmso,500MHz),8.76(2H,dd),8.40(1H,d),8.33(2H,dd),7.70(1H,d),3.88(4H,t),2.94-2.92(4H,m),2.93(3H,s)

General Synthesis scheme B1 for substituted 2-Aminopyridyl-substituted 2- (2-amino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamine derivatives of the general formula [ G-003]

General formula [ G-002]2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of]The pyrimidin-4-ylamine derivatives were prepared as follows: general formula [ G-001 ]]2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP in a polar aprotic solvent such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl esters with general formula [ G-004]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. By the general formula [ G-005]Suitable amine, palladium catalysts such as Pd (dba)₂Or Pd (OAc)₂Ligands such as Xantphos and bases such as NaOtBu or Cs₂CO₃In a polar solvent such as dioxane or a combination of dioxane and DMA, at an elevated temperature obtained by heating or using a microwave reactor, the general formula [ G-002]2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of]Reacting a pyrimidin-4-ylamine derivative with a Buchwald-type reaction to obtain a compound of the general formula [ G-003]]Substituted 2-aminopyridyl-substituted 2- (2-amino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ylamine derivatives. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography, deprotection of the N-Boc derivative under acidic conditions with strong acids such as TFA, HCl in solvents such as DCM, DCE or 1, 4-dioxane, or deprotection of the N-Boc derivative by capture and release of sulfonic acid resins such as polymer-supported toluenesulfonic acid, and purification of the crude reaction product by normal phase chromatography or reverse phase preparative HPLC.

Scheme B1

Synthesis of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine [200]

2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol [ B001]

To a solution of 2-chloro-4-pyridinecarbonitrile (0.97g, 7.03mmol) in methanol (35mL) was added NaOMe (0.08g, 1.46mmol) under nitrogen at room temperature and stirring continued for 60 min. A solution of 3-amino-5-methoxy-isonicotinic acid (1g, 5.86mmol) in methanol (15mL) was then added dropwise over 5-10 minutes (via syringe) to the dark brown mixture. The solution was stirred at room temperature for 2 hours and then at 85 ℃ overnight. After cooling, the solid was filtered and washed with methanol, which was used without further purification, to give the title compound [ B001] (0.97g, 57% yield): LCMS method 5, RT 6.32min, MI287.34[ M + H ].

4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B002]

Reacting 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol [ B001]A mixture of (0.58g, 2mmol), anhydrous DMA (5mL), triethylamine (0.58mL, 4mmol) and DMAP (20mg, 0.16mmol) was sonicated for 10 min and then stirred at room temperature for 10 min. 2,4, 6-triisopropyl-benzenesulfonyl chloride (0.67g, 2.2mmol) was added and the mixture was sonicated for 5 minutes and stirring continued at room temperature for 2 hours. During which time the material goes into solution to form a viscous solution. A solution of Boc piperazine (0.56g, 3mmol) in anhydrous DMA (1mL) was added and the reaction mixture was stirred at room temperature overnight. Water (20mL) was added, the reaction mixture was extracted with DCM (2 × 30mL), the extracts combined andwashed with water (20mL), saturated bicarbonate solution (2X20mL) and water (20mL), dried (MgSO 4)₄) Filtered and evaporated under reduced pressure to give a pale yellow oil which is purified by flash column chromatography (SP1, 50g SiO₂Cartridge, 100% ethyl acetate to 95% ethyl acetate: 5% methanol gradient) to give the title compound as a colorless solid [ B002](0.22g, 24% yield). LCMS method 5, RT 10.86min, MI 457[ M + H ]]；NMR:(1H,500MHz,CDCl₃)；9.0(1H,s),8.53(1H,d),8.35(1H,s),8.28(1H,1H,d),8.23(1H,s),3.70(4H,br s),3.64(4H,br s),1.50(9H,s)

4- (5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B003]

Adding 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d to a microwave vial]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B002](0.100g，0.22mmol)、Pd(dba)₂(10mg, 0.013mmol), Xantphos (17.5mg, 0.025mmol), NaOtBu (43mg, 0.440mmol) and anhydrous dioxane (4 ml). Aniline was then added, the vial was sealed and heated at 150 ℃ for 20 minutes. Water (10mL) was added, the reaction mixture was extracted with DCM (2X10mL), the extracts were combined and washed with water (10mL), saturated bicarbonate (2X10mL) and water (10mL), MgSO 2₄Dried, filtered and evaporated to give a pale yellow oil which is purified by flash column chromatography (SP1, 25g SiO)₂Cartridge, 100% ethyl acetate to 95% ethyl acetate: 5% methanol gradient) to give the title compound as a colorless solid [ B003](0.04g, 36% yield). LCMS method 5, RT 7.80min, MI 514[ M + H ]]；NMR:(1H,500MHz,CDCl₃)；8.93(1H,s),8.65(1H,d),8.41(1H,s),7.39(1H,d),7.58(5H,m),6.55(1H,br s),3.63(4H,m),3.57(4H,m),1.49(9H,s)。

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine [200]

4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] in DCM (1ml)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B003](0.040g, 0.080mmol) was added to the mixture TFA (1ml) and the mixture was stirred at room temperature for 2 hours. After completion, the crude reaction mixture was diluted with DCM (5mL) and poured onto a 1g SCX-2 cartridge, washed with DCM and methanol, then 2N NH₃Methanol elution, evaporation gave a pale yellow oil which was evaporated in Genevac to give a pale yellow solid (25 mg). LCMS method 5, RT 3.12min, MI 414.22[ M + H ]]；NMR:(1H,500MHz,d6-dmso)；9.32(1H,br s),8.8(1H,s),8.29(2H,m),7.88(1H,s),7.76(2H,d),7.64(1H,d),7.29(2H,m),6.88(2H,m),4.04(3H,s),3.64(4H,m),2.88(4H,m)。

2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ B004]

To a solution of 2-chloro-4-pyridinecarbonitrile (2.18g, 15.77mmol) in anhydrous THF (20mL) was added methyl 3-amino-isonicotinate (2g, 13.1mmol) followed by potassium tert-amylate (15.5mL, 26.3mmol, 1.7M in toluene). The reaction was stirred at room temperature overnight. The precipitate was collected by filtration to give the title compound, which was used without further purification: LCMS method 5, RT 4.05min, MI 259[ M + H ].

(R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -pyrrolidine-1-carboxylic acid tert-butyl ester [ B005]

A mixture of 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ B003] (1g, 3.86mmol), anhydrous DMA (10mL), triethylamine (1.1mL, 7.73mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (1.29g, 3.25mmol) and DMAP (47mg, 0.386mmol) was stirred at room temperature for 1 hour and (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (940mg, 5.02mmol) was added. The reaction mixture was stirred overnight and the solvent was evaporated under reduced pressure. DCM and ether were added and the resulting solid was collected and used in the next step without further purification. LCMS method 5, RT 6.19min, MI427 [ M + H ].

The following compounds were synthesized according to the general synthesis shown in scheme [ B1] (example 1):

synthesis of {1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-yl } -methanol [244]

5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ B006]

Reacting 42- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol [ B003]](0.100g，0.346mmol)、Pd(OAc)₂A mixture of (4mg, 0.018mmol), Xantphos (21mg, 0.035mmol), cesium carbonate (225mg, 0.695mmol) and anhydrous dioxane (1ml) was heated at 90 ℃ overnight. Water (5mL) was added and the reaction mixture was triturated for 30 min before collecting the yellow solid by filtration and washing with water (20mL) and DCM (20mL) to give the title compound as a yellow solid (0.07g, 59% yield) which was used in the next step without further purification. LCMS method 1, RT:2.23min, MI 346.24[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；9.30(1H,s),8.60(1H,s),8.25(1H,d),7.71(2H,d),7.65(1H,s),7.45(1H,dd),7.26(2H,t),6.89(1H,t),3.96(3H,s)。

{1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-yl } -methanol [244]

Reacting 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ol [ B003]](70mg, 0.203mmol), TEA (84. mu.l, 0.609mmol) and DMAP (25mg, 0.203mmol) were sonicated in DMF (1.5ml) for 30 min. 2,4, 6-triisopropylbenzenesulfonyl chloride (74mg, 0.243mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. 4-Piperidinol (28mg, 0.243mmol) was then added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give a pale yellow solid which was purified by flash column chromatography (SP1, 12g SiO₂Cartridge, 100% DCM to 95% DCM: 5% methanol gradient) to give the title compound as a yellow solid (38mg, 42% yield). LCMS method 1, RT 5.26min, MI 443.35[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；9.30(1H,s),8.79(1H,s),8.31(1H,s),8.28(1H,d),7.89(1H,s),7.74(2H,d),7.65(1H,d),7.27(2H,t),6.88(1H,t),4.52(1H,t),4.30(2H,d,br),4.07(3H,s),3.16(1H,d),3.11(2H,t,br),1.83(2H,d,br),1.72(1H,s,br),1.33(2H,q,br),1.13(2H,dd)

Synthesis of 2- {3- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -R-pyrrolidin-1-yl } -acetamide [245]

[ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] in DMF (1mL)]Pyrimidin-4-yl]- (R) -pyrrolidin-3-yl-amine [ 238)](50mg, 0.121mmol) and K₂CO₃(50mg, 0.363mmol) of the mixture was added 2-bromoacetamide (17mg, 0.121 mmol). The reaction mixture was heated at 80 ℃ for 4 hours. Water (10mL) was added, the reaction mixture was extracted with ethyl acetate (2X10mL), the extracts combined and washed with brine (20mL), dried (MgSO)₄) Filtered and evaporated under reduced pressure to give a pale yellow oil which was diluted with methanol (5mL) and poured onto a 1g SCX-2 cartridge, washed with methanol and then 2N NH₃Methanol elution, which was evaporated. The resulting oil was triturated in ether to give the title compound as a white solid (12mg, 17% yield). LCMS method 1, RT:2.17min, MI 471[ M + H]；NMR:(1H,300MHz,d6-dmso)；9.32(1H,s),8.78(1H,s),8.35(1H,s),8.31(1H,d),8.23(1H,d),7.76(2H,d),7.70(1H,d),7.28(2H,t),7.13(1H,s),6.90(1H,t),4.82(1H,s),4.15(3H,s),3.10(2H,d),3.00(1H,m),2.89(1H,m),2.81(1H,m),2.57(1H,m),2.40(1H,m),1.88(1H,m)。

General Synthesis scheme B2 for 5-chloro-substituted 2-aminopyridyl-substituted 2- (2-amino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamine derivatives of the general formula [ G-008]

General formula [ G-007 ]]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]The pyrimidin-4-ylamine derivatives were prepared as follows: general formula [ G-006]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP in a polar aprotic solvent such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl esters with general formula [ G-004]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. By the general formula [ G-005]Suitable amine, palladium catalysts such as Pd (dba)₂Or Pd (OAc)₂Ligands such as Xantphos and bases such as NaOtBu or Cs₂CO₃In a polar solvent such as dioxane or a combination of dioxane and DMA, at elevated temperature obtained by heating or using a microwave reactor, the general formula [ G-007]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]The pyrimidin-4-ylamine derivatives undergo a Buchwald type reaction. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography, deprotection of the N-Boc derivative with a strong acid such as TFA, HCl under acidic conditions in a solvent such as DCM, DCE or 1, 4-dioxane, or by capture and release of a sulfonic acid resin such as polymerizationSupported toluenesulfonic acid deprotected N-Boc derivative and purified crude reaction product by normal phase chromatography or reverse phase preparative HPLC.

Scheme B2

Synthesis of [4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine [246]

3, 5-dichloro-N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -isonicotinamide [ B007]

A mixture of 3, 5-dichloropyridine-4-carboxylic acid (15g, 78.12mmol), DIPEA (37.5mL, 214mmol) in DMF (400mL) was stirred at room temperature, then HATU (29.7g, 78.12mmol) was added in one portion and the mixture was stirred for 45 min. 2-chloro-isonicotinamide (14.25g, 74.2mmol) was added and the mixture was stirred for a further 2 hours. The crude reaction mixture was then poured onto water (800mL) and stirring was continued overnight. The crude reaction mixture was filtered, the solid washed with water and then dried in a vacuum oven overnight to give the title compound as an off-white solid (22g, 85% yield): LCMS method 1, RT 4.89min, MI 330[ M + H ]; NMR (1H,300MHz, d 6-dmso); 10.25(1H, br s),10.10(1H, br s),8.70(2H, s),8.57(1H, s),7.99(1H, s),7.88(1H, s).

5-chloro-2- (2- (2-chloro-pyridin-4-yl)) -pyrido [3,4-d ] pyrimidin-4-ol [ B008]

3, 5-dichloro-N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -isonicotinamide [ B007] (10g, 30.34mmol), cesium carbonate (19.8g, 60.69mmol) and DMA (180mL) were stirred at room temperature. The mixture was purged with nitrogen, then iron (III) chloride (0.98g, 6.07mmol) was added and the mixture was heated at 140 ℃ overnight under nitrogen. The crude reaction mixture was cooled and then poured onto a mixture of ice and water, the mixture was acidified by addition of glacial acetic acid and the mixture was then stirred at room temperature for 2 hours. The solid precipitate was collected by filtration, washed with water, and then dried in a vacuum oven overnight to give the title compound as a light brown solid (5.26g, 59% yield): LCMS method 1, RT 4.83min, MI 293[ M + H ];

4- (5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B009]

Reacting 5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ol [ B008]]A mixture of (1.05g, 3.58mmol), anhydrous DMF (40mL), triethylamine (1.5mL, 10.7mmol) and DMAP (440mg, 3.58mmol) was sonicated for 45 min. 2,4, 6-triisopropyl-benzenesulfonyl chloride (1.3g, 4.3mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. During which time the material goes into solution to form a viscous solution. 1-Boc-piperazine (0.800g, 4.3mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue triturated in DCM to give a brown solid which was purified by flash column chromatography (SP1, 20g SiO₂Cartridge, 100% DCM to 95% DCM: 5% methanol gradient) to give the title compound as a beige solid (1.1g, 67% yield). LCMS method 1, RT 5.50min, MI 461[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；9.20(1H,s),8.67(1H,s),8.62(1H,d),8.33(1H,d),8.32(1H,s),7.94(1H,s),3.72(4H,m,br),3.53(4H,m,br),1.41(9H,s)。

4- [ 5-chloro-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B010]

Reacting 4- [ 5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B009](0.150g, 0.325mmol), aniline (61. mu.L, 0.650mmol), Pd (OAc)₂A mixture of (4mg, 0.017mmol), Xantphos (19mg, 0.033mmol), cesium carbonate (212mg, 0.650mmol) and anhydrous dioxane (1ml) was heated at 90 deg.C overnight. The solvent was evaporated under reduced pressure and purified by flash column chromatography (SP1, 20g SiO)₂Cartridge, 100% DCM to 97% DCM: 3% methanol gradient) to give the title compound as a beige solid [ B010](65mg, 39% yield). LCMS method 1, RT:4.34min, MI:518.31[ M + H ]]。

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine [246]

4- [ 5-chloro-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] in 4N HCl in dioxane mL)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B010]](60mg, 0.125mmol) of the mixture was stirred at room temperature for 2 hours. After completion the solvent was evaporated in vacuo, the residue diluted with methanol (5mL) and poured onto a 1g SCX-2 cartridge, washed with DCM and methanol, then 2N NH₃Methanol elution and evaporation under reduced pressure. By flash column chromatography (SP1, 20 gSiO)₂Cartridge, 100% DCM to 90% DCM: 10% methanol gradient) to give the title compound as a yellow solid [246]](23mg, 44% yield). LCMS method 1, RT 5.48min, MI 418.29[ M + H ]]；NMR:(1H,300MHz,d6-dmso)；9.33(1H,s),9.12(1H,s),8.60(1H,s),8.32(1H,d),7.89(1H,s),7.74(2H,d),7.65(1H,dd),7.27(2H,t),6.89(1H,t),3.68(4H,m),3.15(1H,d),2.86(4H,m)。

The following compounds were synthesized following the general synthesis shown in scheme [ B2 ]:

general Synthesis scheme B3 for substituted 2-Aminopyridyl-substituted 2- (2-amino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamine derivatives of the general formula [ G-003]

General formula [ G-007 ]]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]The pyrimidin-4-ylamine derivatives were prepared as follows: general formula [ G-006]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP in a polar aprotic solvent such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl esters with general formula [ G-004]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. By the general formula [ G-005]Suitable amine, palladium catalysts such as Pd (dba)₂Or Pd (OAc)₂Ligands such as Xantphos and bases such as NaOtBu or Cs₂CO₃In a polar solvent such as dioxane or a combination of dioxane and DMA, at elevated temperature obtained by heating or using a microwave reactor, the general formula [ G-007]5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (1)]The pyrimidin-4-ylamine derivatives undergo a Buchwald type reaction. By the general formula [ G-009]Suitable boric acid or boric acid ester(s) of (a),palladium catalysts such as Pd (PPh)₃)₄Or Pd (PPh)₃)₂Cl₂Bases such as Et₃N、KOH、Na₂CO₃Or NaOH in a polar solvent such as EtOH, THF, DMA or dioxane, at elevated temperatures obtained by heating or using a microwave reactor, to the general formula [ G-008]2- (2-amino-pyridin-4-yl) -pyrido [3,4-d substituted with 5-chloro-2-amino-pyridinyl]The pyrimidin-4-ylamine derivatives are reacted in a Suzuki type reaction. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography, deprotection of the N-Boc derivative under acidic conditions with strong acids such as TFA, HCl in solvents such as DCM, DCE or 1, 4-dioxane, or deprotection of the N-Boc derivative by capture and release of sulfonic acid resins such as polymer-supported toluenesulfonic acid, and purification of the crude reaction product by normal phase chromatography or reverse phase preparative HPLC.

Scheme B3

Synthesis of [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine [263]

4- { 5-chloro-2- [2- (2-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B010]

Reacting 4- [ 5-chloro-2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B009](3g, 6.48mmol), 2-fluoroaniline (654. mu.L, 6.48mmol), Pd (OAc)₂A mixture of (79mg, 0.324mmol), Xantphos (375mg, 0.648mmol), cesium carbonate (4.11g, 12.6mmol) and anhydrous dioxane (20ml) was heated at 90 ℃ overnight. The solvent was evaporated under reduced pressure, toUltrafast column chromatography (ISCO, 120g SiO₂Barrel, 100% cyclohexane to 70% cyclohexane: 30% ethyl acetate gradient) to give the title compound as a yellow solid [ B010%](1.2g, 52% yield). LCMS method 5, RT 4.19min, MI 516.57[ M + H ]]。

4- { 5-cyclopropyl-2- [2- (2-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B011]

To a microwave vial was added 4- { 5-chloro-2- [2- (2-fluoro-phenylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B010]](1.8g，3.36mmol)、Pd(dppf)Cl₂.CH₂Cl₂(137mg，0.168mmol)、K₃PO₄(2.14g, 10.075mmol), cyclopropylboronic acid (578mg, 6.72mmol) and anhydrous dioxane (30ml) and a few drops of DMA were added dropwise. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (ISCO, 40g SiO)₂Barrel, 100% cyclohexane to 70% cyclohexane: 30% ethyl acetate gradient) to give the title compound [ B011] as a yellow solid](950mg, 52% yield). LCMS method 5, RT 4.72min, MI 542[ M + H]。

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine [263]

4- { 5-cyclopropyl-2- [2- (2-fluoro-phenylamino) -pyridin-4-yl in 4N HCl in 1.5mL of dioxane)]-pyrido [3,4-d]Pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B011]](300mg, 0.554mmol) of the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase flash column chromatography (ISCO, 24g SiO)₂Barrel, 100% H₂O: 0.1% formic acid to 20% H₂O: 0.1% formic acid: 80% methanol: 0.1% formic acid gradient) the residue. The residue was diluted with methanol (5mL) and poured onto a 1g SCX-2 cartridge, washed with DCM and methanol, then 2N NH₃Methanol elution, evaporation under reduced pressure to give the title compound as a yellow solid [263](110mg, 45% yield). LCMS method 1, RT 4.03min, MI 442[ M + H ]]；NMR:(1H,500MHz,d6-dmso)；8.95(1H,s),8.27(1H,d),8.21(1H,m),8.08(1H,s),8.03(1H.s),7.70-7.69(1H,dd),7.23(1H,m),7.14(1H,m),6.99(1H,m),3.78-3.62(4H,m),2.84(4H,s),2.61(1H,m),1.25-1.24(2H,m),1.02-1.01(2H,m)。

The following compounds were synthesized following the general synthesis shown in scheme [ B3 ]:

overall Synthesis of 5-cyclopropyl substituted 2-aminopyridyl substituted 2- (2-amino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamine derivatives of the general formula [ G-012]

Scheme B4

General formula [ G-011 ]]5-cyclopropyl 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (a)]The pyrimidin-4-ylamine derivatives are prepared by reacting a compound of the formula [ G-010 ]]5-cyclopropyl 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (a)]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM and catalytic amounts of DMAPProtic solvents such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl esters with general formula [ G-004]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. By the general formula [ G-005]Suitable amine, palladium catalysts such as Pd (dba)₂Or Pd (OAc)₂Ligands such as Xantphos and bases such as NaOtBu or Cs₂CO₃In a polar solvent such as dioxane or a combination of dioxane and DMA, at elevated temperature obtained by heating or using a microwave reactor, the general formula [ G-011 ]]5-cyclopropyl 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d of (a)]The pyrimidin-4-ylamine derivatives undergo a Buchwald type reaction. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography, deprotection of the N-Boc derivative under acidic conditions with strong acids such as TFA, HCl in solvents such as DCM, DCE or 1, 4-dioxane, or deprotection of the N-Boc derivative by capture and release of sulfonic acid resins such as polymer-supported toluenesulfonic acid, and purification of the crude reaction product by normal phase chromatography or reverse phase preparative HPLC.

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4, 5-dimethyl-)Azol-2-yl) -amine [272]Synthesis of (2)

Synthesis of 3-bromo-5-fluoro-isonicotinic acid tert-butyl ester [ B012]

To a solution of LDA (2M, 72mL, 144mmol) in THF (100mL) cooled to about-70 deg.C was added dropwise via catheter a solution of 3-bromo-5-fluoropyridine (21.12g, 120mmol) in anhydrous THF (50mL) pre-cooled to-70 deg.C. The addition rate was controlled so that the internal temperature did not rise above-65 ℃. The dark red-brown solution was stirred for 1 hour. Di-tert-butyldicarbonate (52.4g, 240mmol) in THF (50mL) was cooled to-10 ℃ in a methanol/ice bath and then added dropwise to the dark red-brown solution via a catheter. The mixture was stirred for 2 hours, then allowed to warm to room temperature and stirred for another 1 hour. Saturated aqueous ammonium chloride (100mL) was added slowly followed by water (200mL) and ethyl acetate (200mL) and the mixture stirred vigorously for 45 minutes. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The THF and ethyl acetate layers were combined, dried over magnesium sulfate, filtered and evaporated. The recovered dark red-brown oil was purified by column chromatography (cyclohexane/AcOEt: 1/0 to 97/3). The fractions containing the desired material were concentrated in vacuo to afford the title compound [ B012] (14g, 85%) as a pale yellow oil. LCMS method 1, RT 5.44min, MI 277[ M + H ]; NMR (1H,300MHz, d 6-dmso); 8.56(s,1H),8.43(s,1H),1.62(s, 9H).

Synthesis of 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester [ B013]

A solution of 3-bromo-5-fluoro-isonicotinic acid tert-butyl ester [ B012] (5.52g, 20mmol), tripotassium phosphate (12.74g, 60mmol) and cyclopropylboronic acid (2.58g, 30mmol) in anhydrous dioxane (100mL) was treated with vacuum/argon balloon (three times). Dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloromethane adduct (0.408g, 0.5mmol) was added and the reaction was heated at 96 ℃ overnight under a positive pressure of nitrogen. The mixture was cooled to room temperature, filtered through a pad of 200g silica and washed with ethyl acetate (1L). The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (cyclohexane/AcOEt: 98:2 to 96: 4). The combined fractions were concentrated under reduced pressure to give the title compound [ B013] (3.42g, 72%) as a colorless oil. LCMS method 1, RT 5.36min, MI 238[ M + H ].

Synthesis of 3-cyclopropyl-5-fluoro-isonicotinic acid [ B014]

In a microwave vial, 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester [ B013] (1.186g, 5mmol) was dissolved in anhydrous methanol and then heated in the microwave at 140 ℃ for 1 hour. The reaction was concentrated in vacuo to give the title compound [ B014]0.84g (92%) as a white crystalline solid. LCMS method 1, RT:1.51min, MI:182[ M + H ].

Synthesis of 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-ol [ B015]

A mixture of 3-cyclopropyl-5-fluoro-isonicotinic acid [ B014] (5g, 27.6mmol) and HATU (10.5g, 82.86mmol) was stirred in DMF (35mL) and DIPEA (14.5mL, 82.86mmol) was added. The mixture was stirred at room temperature for 1 hour, then 2-chloro-isonicotinamidinimide hydrochloride (5.3g, 27.52mmol) was added in one portion and the mixture was stirred at room temperature for 18 hours. The crude reaction mixture was poured onto water (180mL) with constant stirring for 2 hours, then the beige solid was collected by filtration, washed with water and dried in a vacuum oven to give N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -3-cyclopropyl-5-fluoro-isonicotinamide (6.60g, 75% yield) which was used in the next step without further purification: LCMS method 1, RT:3.45min, MI:319[ M + H ]; NMR (1H,300MHz, d 6-dmso); 10.25(s, br,1H),9.92(s, br,1H),8.59(d,1H),8.42(s,1H),8.11(s,1H),8.00(s,1H),7.92(dd,1H),2.01(m,1H),0.98(m,2H),0.85(m, 2H).

A mixture of N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -3-cyclopropyl-5-fluoro-isonicotinamide (6.60g, 20.70mmol) and Cs2CO3(6.7g, 20.7mmol) and DMA (90mL) was heated at 90 ℃ overnight. The reaction mixture was poured into ice/water (100ml) and then acidified by dropwise addition of glacial acetic acid, and the mixture was stirred at 0 ℃ for 1 hour. The beige precipitate was collected by filtration, washed with water, and then dried in a vacuum oven to give the title compound [ B015] (4.8g, 78% yield). LCMS method 1, RT:3.90min, MI:299[ M + H ]; NMR (1H,300MHz, d 6-dmso); 12.92(s,1H),8.88(s,1H),8.66(d,1H),8.25(dd,2H),8.16(dd,1H),3.39(m,1H),1.11(m,2H),0.94(m, 2H).

4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B016]

Reacting 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-ol [ B015]]A mixture of (280mg, 0.937mmol), anhydrous DMF (9mL), triethylamine (0.390mL, 2.81mmol) and DMAP (115mg, 0.937mmol) was sonicated for 10 min and then stirred at room temperature for 10 min. 2,4, 6-triisopropyl-benzenesulfonyl chloride (340mg, 1.12mmol) was added and the mixture was sonicated for 5 minutes, then stirring was continued at room temperature for 2 hours. During which time the material goes into solution to form a viscous solution. 1-Boc-piperazine (190mg, 1.03mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and purified by flash column chromatography (SP1, 20g SiO)₂Cartridge, 100% DCM to 95% DCM: 5% methanol gradient) to give the title compound as a yellow solid [ B016](276mg, 63% yield). LCMS method 5, RT 5.16min, MI 467[ M + H](ii) a NMR (1H,500MHz, d 6-dmso); 9.02(1H, s),8.61(1H, dd),8.34(2H, m),8.15(1H, s),3.68-3.83(4H, very wide s),3.51(4H, br s),2.59(1H, m),1.24(2H, m),1.16(2H, m).

4- { 5-cyclopropyl-2- [2- (4, 5-dimethyl-Azol-2-ylamino) -pyridin-4-yl]-pyrido [ alpha ], [ alpha3,4-d]Pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B017 ]]

Reacting 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B016](280mg, 0.591mmol), 4, 5-dimethyl-Azol-2-ylamine (132mg, 1.18mml), Pd (OAc)₂A mixture of (7mg, 0.030mmol), Xantphos (35mg, 0.060mmol), cesium carbonate (384mg, 1.18mmol) and anhydrous dioxane (1.5ml) was heated at 90 deg.C overnight. The solvent was evaporated under reduced pressure and purified by flash column chromatography (SP1, 20 gSiO)₂Cartridge, 100% DCM to 96% DCM: 4% methanol gradient) to give the title compound as a beige solid [ B017](61mg, 19% yield). LCMS method 5, RT 4.07min, MI 543[ M + H ]]。

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4, 5-dimethyl-)Azol-2-yl) -amine [272]

4- { 5-cyclopropyl-2- [2- (4, 5-dimethyl-Azol-2-ylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ B017 ]](60mg, 0.112mmol) of the mixture was stirred at room temperature for 2 hours. After completion the solvent was evaporated under reduced pressure, the residue diluted with methanol (5mL) and poured onto a 1g SCX-2 cartridge, washed with DCM and methanol, then 2N NH₃Methanol elution and evaporation under reduced pressure. Then by flash column chromatography (SP1, 10g SiO)₂Cartridge, 100% DCM to 90% DCM: 10% methanol gradient) to give the title compound as a yellow solid [272](22mg, 44% yield). LCMS method 5, RT 2.70min, MI 443[ M + H ]]；NMR:(1H,500MHz,d6-dmso)；10.61(1H,s),9.17(1H,s),9.05(1H,s),8.38(1H,d),8.16(1H,s),7.87(1H,d),3.94(1H,s,br),3.26(4H,m,br),2.69(2H,m),2.19(3H,s),2.04(3H,s),1.25-1.22(3H,m),1.06-1.05(2H,m)。

The following compounds were synthesized following the general synthesis shown in scheme [ B4 ]:

synthesis of cyclopentyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine [281]

4- [2- (2-Cyclopentylamino-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ B018]

Reacting 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B016][ preparation following the general Synthesis shown in scheme B4](170mg, 0.364mmol), cyclopentylamine (73. mu.L, 0.728mmol), Pd (t-Bu)₃P)₂A mixture of (38mg, 0.073mmol), sodium tert-butoxide (54mg, 0.546mmol) and anhydrous dioxane (2ml) was heated at 110 ℃ overnight. The solvent was evaporated under reduced pressure and purified by flash column chromatography (SP1, 20g SiO)₂Cartridge, 100% DCM to 96% DCM: 4% methanol gradient) to give the title compound as a yellow solid [ B018%](92mg, 48% yield). LCMS method 5, RT 4.19min, MI 516.57[ M + H ]]。

Cyclopentyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine [281]

4- [2- (2-Cyclopentylamino-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] in 4N HCl in dioxane (2mL)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester [ B018](90mg, 0.178mmol) of the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue diluted with methanol (5mL) and poured onto a 1g SCX-2 cartridge, washed with DCM and methanol, then 2N NH₃Methanol elution and evaporation under reduced pressure. Then by flash column chromatography (SP1, 10 gSiO)₂Cartridge, 100% DCM to 95% DCM: 5% methanol gradient) to give the title compound as a yellow solid [281](26mg, 37% yield). LCMS method 5, RT 2.22min, MI 416.25[ M + H ]]；NMR:(1H,500MHz,d6-dmso)；8.95(1H,s),8.10(2H,d),8.08(1H,s),7.51(1H,s),7.38(1H,dd),6.75(1H,d),4.17(1H,m),3.84-3.65(4H,m),3.11(4H,m),2.91(1H,m),2.62(2H,m),1.98-1.92(2H,m),1.69(2H,m),1.55(2H,m),1.46(2H,m),1.24-1.22(2H,m),1.03(2H,m)。

The following compounds were synthesized following the general synthesis shown in scheme [ B4 ]:

example 303.2-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide

303a) Preparation of 2- (2-chloro-pyrido) from 2-chloro-isonicotinic acid (0.60g, 4.3mmol) and 3-amino-isonicotinic acid (0.50g, 3.6mmol) in analogy to example 1aPyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ol. The product was isolated as a dark brown solid (0.479g, 51%).¹HNMR(400MHz,d6-DMSO,,ppm):13.13(br s,1H),9.19(s,1H),8.74(d,J＝4.2Hz,1H),8.66(d,J＝5.1Hz,1H),8.24(s,1H),8.15(d,J＝5.1Hz,1H),8.02(d,J＝4.8Hz,1H)。MS＝259,261(MH)+。

303b) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Preparation of (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] using pyrimidin-4-ol (1.50g, 5.80mmol) and (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1.1mL, 6.6mmol)]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester. The product was isolated as a yellow foam (2.15g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):9.22(s,1H),8.76(d,J＝5.7Hz,1H),8.69(d,J＝5.4Hz,1H),8.61(d,J＝4.6Hz,1H),8.37-8.29(m,3H),4.94(br s,1H),3.88-3.71(m,1H),3.55-3.29(m,3H),2.37-2.25(m,1H),2.19-2.04(m,1H),1.46-1.39(m,9H)。MS＝427,429(MH)+。

303c) Charging a tube with (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d under a nitrogen atmosphere]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol), 2-amino-benzamide (35.0mg, 0.257mmol), palladium acetate (5.0mg, 0.022mmol), 4, 5-bis- (di-tert-butyl-phosphino) -9, 9-dimethyl-9H-xanthene (12.0mg, 0.0241mmol), cesium carbonate (115.0mg, 0.3530mmol) and 1, 4-dioxane (1mL, 10 mmol). The tube was carefully evacuated and back flushed once with nitrogen. The tube was sealed and heated at 100 ℃ and stirred overnight. The mixture was cooled to room temperature, diluted with dichloromethane (10mL), filtered through a plug of celite and evaporated to a dark resin. Trifluoroacetic acid (0.5mL) and dichloromethane (0.5mL) were added to the residue. The mixture was stirred for 1 hour and the volatiles were evaporated. The residue was purified by reverse phase chromatography (10% → 30% acetonitrile: water w/TFA modifier) using a Gilson instrument. Isolation of yellow lyophilisate 2-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] as trifluoroacetate salt]Pyrimidin-2-yl]-pyridin-2-yl } -benzamide (0.009g, 9%).¹HNMR(400MHz,d6-DMSO,,ppm):9.28(s,1H),9.15(s,1H),8.88(br s,2H),8.75-8.70(m,2H),8.55(d,J＝5.1Hz,1H),8.27(d,J＝5.4Hz,1H),8.13(d,J＝4.3Hz,1H),7.77(d,J＝8.4Hz,1H),7.24(t,J＝8.4Hz,1H),6.80(d,J＝8.6Hz,1H),6.60(t,J＝7.2Hz,1H),4.93(br s,1H),3.80-3.70(m,1H),3.52-3.35(m,3H),2.53-2.40(m,2H),2.32-2.24(m,1H)。MS＝427(MH)+。

Example 304.4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -benzamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] using tert-butyl-pyrrolidine-1-carboxylate (100.0mg, 0.2342mmol) and 4-amino-benzamide (35.0mg, 0.257mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -benzamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.008g, 8%).¹HNMR(400MHz,d6-DMSO,,ppm):9.67(s,1H),9.24(s,1H),8.87(br s,2H),8.74-8.69(m,1H),8.40(d,J＝5.2Hz,1H),8.26(d,J＝5.7Hz,1H),8.02(s,1H),7.84-7.74(m,6H),7.13(br s,1H),4.95(br s,1H),3.80-3.30(m,3H),2.52-2.38(m,2H),2.31-2.22(m,1H)。MS＝427(MH)+。

Example 305.4-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide

4-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -benzamide is the by-product isolated from example 304 as an orange-brown lyophilizate of trifluoroacetate (0.012g, 12%).¹HNMR(400MHz,d6-DMSO,,ppm):10.41(s,1H),9.28(s,1H),9.23(s,1H),8.87(brs,2H),8.75-8.70(m,2H),8.54-8.50(m,1H),8.27(d,J＝5.2Hz,1H),8.10(d,J＝4.8Hz,1H),7.85(d,J＝8.1Hz,2H),6.61(d,J＝7.7Hz,2H),4.95-4.88(m,1H),3.82-3.30(m,3H),2.55-2.40(m,2H),2.33-2.25(m,1H)。MS＝427(MH)+。

EXAMPLE 306 {4- [ (1S,4S) -4- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine

306a) From 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 301b]Pyrimidin-4-ol (250.0mg, 0.9665mmol) and (1S,4S) -2, 5-diaza-bicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (215.0mg, 1.084mmol) preparation of (1S,4S) -5- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-2, 5-diaza-bicyclo [2.2.1]Tert-butyl heptane-2-carboxylate. The product was isolated as a yellow resin (0.110g, 26%).¹HNMR(400MHz,d6-DMSO,,ppm):9.22(s,1H),8.62-8.55(m,2H),8.37-8.32(m,2H),8.07-8.03(m,1H),5.53(d,J＝18.5Hz,1H),4.62(d,J＝18.5Hz,1H),4.33(br s,1H),3.92(br s,1H),3.62-3.44(m,2H),2.08-2.00(m,2H),1.45-1.30(m,9H)。MS＝439,441(MH)+。

306b) From (1S,4S) -5- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-yl]-2, 5-diaza-bicyclo [2.2.1]Preparation of tert-butyl heptane-2-carboxylate (115.0mg, 0.2620mmol) and aniline (27.0. mu.L, 0.296mmol) to {4- [ (1S,4S) -4- (2, 5-diaza-bicyclo [2.2.1]Hept-2-yl) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -phenyl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.133g, 128%).¹HNMR(400MHz,d6-DMSO,,ppm):9.49(br s,1H),9.28(s,1H),9.23(br s,1H),8.65(d,J＝5.4Hz,1H),8.45(br s,1H),8.33-8.29(m,1H),8.03(d,J＝5.6Hz,1H),7.99(s,1H),7.76-7.70(m,3H),7.32(t,J＝7.4Hz,2H),7.00-6.93(m,1H),5.49(s,1H),4.62(s,1H),4.44(d,J＝10.8Hz,1H),4.12(d,J＝11.1Hz,1H),3.61-3.41(m,2H),2.34(d,J＝10.4Hz,1H),2.07(d,J＝10.9Hz,1H)。MS＝396(MH)+。

Example 307 pyrazine-2-carboxylic acid {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and pyrazine-2-carboxylic acid amide (32.0mg, 0.260mmol) to prepare pyrazine-2-carboxylic acid {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -amide. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.099g, 100%).¹HNMR(400MHz,d6-DMSO,,ppm):10.50(s,1H),9.40(s,1H),9.34(s,1H),9.30(s,1H),9.02-8.86(m,4H),8.77(d,J＝4.4Hz,1H),8.74(d,J＝5.4Hz,1H),8.60(d,J＝5.0Hz,1H),8.28(d,J＝5.5Hz,1H),8.21(d,J＝5.1Hz,1H),4.98-4.90(m,1H),3.84-3.74(m,2H),3.54-3.38(m,3H),2.53-2.42(m,1H),2.35-2.25(m,1H)。MS＝414(MH)+。

Example 308.3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -benzamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] from-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 3-amino-benzamide (35.0mg, 0.257mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -benzamide. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.005g, 5%).¹HNMR(400MHz,d6-DMSO,,ppm):9.49(s,1H),9.24(s,1H),8.85(br s,1H),8.72(d,J＝5.1Hz,1H),8.70-8.67(m,1H),8.36(d,J＝5.4Hz,1H),8.24(d,J＝5.0Hz,1H),8.18(s,1H),7.99(s,1H),7.95-7.88(m,2H),7.77(d,J＝4.5Hz,1H),7.41(d,J＝7.2Hz,1H),7.37(d,J＝8.1Hz,1H),7.34-7.29(m,1H),4.99-4.91(m,1H),3.76-3.69(m,1H),3.51-3.45(m,1H),3.43-3.34(m,3H),2.50-2.38(m,2H),2.31-2.22(m,1H)。MS＝427(MH)+。

Example 309.3-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide

3-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -benzamide was isolated as the free base from example 309By-product as an off-white solid (0.007g, 7%).¹HNMR(400MHz,d6-DMSO,,ppm):10.53(s,1H),9.21(s,2H),8.66(d,J＝5.3Hz,1H),8.54(br s,1H),8.53(d,J＝4.5Hz,1H),8.35-8.30(m,1H),8.12(d,J＝4.8Hz,1H),7.24-7.19(m,2H),7.15(t,J＝7.5Hz,1H),6.77(d,J＝7.7Hz,1H),5.31(s,2H),4.77(br s,1H),3.24(br s,1H),3.05-2.80(m,3H),2.23(br s,1H),1.90(br s,1H)。MS＝427(MH)+。

Example 310.2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide

310a) To a stirred suspension of 4-nitrophenol (2.00g, 14.4mmol) and potassium carbonate (3.0g, 22mmol) in acetone (20mL, 300mmol) was added ethyl bromoacetate (1.60mL, 14.4 mmol). The mixture was heated at 30 ℃ overnight. The mixture was cooled to room temperature, diluted with ether (50mL) and filtered through a plug of celite and evaporated. (4-Nitro-phenoxy) -acetic acid ethyl ester was isolated as an off-white solid (3.20g, 99%).¹HNMR(400MHz,CDCl3,,ppm):8.22(d,J＝7.8Hz,2H),6.98(d,J＝7.8Hz,2H),4.72(s,2H),4.29(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H)。MS＝226(MH)+。

310b) A parr (Paar) bottle (500mL) was charged with 10% palladium on carbon (50% wet) (5:45:50, palladium: carbon black: water, 3.0g, 1.4mmol), followed by 2:1 ethyl acetate: (4-Nitrophenoxy) -acetic acid ethyl ester (3.20g, 14.2mmol) in methanol (2:1, ethyl acetate: methanol, 75mL, 510 mmol). The mixture was degassed and loaded with hydrogen (50 psi). The mixture was shaken on a parr instrument until hydrogen adsorption ceased. The mixture was degassed and back flushed with nitrogen. The mixture was filtered through a plug of celite and evaporated. (4-amino-phenoxy) -acetic acid ethyl ester was isolated as a dark brown solid (2.65g, 96%).¹HNMR(400MHz,CDCl3,,ppm):6.77(d,J＝7.9Hz,1H),6.63(d,J＝7.8Hz,1H),4.54(s,2H),4.26(q,J＝7.1Hz,2H),3.40(br s,2H),1.29(t,J＝7.1Hz,3H)。MS＝196(MH)+。

310c) From (R) -3- [2- (2-chloro) in a similar manner to example 303c-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ylamino]Preparation of (R) -3- {2- [2- (4-ethoxycarbonylmethoxy-phenylamino) -pyridin-4-yl ] -3- {2- [2- (4-ethoxycarbonylmethoxy-phenylamino) -p-yridine-4-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester (200.0mg, 0.4685mmol) and (4-amino-phenoxy) -acetic acid ethyl ester (100.0mg, 0.5122mmol)]-pyrido [3,4-d]Pyrimidin-4-ylamino } -pyrrolidine-1-carboxylic acid tert-butyl ester. The orange residue was suspended in methanol (1mL, 20mmol) and water (1mL, 60mmol), and lithium hydroxide monohydrate (25.0mg, 0.596mmol) was added. The mixture was stirred at room temperature overnight. The volatiles were evaporated to give an orange solid. The orange solid was suspended in 1, 4-dioxane (5mL, 60 mmol). Pyridine (0.1mL, 1mmol) was added followed by di-tert-butyl dicarbonate (105.0mg, 0.4811mmol) and ammonium carbonate (70.0mg, 0.728 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (25mL), filtered through a plug of celite and the filtrate evaporated. The solid was dissolved in dichloromethane (1mL) and trifluoroacetic acid (0.5mL) was added. The mixture was stirred at room temperature for 1 hour, then the volatiles were evaporated. The residue was purified by reverse phase chromatography (5% → 30% acetonitrile: water w/0.1% TFA modifier) using a Gilson instrument. 2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) as trifluoroacetate salt isolated as an orange yellow lyophilizate]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenoxy) -acetamide (0.118g, 55%).¹HNMR(400MHz,d6-DMSO,,ppm):9.62(br s,1H),9.24(s,1H),8.98(br s,2H),8.76(d,J＝4.5Hz,1H),8.73(d,J＝5.3Hz,1H),8.27(d,J＝5.6Hz,1H),8.21(d,J＝5.3Hz,1H),7.96(s,1H),7.74(d,J＝5.5Hz,1H),7.57(d,J＝8.1Hz,2H),7.54(s,1H),7.42(s,1H),6.99(d,J＝8.4Hz,2H),4.96-4.86(m,1H),4.43(s,2H),3.74-3.64(m,1H),3.54-3.34(m,3H),2.45-2.35(m,1H),2.31-2.21(m,1H)。MS＝457(MH)+。

Example 311.2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide

311a) (3-Nitrophenoxy) -acetic acid ethyl ester was prepared in a similar manner to example 310a from m-nitrophenol (2.00g, 14.4mmol) and ethyl bromoacetate (1.60mL, 14.4 mmol). Is separated outProduct of yellow oil (3.20g, 99%).¹HNMR(400MHz,CDCl3,,ppm):7.88(d,J＝8.1Hz,1H),7.73(s,1H),7.46(t,J＝8.3Hz,1H),7.27(d,J＝8.5Hz,1H),4.71(s,2H),4.30(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H)。LC/MS＝248(M+Na)+。

311b) (3-Aminophenoxy) -acetic acid ethyl ester was prepared in a similar manner to example 310b from (3-nitrophenoxy) -acetic acid ethyl ester (3.20g, 14.2 mmol). The product was isolated as an orange oil (2.60g, 94%).¹HNMR(400MHz,CDCl3,,ppm):7.05(t,J＝7.8Hz,1H),6.35-6.26(m,3H),4.57(s,2H),4.27(q,J＝7.2Hz,2H),3.67(br s,2H),1.30(t,J＝7.1Hz,3H)。MS＝196(MH)+。

311c) From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 310c]Pyrimidin-4-ylamino]Preparation of 2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] using tert-butyl-pyrrolidine-1-carboxylate (200.0mg, 0.4685mmol) and ethyl (3-aminophenoxy) -acetate (100.0mg, 0.5122mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenoxy) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.011g, 5%).¹HNMR(400MHz,d6-DMSO,,ppm):9.40(br s,1H),9.23(s,1H),8.85(brs,2H),8.72(d,J＝5.3Hz,1H),8.69D,J＝5.1Hz,1H),8.35(d,J＝4.8Hz,1H),8.26(d,J＝5.3Hz,1H),7.98(s,1H),7.75(d,J＝5.2Hz,1H),7.55(s,1H),7.52(s,1H),7.39(s,1H),7.28(d,J＝7.9Hz,1H),7.20(t,J＝7.9Hz,1H),6.51(d,J＝8.3Hz,1H),4.98-4.90(m,1H),4.41(s,2H),3.76-3.70(m,1H),3.52-3.33(m,3H),2.45-2.38(m,1H),2.30-2.23(m,1H)。MS＝457(MH)+。

Example 313.2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide

313a) [ A ] into 1, 4-dioxane (10mL, 100mmol)]A stirred suspension of 4-nitrophenylacetic acid (1.0g, 5.5mmol) and pyridine (0.27mL, 3.3mmol) was added di-tert-butyl dicarbonate (1.3g, 6.1 mmol). The mixture was stirred at room temperature for 10 minutes, then ammonium carbonate (0.80g, 8.3mmol) was added. Will be mixed withThe mixture was stirred at room temperature overnight. The volatiles were evaporated to leave an off-white solid. The solid was triturated with methanol, filtered and rinsed with methanol. The methanol filtrate was evaporated. 2- (4-Nitro-phenyl) -acetamide was isolated as an off-white solid (0.65g, 65%).¹HNMR(400MHz,d6-DMSO,,ppm):8.18(d,J＝7.9Hz,2H),7.59(br s,1H),7.54(d,J＝7.9Hz,2H),7.01(br s,1H),3.55(s,2H)。LC/MS＝181(MH)+。

313b) 2- (4-amino-phenyl) -acetamide was prepared in analogy to example 310b from 2- (4-nitro-phenyl) -acetamide (0.65g, 3.6 mmol). The product was isolated as a pale yellow solid (0.57g, 99%).¹HNMR(400MHz,d6-DMSO,,ppm):7.25(br s,1H),6.89(d,J＝8.1Hz,2H),6.74(br s,1H),6.47(d,J＝8.2Hz,2H),4.89(br s,2H),3.14(s,2H)。MS＝151(MH)+。

313c) In a manner analogous to example 303c from [ A ]](R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ylamino]Preparation of 2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -c-yrido [3, 4-d) from tert-butyl-pyrrolidine-1-carboxylate (200.0mg, 0.4685mmol) and 2- (4-amino-phenyl) -acetamide (85.0mg, 0.566mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.029g, 14%).¹HNMR(400MHz,d6-DMSO,,ppm):9.36(br s,1H),9.23(s,1H),8.85(brs,2H),8.72(d,J＝5.6Hz,1H),8.70-8.67(m,1H),8.30(d,J＝5.1Hz,1H),8.25(d,J＝5.5Hz,1H),7.96(s,1H),7.72(d,J＝5.2Hz,1H),7.63(d,J＝7.4Hz,2H),7.42(br s,1H),7.20(d,J＝8.3Hz,2H),6.86(br s,1H),4.96-4.87(m,1H),3.75-3.65(m,1H),3.51-3.30(m,5H),2.46-2.36(m,1H),2.31-2.21(m,1H)。MS＝441(MH)+。

Example 314.2- (4-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

2- (4-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide is a by-product from example 313. Isolating yellow lyophilisateProduct as trifluoroacetate (0.018g, 8%).¹HNMR(400MHz,d6-DMSO,,ppm):10.84(s,1H),9.24(s,1H),9.12(s,1H),8.94(br s,2H),8.71(d,J＝5.5Hz,2H),8.50(d,J＝5.2Hz,1H),8.26(d,J＝5.7Hz,1H),8.09(d,J＝4.6Hz,1H),7.34(d,J＝8.0Hz,2H),7.08(d,J＝7.5Hz,2H),4.95-4.87(m,1H),3.77-3.65(m,3H),3.51-3.33(m,3H),2.47-2.36(m,1H),2.31-2.21(m,1H)。MS＝441(MH)+。

Example 316.2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide

316a) 2- (3-Nitro-phenyl) -acetamide was prepared in analogy to example 13a from (3-nitro-phenyl) -acetic acid (1.0g, 5.5 mmol). The crude product was isolated as an off-white solid (1.2g, 50%).¹HNMR(400MHz,d6-DMSO,,ppm):8.15(s,1H),8.10(d,J＝8.2Hz,1H),7.71(d,J＝7.7Hz,1H),7.63-7.54(m,2H),7.01(br s,1H),3.56(s,2H)。MS＝181(MH)+。

316b) 2- (3-amino-phenyl) -acetamide was prepared in analogy to example 10b from 2- (3-nitro-phenyl) -acetamide (1.2g, 6.7 mmol). The product was isolated as an off-white solid (1.0g, 70%).¹HNMR(400MHz,d6-DMSO,,ppm):7.32(br s,1H),6.90(t,J＝7.7Hz,1H),6.79(br s,1H),6.46(s,1H),6.42-6.37(m,2H),4.97(br s,2H),3.18(s,2H)。MS＝151(MH)+。

316c) From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -p-yrido [3,4-d ] using tert-butyl-pyrrolidine-1-carboxylate (200.0mg, 0.4685mmol) and 2- (3-amino-phenyl) -acetamide (85.0mg, 0.566mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.055g, 26%).¹HNMR(400MHz,d6-DMSO,,ppm):9.50(br s,1H),9.24(s,1H),8.91(br s,2H),8.72(d,J＝5.5Hz,1H),8.31(d,J＝5.4Hz,1H),8.26(d,J＝5.7Hz,1H),7.99(s,1H),7.75(d,J＝5.4HZ,1H),7.66(d,J＝8.6Hz,1H),7.54(s,1H),7.48(br s,1H),7.25(t,J＝7.7Hz,1H),6.93-6.86(m,2H),4.97-4.87(m,1H),3.76-3.66(m,1H),3.54-3.34(m,5H),2.46-2.36(m,1H),2.31-2.21(m,1H)。MS＝441(MH)+。

Example 317.2- (3-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

2- (3-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide is a by-product from example 16. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.047g, 23%).¹HNMR(400MHz,d6-DMSO,,ppm):10.90(s,1H),9.24(s,1H),9.14(s,1H),8.94(br s,2H),8.75-8.70(m,2H),8.51(d,J＝5.1Hz,1H),8.26(d,J＝5.5Hz,1H),8.10(dd,J＝5.1,1.1Hz,1H),7.28(t,J＝7.8Hz,1H),7.10-7.02(m,3H),6.94(d,J＝6.6Hz,1H),6.40-4.00(m,3H),3.76(s,2H),3.75-3.65(m,1H),3.52-3.32(m,3H),2.47-2.36(m,1H),2.31-2.21(m,1H)。MS＝441(MH)+。

EXAMPLE 318 {2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -2-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0mg, 0.176mmol) and 5-phenyl-pyridin-2-ylamine (36.0mg, 0.212mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.098g, 97%).¹HNMR(400MHz,d6-DMSO,,ppm):9.28(s,1H),8.92(br s,2H),8.78-8.74(m,2H),8.66-8.63(m,2H),8.49(d,J＝5.8Hz,1H),8.29(d,J＝5.2Hz,1H),8.24-8.18(m,1H),8.04-8.01(m,1H),7.80-7.71(m,3H),7.55-7.49(m,2H),7.44-7.39(m,1H),5.00-4.92(m,1H),3.80-3.71(m,1H),3.55-3.35(m,3H),2.48-2.40(m,1H),2.34-2.25(m,1H)。MS＝461(MH)+。

EXAMPLE 319 {2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyridin-3-ylamine from-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0mg, 0.176mmol) and 6-morpholin-4-yl-pyridin-3-ylamine (39.0mg, 0.218mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as an orange-brown lyophilizate (0.082g, 80%).¹HNMR(400MHz,d6-DMSO,,ppm):9.71(br s,1H),9.24(s,1H),9.01(br s,2H),8.77(d,J＝5.5Hz,1H),8.73(d,J＝5.5Hz,1H),8.62(br s,1H),8.29-8.24(m,2H),8.01-7.95(m,2H),7.78(dd,J＝5.5,1.3Hz,1H),7.15(d,J＝9.2Hz,1H),4.98-4.90(m,1H),3.78-3.67(m,5H),3.55-3.34(m,8H),2.46-2.36(m,1H),2.31-2.21(m,1H)。MS＝470(MH)+。

EXAMPLE 320 (2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d } pyrimidin-4-ylamino in a similar manner to example 303c]Preparation of (2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino-n-yl) -pyridin-3-ylamine from (tert-butyl) -pyrrolidine-1-carboxylate (75.0mg, 0.176mmol) and 6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamine (41.0mg, 0.213mmol)]-pyridin-4-yl } -pyrido [3,4-d]Pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a brown lyophilizate (0.094g, 90%).¹HNMR(400MHz,d6-DMSO,,ppm):9.86(br s,1H),9.45(brs,1H),9.22(s,1H),9.04(br s,2H),8.76(d,J＝5.4Hz,1H),8.72(d,J＝5.6Hz,1H),8.51(d,J＝2.7Hz,1H),8.27(d,J＝5.8Hz,1H),8.24(d,J＝5.6Hz,1H),8.02(dd,J＝9.0,2.6Hz,1H),7.93(s,1H),7.73(dd,J＝5.4,1.2Hz,1H),7.02(d,J＝9.2Hz,1H),4.99-4.90(m,1H),4.38-4.25(m,2H),3.78-3.68(m,1H),3.59-3.34(m,5H),3.18-3.02(m,4H),2.87(s,3H),2.47-2.36(m,1H),2.31-2.22(m,1H)。MS＝483(MH)+。

Example 321.2- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

2- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile was prepared in analogy to example 303c from (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -pyrrolidine-1-carboxylic acid tert-butyl ester (75.0mg, 0.176mmol) and 2-amino-isonicotinonitrile (25.0mg, 0.210 mmol). The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.012g, 13%).

EXAMPLE 322 {2- [2- (4-Imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (4-imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl-aniline (75.0mg, 0.176mmol) from tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.176mmol) and 4-imidazol-1-ylmethyl-aniline (37.0mg, 0.214mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.097g, 95%).¹HNMR(400MHz,d6-DMSO,,ppm):9.56(s,1H),9.24(t,J＝1.4Hz,1H),9.22(s,1H),9.06(br s,2H),8.77(d,J＝5.4Hz,1H),8.71(d,J＝5.5Hz,1H),8.33(d,J＝5.5Hz,1H),8.27(d,J＝5.8Hz,1H),7.97(s,1H),7.83-7.76(m,4H),7.70(t,J＝1.7Hz,1H),7.38(d,J＝8.7Hz,2H),5.36(s,2H),5.01-4.92(m,1H),3.78-3.69(m,1H),3.55-3.34(m,3H),2.47-2.36(m,1H),2.31-2.22(m,1H)。MS＝464(MH)+。

Example 323.2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 10c and example 1c]Pyrimidin-4-ylamino]Preparation of 2-3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] -2-3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -acetic acid tert-butyl ester (150.0mg, 0.3283mmol) and (3-aminophenoxy) -acetic acid ethyl ester (75.0mg, 0.384mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenoxy) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.082g, 41%).¹HNMR(400MHz,d6-DMSO,,ppm):9.42(s,1H),8.94(br s,1H),8.89-8.80(m,2H),8.41(s,1H),8.34(d,J＝5.2Hz,1H),8.16(d,J＝6.2Hz,1H),7.95(s,1H),7.72(dd,J＝5.4,1.3Hz,1H),7.54(t,J＝2.1Hz,1H),7.52(s,1H),7.38(s,1H),7.30-7.25(m,1H),7.20(t,J＝8.2Hz,1H),6.51(dd,J＝7.8,1.7Hz,1H),5.05-4.95(m,1H),4.41(s,2H),4.16(m,3H),3.73-3.64(m,1H),3.52-3.30(m,3H),2.53-2.45(m,1H),2.27-2.16(m,1H)。MS＝487(MH)+。

Example 324.2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -e-ridine-3-d) with tert-butyl-pyrrolidine-1-carboxylate (150.0mg, 0.3283mmol) and 2- (3-amino-phenyl) -acetamide (60.0mg, 0.400mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.043g, 22%).¹HNMR(400MHz,d6-DMSO,,ppm):9.36(s,1H),9.00-8.77(m,3H),8.40(s,1H),8.31(d,J＝5.4Hz,1H),8.15(d,J＝6.2Hz,1H),7.94(s,1H),7.72-7.65(m,2H),7.56(s,1H),7.46(s,1H),7.22(t,J＝7.7Hz,1H),6.90-6.83(m,2H),5.05-4.95(m,1H),4.16(s,3H),3.73-3.63(m,1H),3.50-3.23(m,5H),2.55-2.45(m,1H),2.26-2.16(m,1H)。MS＝471(MH)+。

Example 325.2- (3-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

2- (3-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide is a by-product from example 24. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.033g, 17%).¹HNMR(400MHz,d6-DMSO,,ppm):10.84(s,1H),9.11(s,1H),9.00-8.78(m,3H),8.50(d,J＝5.5Hz,1H),8.40(s,1H),8.15(d,J＝5.9Hz,1H),8.06(dd,J＝5.2,1.4Hz,1H),7.25-7.10(m,1H),7.00-6.65(m,3H),5.00-4.01(m,1H),4.15(s,3H),3.80-3.28(m,8H),2.55-2.45(m,1H),2.26-2.16(m,1H)。MS＝471(MH)+

Example 326.2- (4- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (4- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (4- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -e-ridine-3-d) with tert-butyl-pyrrolidine-1-carboxylate (150.0mg, 0.3283mmol) and 2- (4-amino-phenyl) -acetamide (60.0mg, 0.400mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.072g, 37%).¹HNMR(400MHz,d6-DMSO,,ppm):9.29(s,1H),9.10-8.80(m,3H),8.40(s,1H),8.31(d,J＝5.3Hz,1H),8.15(d,J＝6.1Hz,1H),7.92(s,1H),7.68(dd,J＝5.3,1.3Hz,1H),7.63(d,J＝8.5Hz,2H),7.43-7.39(m,1H),7.18(d,J＝8.5Hz,2H),6.84(s,1H),5.05-4.95(m,1H),4.16(s,3H),3.72-3.63(m,1H),3.50-3.20(m,5H),2.54-2.45(m,1H),2.26-2.16(m,1H)。MS＝471(MH)+。

Example 327.2- (4-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

2- (4-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide is a by-product from example 26. The product was isolated as the trifluoroacetate salt as a yellow lyophilizate (0.025g, 13%).¹HNMR(400MHz,d6-DMSO,,ppm):10.81(s,1H),9.09(s,1H),9.02-8.83(m,3H),8.49(dd,J＝5.2,0.70Hz,1H),8.40(s,1H),8.16(d,J＝6.0Hz,1H),8.05(dd,J＝5.2,1.5Hz,1H),7.28(d,J＝7.8Hz,2H),7.00-6.93(m,2H),5.01-4.91(m,1H),4.15(s,3H),3.72-3.61(m,3H),3.47-3.28(m,3H),2.54-2.44(m,1H),2.26-2.16(m,1H)。MS＝471(MH)+。

Example 328.1- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0mg, 0.176mmol) and 1H-pyrrolo [2,3-b ]]Preparation of 1- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] using pyridine-4-carbonitrile (30.0mg, 0.210mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -1H-pyrrolo [2, 3-b)]Pyridine-4-carbonitrile. The product was isolated as trifluoroacetate salt as an off-white lyophilizate (0.068g, 71%).¹HNMR(400MHz,d6-DMSO,,ppm):9.83(s,1H),9.31(s,1H),8.89(brs,2H),8.79-8.75(m,4H),8.72(d,J＝4.9Hz,1H),8.37(d,J＝5.2Hz,1H),8.30(d,J＝5.6Hz,1H),7.87(d,J＝4.9Hz,1H),7.04(d,J＝3.9Hz,1H),5.00-4.91(m,1H),3.83-3.74(m,1H),3.57-3.39(m,3H),2.54-2.44(m,1H),2.37-2.30(m,1H)。MS＝434(MH)+。

EXAMPLE 329 { 5-methoxy-2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (C) in a manner analogous to example 303c2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ylamino]Preparation of { 5-methoxy-2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -5-methoxy-2-amine from-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0mg, 0.164mmol) and 5-phenyl-pyridin-2-ylamine (31.0mg, 0.182mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.043g, 43%).¹HNMR(400MHz,d6-DMSO,,ppm):9.04-8.85(m,3H),8.66-8.61(m,2H),8.48(d,J＝5.5Hz,1H),8.44(s,1H),8.23-8.15(m,2H),8.00-7.95(m,1H),7.82-7.75(m,1H),7.74-7.71(m,2H),7.51(t,J＝7.6Hz,2H),7.41(t,J＝7.1Hz,1H),5.07-5.00(m,1H),4.18(s,3H),3.76-3.66(m,1H),3.54-3.30(m,3H),2.55-2.45(m,1H),2.30-2.20(m,1H)。MS＝491(MH)+。

EXAMPLE 330 { 5-methoxy-2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of { 5-methoxy-2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyridin-3-ylamine from (75.0mg, 0.164mmol) tert-butyl-pyrrolidine-1-carboxylate and (33.0mg, 0.184mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a dark brown lyophilizate (0.033g, 33%).¹HNMR(400MHz,d6-DMSO,,ppm):9.02-8.82(m,3H),8.60-8.52(m,1H),8.41(s,1H),8.26(d,J＝4.8Hz,1H),8.17(d,J＝4.4Hz,1H),8.00-7.95(m,1H),7.89(s,1H),7.72-7.68(m,1H),7.10-6.98(m,1H),5.05-4.95(m,1H),4.16(s,3H),3.76-3.63(m,5H),3.50-3.29(m,7H),2.54-2.45(m,1H),2.26-2.16(m,1H)。MS＝500(MH)+。

EXAMPLE 331 (5-methoxy-2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of (5-methoxy-2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino) -pyridin-3-ylamine from (tert-butyl) -pyrrolidine-1-carboxylate (75.0mg, 0.164mmol) and 6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamine (35.0mg, 0.182mmol)]-pyridin-4-yl } -pyrido [3,4-d]Pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine. The product was isolated as bis-trifluoroacetate as a brown lyophilizate (0.036g, 29%).¹HNMR(400MHz,d6-DMSO,,ppm):9.69(br s,1H),9.26(br s,1H),9.06-8.81(m,3H),8.51(d,J＝2.6Hz,1H),8.40(s,1H),8.25(d,J＝5.5Hz,1H),8.16(d,J＝6.0Hz,1H),8.04(dd,J＝9.1,2.6Hz,1H),7.86(s,1H),7.67(d,J＝5.3Hz,1H),6.98(d,J＝9.0Hz,1H),5.04-4.98(m,1H),4.32-4.26(m,2H),4.16(s,3H),3.71-3.65(m,1H),3.55-3.50(m,2H),3.50-3.30(m,3H),3.16-3.01(m,4H),2.86(d,J＝4.3Hz,3H),2.53-2.43(m,1H),2.26-2.16(m,1H)。MS＝513(MH)+。

Example 332.2- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -e-nzo [ 3.4-d ] using tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.164mmol) and 2-amino-isonicotinic acid (22.0mg, 0.185mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -isonicotinonitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.014g, 15%).¹HNMR(400MHz,d6-DMSO,,ppm):10.42(s,1H),8.98-8.80(m,3H),8.60(s,1H),8.51(d,J＝5.1Hz,1H),8.48(d,J＝5.3Hz,1H),8.42(s,1H),8.34(s,1H),8.16(d,J＝5.8Hz,1H),7.92(dd,J＝5.2,1.3Hz,1H),7.32(dd,J＝5.0,1.3Hz,1H),5.03-4.95(m,1H),4.17(s,3H),3.75-3.66(m,1H),3.50-3.30(m,3H),2.55-2.45(m,1H),2.28-2.18(m,1H)。MS＝440(MH)+。

EXAMPLE 333 {2- [2- (4-Imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (4-imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl-aniline (75.0mg, 0.164mmol) from tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.164mmol) and 4-imidazol-1-ylmethyl-aniline (32.0mg, 0.185mmol)]-5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a yellow-orange lyophilizate (0.037g, 37%).¹HNMR(400MHz,d6-DMSO,,ppm):9.53(s,1H),9.24-9.22(m,1H),9.18-8.92(m,2H),8.82(s,1H),8.40(s,1H),8.33(d,J＝5.3Hz,1H),8.18(d,J＝6.3Hz,1H),7.94(s,1H),7.81(d,J＝8.6Hz,2H),7.78(t,J＝1.7Hz,1H),7.74(dd,J＝5.2,1.3Hz,1H),7.70(t,J＝1.7Hz,1H),7.37(d,J＝8.7Hz,2H),5.36(s,2H),5.08-4.99(m,1H),4.16(s,3H),3.74-3.64(m,1H),3.52-3.29(m,3H),2.53-2.43(m,1H),2.26-2.16(m,1H)。MS＝494(MH)+。

Example 334.2-phenyl-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2-phenyl-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] using tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.176mmol) and phenylacetamide (27.0mg, 0.200mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a dark brown lyophilizate (0.036g, 38%).¹HNMR(400MHz,d6-DMSO,,ppm):10.89(s,1H),9.25(s,1H),9.14(s,1H),8.90(br s,2H),8.73-8.69(m,2H),8.50(dd,J＝5.2,0.6Hz,1H),8.25(d,J＝5.2Hz,1H),8.09(dd,J＝5.2,1.4Hz,1H),7.41-7.24(m,5H),4.93-4.85(m,1H),3.79(s,2H),3.75-3.65(m,1H),3.51-3.33(m,3H),2.47-2.37(m,1H),2.31-2.21(m,1H)。MS＝426(MH)+。

Example 335.2- (4-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (4-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) -2- (4-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) with tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.176mmol) and 4-methoxyphenylacetamide (33.0mg, 0.200mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.021g, 21%).¹HNMR(400MHz,d6-DMSO,,ppm):10.81(s,1H),9.24(s,1H),9.13(s,1H),8.88(br s,2H),8.71(d,J＝5.6Hz,1H),8.69(d,J＝4.8Hz,1H),8.49(d,J＝5.2Hz,1H),8.25(d,J＝5.3Hz,1H),8.08(dd,J＝5.1,1.5Hz,1H),7.30(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),4.93-4.85(m,1H),3.75-3.65(m,6H),3.49-3.34(m,3H),2.47-2.37(m,1H),2.31-2.21(m,1H)。MS＝456(MH)+。

Example 336.2- (2-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

336a) 2- (2-methoxy-phenyl) -acetamide was prepared in a similar manner to example 13a from 2-methoxyphenylacetic acid (1.0g, 6.0 mmol). The product was isolated as a white solid (0.64g, 64%).¹HNMR(400MHz,d6-DMSO,,ppm):7.24-7.18(m,2H),7.15(dd,J＝7.5,1.6Hz,1H),6.95(d,J＝7.7Hz,1H),6.90-6.84(m,1H),6.81(br s,1H),3.75(s,3H),3.35(s,2H)。MS＝166(MH)+。

336b) From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (2-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) -2- (2-methoxy-phenyl) -acetamide (32.0mg, 0.194mmol) from tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.176mmol) and 2- (2-methoxy-phenyl) -acetamide]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. Isolation of dark brown lyophilisate as trifluoroacetic acid saltSubstance (0.048g, 48%).¹HNMR(400MHz,d6-DMSO,,ppm):10.66(s,1H),9.24(s,1H),9.12(s,1H),8.84(br s,2H),8.71(d,J＝5.7Hz,1H),8.69-8.65(m,1H),8.50(d,J＝5.2Hz,1H),8.25(d,J＝5.3Hz,1H),8.08(dd,J＝5.3,1.3Hz,1H),7.30-7.23(m,2H),7.01(d,J＝7.8Hz,1H),6.95-6.90(m,1H),4.93-4.85(m,1H),3.80-3.74(m,5H),3.72-3.63(m,1H),3.49-3.30(m,3H),2.45-2.37(m,1H),2.30-2.20(m,1H)。MS＝456(MH)+。

Example 337.2- (3-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 2- (3-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) -2- (3-methoxy-phenyl) -acetamide (32.0mg, 0.194mmol) from tert-butyl-pyrrolidine-1-carboxylate (75.0mg, 0.176mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a dark brown lyophilizate (0.099 g).¹HNMR(400MHz,d6-DMSO,,ppm):10.86(s,1H),9.25(s,1H),9.13(s,1H),8.89(br s,2H),8.73-8.68(m,2H),8.50(d,J＝5.2Hz,1H),8.25(d,J＝5.2Hz,1H),8.09(dd,J＝5.2,1.5Hz,1H),7.26(t,J＝7.8Hz,1H),6.98-6.94(m,2H),6.86-6.82(m,1H),4.94-4.85(m,1H),3.77-3.65(m,6H),3.51-3.34(m,3H),2.47-2.37(m,1H),2.31-2.21(m,1H)。MS＝456(MH)+。

EXAMPLE 338 {2- [2- (4-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (4-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 4-methyl-pyridin-2-ylamine (31.0mg, 0.287mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. Separating light yellow jellyDry product as trifluoroacetate salt (0.107 g).¹HNMR＝31550651(400MHz,d6-DMSO,,ppm):9.28-9.27(m,1H),8.99(br s,2H),8.84-8.79(m,1H),8.77-8.74(m,1H),8.55(d,J＝5.4Hz,1H),8.42-8.36(m,1H),8.31-8.26(m,2H),8.18-8.14(m,1H),7.27(s,1H),7.16-7.12(m,1H),5.04-4.94(m,1H),3.78-3.68(m,1H),3.54-3.34(m,3H),2.48(s,3H),2.46-2.36(m,1H),2.32-2.22(m,1H)。MS＝399(MH)+。

EXAMPLE 339 {2- [2- (4-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (4-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (105.0mg, 0.2460mmol) and 4-chloro-pyridin-2-ylamine (37.0mg, 0.288mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.124g, 96%).¹HNMR(400MHz,d6-DMSO,,ppm):10.43(br s,1H),9.26(s,1H),8.90(br s,2H),8.75-8.70(m,2H),8.64(s,1H),8.46(d,J＝5.6Hz,1H),8.30-8.25(m,2H),8.01(s,1H),7.95(d,J＝5.4Hz,1H),7.07(d,J＝5.3Hz,1H),4.97-4.89(m,1H),3.80-3.70(m,1H),3.53-3.35(m,3H),2.49-2.39(m,1H),2.34-2.24(m,1H)。MS＝419(MH)+。

EXAMPLE 340 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazin-2-yl-amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-yl]Preparation of tert-butyl (352.0mg, 0.7704mmol) piperazine-1-carboxylate and 2-aminopyrazine (81mg, 0.85mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyrazin-yl-amine. The product was isolated as a free base as an off-white solid (0.050g, 16%).¹HNMR(400MHz,d6-DMSO,,ppm):10.22(s,1H),9.17(d,J＝1.4Hz,1H),8.83(s,1H),8.72(s,1H),8.43(d,J＝5.2Hz,1H),8.33(s,1H),8.28(dd,J＝1.6,2.6Hz,1H),8.12(d,J＝2.7Hz,1H),7.86(dd,J＝1.3,5.2Hz,1H),4.07(s,3H),3.70-3.65(m,4H),2.90-2.85(m,4H)。MS＝416(MH)+。

Example 341.6- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -nicotinonitrile

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 6- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] from-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 6-amino-nicotinonitrile (33.0mg, 0.277mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -nicotinonitrile. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.016g, 13%).¹HNMR(400MHz,d6-DMSO,,ppm):10.60(s,1H),9.26(s,1H),8.92-8.80(m,3H),8.75-8.72(m,2H),8.69(d,J＝4.6Hz,1H),8.48(d,J＝5.3Hz,1H),8.28(d,J＝5.2Hz,1H),8.10(dd,J＝8.9,2.3Hz,1H),8.00(dd,J＝5.2,1.3Hz,1H),7.90(d,J＝8.9Hz,1H),4.94-4.89(m,1H),3.78-3.70(m,1H),3.51-3.35(m,3H),2.46-2.40(m,1H),2.35-2.25(m,1H)。MS＝410(MH)+。

Example 342.2- [4- (4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile

342a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d]Preparation of 4- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] using pyrimidin-4-ol (500.0mg, 1.933mmol) and tert-butyl 1-piperazinecarboxylate (432.0mg, 2.320mmol)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. The product was isolated as a yellow foam (0.817g, 99%).¹HNMR(400MHz,d6-DMSO,,ppm):9.30(s,1H),8.64-8.60(m,2H),8.38-8.35(m,2H),8.01-7.98(m,1H),4.06-4.01(m,4H),3.67-3.62(m,4H),3.32(s,3H),1.45(s,9H)。MS＝427(MH)+。

342b) From 4- [2- (2-Chloro-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]Preparation of 2- [4- (4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2342mmol) tert-butyl-piperazine-1-carboxylate and (31.0mg, 0.260mmol) 2-amino-isonicotinonitrile]Pyrimidin-2-yl) -pyridin-2-ylamino]-isonicotinic acid nitrile. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.015g, 12%).¹HNMR(400MHz,d6-DMSO,,ppm):10.44(s,1H),9.36(s,1H),8.90(br s,2H),8.69-8.66(m,2H),8.53-8.48(m,2H),8.36(s,1H),8.04(d,J＝5.7Hz,1H),7.95(dd,J＝5.3,1.3Hz,1H),7.33(dd,J＝5.1,1.3Hz,1H),4.18-4.13(m,4H),3.42-3.37(m,4H)。MS＝410(MH)+。

EXAMPLE 343- {2- [2- (4-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 4-morpholin-4-yl-pyridin-2-ylamine (47.0mg, 0.262mmol) [ preparation as described in WO2006/040520]Preparation of {2- [2- (4-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as the free base as a pale yellow solid (0.016g, 14%).¹HNMR(400MHz,d6-DMSO,,ppm):9.51(s,1H),9.17(s,1H),8.86(s,1H),8.67-8.52(m,2H),8.35-8.27(m,2H),7.95(d,J＝6.0Hz,1H),7.81-7.78(m,1H),7.30-7.27(m,1H),6.52-6.47(m,1H),4.97-4.75(m,1H),3.77-3.72(m,4H),3.35-3.30(m,1H),3.26-3.22(m,4H),3.06-2.98(m,1H),2.92-2.84(m,2H),2.31-2.21(m,1H),1.93-1.83(m,1H)。MS＝470(MH)+。

Example 344.6- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -nicotinonitrile

344a) 2- (2-Chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol. The product was isolated as a dark brown solid (0.774g, 46%).¹HNMR(400MHz,d1-TFA,,ppm):9.24(s,1H),9.11(d,J＝6.2Hz,1H),8.93(s,1H),8.85(d,J＝6.0Hz,1H),8.71(s,1H),4.36(s,3H)。MS＝289(MH)+。

344b) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (0.50g, 1.7mmol) and (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.32mL, 1.9mmol)]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester. The product was isolated as a light brown solid (0.50g, 63%).¹HNMR(400MHz,d6-DMSO,,ppm):8.84(s,1H),8.61(d,J＝5.0Hz,1H),8.39(s,1H),8.36-8.32(m,2H),8.24-8.17(m,1H),5.09-4.92(m,1H),4.14(s,3H),3.86-3.72(m,1H),3.55-3.32(m,3H),2.37-2.25(m,1H),2.21-2.07(m,1H),1.45-1.38(m,9H)。MS＝457(MH)+。

344c) From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of 6- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] from-pyrrolidine-1-carboxylic acid tert-butyl ester (160.0mg, 0.3502mmol) and 6-amino-nicotinonitrile (50.0mg, 0.420mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -nicotinonitrile. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.043g, 22%).¹HNMR(400MHz,d6-DMSO,,ppm):10.60(s,1H),9.00-8.80(m,4H),8.72(d,J＝2.2Hz,1H),8.48(d,J＝5.3Hz,1H),8.42(s,1H),8.15(d,J＝5.8Hz,1H),8.10(dd,J＝8.9,2.4Hz,1H),7.97(dd,J＝5.3,1.5Hz,1H),7.90(d,J＝9.0Hz,1H),5.01-4.93(m,1H),4.17(s,3H),3.75-3.65(m,1H),3.52-3.30(m,3H),2.55-2.45(m,1H),2.29-2.19(m,1H)。MS＝440(MH)+。

EXAMPLE 345 {2- [2- (5-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pir-zine in a manner analogous to example 303cPyrido [3,4-d]Pyrimidin-4-ylamino]Preparation of {2- [2- (5-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -2-pyrrolidino-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 5-methyl-pyridin-2-ylamine (30.0mg, 0.277mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.033g, 27%).¹HNMR(400MHz,d6-DMSO,,ppm):9.27(s,1H),8.93(br s,2H),8.81-8.77(m,1H),8.76(d,J＝5.6Hz,1H),8.52-8.45(m,2H),8.29(d,J＝5.5Hz,1H),8.20(s,1H),8.08(br s,1H),7.87(br s,1H),7.49(br s,1H),5.00-4.90(m,1H),3.79-3.69(m,1H),3.55-3.35(m,3H),2.47-2.37(m,1H),2.34-2.24(m,4H)。MS＝399(MH)+。

EXAMPLE 346 {2- [2- (5-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]Preparation of {2- [2- (5-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -2-amino-5-chloropyridine (36.0mg, 0.280mmol) from-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 2-amino-5-chloropyridine (36.0mg, 0.280mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as the trifluoroacetate salt as a yellow lyophilizate (0.081g, 65%).¹HNMR(400MHz,d6-DMSO,,ppm):10.36(br s,1H),9.26(s,1H),8.89(br s,2H),8.74(d,J＝5.6Hz,1H),8.71(d,J＝4.8Hz,1H),8.67(s,1H),8.42(d,J＝5.5Hz,1H),8.34-8.32(m,1H),8.27(d,J＝5.1Hz,1H),7.93(d,J＝5.5Hz,1H),7.88-7.82(m,2H),4.97-4.87(m,1H),3.79-3.70(m,1H),3.55-3.35(m,3H),2.50-2.40(m,1H),2.34-2.24(m,1H)。MS＝419(MH)+。

Example 347.2- [2- (pyrimidin-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and pyrimidin-4-ylamine (27.0mg, 0.284mmol) to prepare {2- [2- (pyrimidin-4-ylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as an off-white lyophilizate (0.033g, 28%).¹HNMR(400MHz,d6-DMSO,,ppm):11.07(br s,1H),9.26(s,1H),9.07(br s,2H),8.95(s,1H),8.87(d,J＝5.3Hz,1H),8.84(s,1H),8.73(d,J＝5.6Hz,1H),8.56-8.53(m,2H),8.35(d,J＝5.5Hz,1H),8.10(d,J＝5.2,1.2Hz,1H),7.97-7.90(m,1H),5.00-4.92(m,1H),3.79-3.69(m,1H),3.55-3.35(m,3H),2.49-2.39(m,1H),2.35-2.25(m,1H)。MS＝386(MH)+。

Example 348.2- (3-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

348a) 2- (3-cyano-phenyl) -acetamide was prepared in a similar manner to example 313a from (3-cyano-phenyl) -acetic acid (1.0g, 6.2 mmol). The product was isolated as an off-white solid (0.50g, 50%).¹HNMR(400MHz,d6-DMSO,,ppm):7.72-7.69(m,2H),7.61-7.58(m,1H),7.56-7.50(m,2H),6.97(br s,1H),3.47(s,2H)。MS＝161(MH)+。

348b) From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-ylamino]Preparation of 2- (3-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (3-cyano-phenyl) -acetamide (45.0mg, 0.281mmol) from tert-butyl-pyrrolidine-1-carboxylate (100.0mg, 0.2342mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.125g, 94%).¹HNMR(400MHz,d6-DMSO,,ppm):10.97(s,1H),9.24(s,1H),9.12(s,1H),8.90(br s,2H),8.73-8.69(m,2H),8.51(dd,J＝5.1,0.5Hz,1H),8.25(dd,J＝5.6,0.7Hz,1H),8.10(dd,J＝5.2,1.5Hz,1H),7.84-7.82(m,1H),7.78-7.75(m,1H),7.74-7.70(m,1H),7.58(t,J＝7.8Hz,1H),4.94-4.85(m,1H),3.90(s,2H),3.74-3.64(m,1H),3.51-3.33(m,3H),2.47-2.37(m,1H),2.30-2.20(m,1H)。MS＝451(MH)+。

Example 349.2- (4-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

349a) 2- (4-cyano-phenyl) -acetamide was prepared in analogy to example 313a from (4-cyano-phenyl) -acetic acid (1.0g, 6.2 mmol). The product was isolated as an off-white solid (0.71g, 71%).¹HNMR(400MHz,d6-DMSO,,ppm):7.77(d,J＝8.3Hz,2H),7.55(br s,1H),7.45(d,J＝8.3Hz,2H),6.98(br s,1H),3.49(s,2H)。MS＝161(MH)+。

349b) From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-ylamino]Preparation of 2- (4-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] 2- (4-cyano-phenyl) -acetamide (45.0mg, 0.281mmol) from tert-butyl-pyrrolidine-1-carboxylate (120.0mg, 0.2811mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a pale orange lyophilizate (0.148g, 93%).¹HNMR(400MHz,d6-DMSO,,ppm):10.98(s,1H),9.23(s,1H),9.12(s,1H),8.87(br s,2H),8.73-8.68(m,2H),8.51(dd,J＝5.1,0.6Hz,1H),8.25(dd,J＝5.7,0.6Hz,1H),8.10(dd,J＝5.1,1.4Hz,1H),7.83(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),4.93-4.84(m,1H),3.92(s,2H),3.73-3.64(m,1H),3.51-3.32(m,3H),2.47-2.36(m,1H),2.30-2.21(m,1H)。MS＝451(MH)+。

EXAMPLE 350 (R) -pyrrolidin-3-yl- {2- [2- (4-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-ylamino]Preparation of (R) -pyrrolidin-3-yl- {2- [2- (4-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 4-trifluoromethyl-pyridin-2-ylamine (46.0mg, 0.284mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } -amine. Separating out light yellowProduct of lyophylization as trifluoroacetate (0.127g, 95%).¹HNMR(400MHz,d6-DMSO,,ppm):10.57(s,1H),9.26(d,J＝0.4Hz,1H),8.94(br s,2H),8.75-8.72(m,2H),8.69(s,1H),8.56(d,J＝5.1Hz,1H),8.47(d,J＝5.4Hz,1H),8.28(dd,J＝5.7,0.6Hz,1H),8.26(s,1H),7.97(dd,J＝5.4,1.5Hz,1H),7.25(dd,J＝5.9,1.0Hz,1H),4.99-4.90(m,1H),3.80-3.71(m,1H),3.55-3.35(m,3H),2.48-2.40(m,1H),2.34-2.24(m,1H)。MS＝453(MH)+。

EXAMPLE 351 (R) -pyrrolidin-3-yl- {2- [2- (5-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-ylamino]Preparation of (R) -pyrrolidin-3-yl- {2- [2- (5-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -2-pyrrolidin-e-l-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 5-trifluoromethyl-pyridin-2-ylamine (46.0mg, 0.284mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } -amine. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.102g, 76%).¹HNMR(400MHz,d6-DMSO,,ppm):10.64(s,1H),9.27(d,J＝0.6Hz,1H),8.94(br s,2H),8.75-7.73(m,3H),8.66-8.63(m,1H),8.48(dd,J＝5.2,0.3Hz,1H),8.28(dd,J＝5.6,0.7Hz,1H),8.08(dd,J＝9.1,2.5Hz,1H),8.03-7.98(m,2H),4.99-4.90(m,1H),3.80-3.70(m,1H),3.55-3.35(m,3H),2.50-2.40(m,1H),2.34-2.24(m,1H)。MS＝453(MH)+。

Example 352.2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile

352a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (2.0g, 6.9mmol) and tert-butyl 1-piperazinecarboxylate (1.5g, 8.3 mmol; supplier ═ Aldrich)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. Separation of off-white solidsProduct (1.35g, 43%).¹HNMR(400MHz,d6-DMSO,,ppm):8.88(s,1H),8.61(dd,J＝4.9,0.8Hz,1H),8.39(s,1H),8.34-8.31(m,2H),4.09(s,3H),3.72-3.67(m,4H),3.57-3.52(m,4H),1.44(s,9H)。MS＝457,459(MH)+。

352b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-yl]Preparation of 2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (31.0mg, 0.260mmol) 2-amino-isonicotinonitrile]Pyrimidin-2-yl) -pyridin-2-ylamino]-isonicotinic acid nitrile. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.105g, 86%).¹HNMR(400MHz,d6-DMSO,,ppm):10.49(s,1H),8.93(s,1H),8.88(br s,2H),8.64(s,1H),8.51(dd,J＝5.1,0.6Hz,1H),8.48(d,J＝5.5Hz,1H),8.43(s,1H),8.34(s,1H),7.92(dd,J＝5.4,1.4Hz,1H),7.34(dd,J＝5.0,1.3Hz,1H),4.11(s,3H),3.93-3.88(m,4H),3.37-3.30(m,4H)。MS＝440(MH)+。

Example 353.6- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -nicotinonitrile

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-yl]Preparation of 6- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-amino-nicotinonitrile (31.0mg, 0.260mmol)]Pyrimidin-2-yl) -pyridin-2-ylamino]-nicotinonitrile. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.109g, 89%).¹HNMR(400MHz,d6-DMSO,,ppm):10.64(s,1H),8.93(s,1H),8.90-8.82(m,3H),8.72(d,J＝2.2Hz,1H),8.49(d,J＝5.4Hz,1H),8.43(s,1H),8.11(dd,J＝8.9,2.4Hz,1H),7.96(dd,J＝5.2,1.4Hz,1H),7.92(d,J＝8.9Hz,1H),4.11(s,3H),3.93-3.88(m,4H),3.37-3.31(m,4H)。MS＝440(MH)+。

EXAMPLE 354 {4- [ 5-methoxy-4- (4-morpholin-4-yl-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine

354a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 2- (2-chloro-pyridin-4-yl) -5-methoxy-4- (4-morpholin-4-yl-piperidin-1-yl) -pyrido [3,4-d ] using pyrimidin-4-ol (190.0mg, 0.6581mmol) and 4-piperidin-4-yl-morpholine (134.0mg, 0.7871mmol)]A pyrimidine. The product was isolated as a red-orange solid (0.146g, 50%).¹HNMR(400MHz,d6-DMSO,,ppm):8.84(s,1H),8.60(dd,J＝4.9,0.6Hz,1H),8.36(s,1H),8.32-8.29(m,2H),4.28(d,J＝11.6Hz,2H),4.08(s,3H),3.60-3.55(m,4H),3.15(t,J＝11.6Hz,2H),2.53-2.46(m,5H),1.96(d,J＝11.3Hz,2H),1.61-1.49(m,2H)。(400MHz,CDCl3,,ppm):8.97(s,1H),8.52(d,J＝4.9Hz,1H),8.37(s,1H),8.28(dd,J＝5.2,1.3Hz,1H),8.21(s,1H),4.36(d,J＝13.2Hz,2H),4.09(s,3H),3.77-3.73(m,4H),3.18-3.09(m,2H),2.63-2.58(m,4H),2.53-2.43(m,1H),2.06(d,J＝12.7Hz,2H),1.74-1.63(m,2H)。MS＝441,443(MH)+。

354b) From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4- (4-morpholin-4-yl-piperidin-1-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of {4- [ 5-methoxy-4- (4-morpholin-4-yl-piperidin-1-yl) -pyrido [3,4-d ] using pyrimidine (80.0mg, 0.181mmol) and aniline (18.6. mu.L, 0.204mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -phenyl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.108g, 97%).¹HNMR(400MHz,d6-DMSO,,ppm):9.74(br s,1H),9.46(br s,1H),8.87(s,1H),8.39(s,1H),8.31(d,J＝5.4Hz,1H),7.94(s,1H),7.75-7.73(m,2H),7.70(dd,J＝5.3,1.3Hz,1H),7.31(t,J＝7.6Hz,2H),6.95(t,J＝7.2Hz,1H),4.42(d,J＝12.6Hz,2H),4.12(s,3H),4.04(d,J＝11.7Hz,2H),3.67(t,J＝12.1Hz,2H),3.62-3.54(m,1H),3.51(d,J＝12.1Hz,2H),3.22-3.10(m,4H),2.25(d,J＝10.4Hz,2H),1.85-1.72(m,2H)。MS＝498(MH)+。

Example 355.2- (4-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1c]Pyrimidin-4-yl]Preparation of 2- (4-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and (45.0mg, 0.281mmol) 2- (4-cyano-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a pale orange lyophilizate (0.102g, 78%).¹HNMR(400MHz,d6-DMSO,,ppm):10.99(s,1H),9.08(s,1H),8.90(s,1H),8.83(br s,2H),8.51(dd,J＝5.2,0.6Hz,1H),8.41(s,1H),8.06(dd,J＝5.1,1.5Hz,1H),7.83(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),4.09(s,3H),3.92(s,2H),3.87-3.83(m,4H),3.31(br s,4H)。MS＝481(MH)+。

Example 356.2- (3-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- (3-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and (45.0mg, 0.281mmol) 2- (3-cyano-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as a pale yellow lyophilizate (0.125g, 96%).¹HNMR(400MHz,d6-DMSO,,ppm):10.97(s,1H),9.07(s,1H),8.91(s,1H),8.87(brs,2H),8.52(dd,J＝5.1,0.4Hz,1H),8.41(s,1H),8.06(dd,J＝5.2,1.4Hz,1H),7.84-7.82(m,1H),7.78-7.74(m,1H),7.73-7.70(m,1H),7.57(t,J＝7.7Hz,1H),4.09(s,3H),3.89(s,2H),3.87-3.83(m,4H),3.31(br s,4H)。MS＝481(MH)+。

EXAMPLE 357 {2- [2- (5-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) in a similar manner to example 303c and example 1501c) -pyrido [3,4-d]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2342mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (48.0mg, 0.268mmol) [ as toyood, p.l.; et al, J.Med.chem.2005,48(7),2388-]Preparation of {2- [2- (5-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.103g, 60%).¹HNMR(400MHz,d6-DMSO,,ppm):9.27(s,1H),8.93(br s,2H),8.83-8.79(m,1H),8.76(d,J＝5.5Hz,1H),8.14(d,J＝5.9Hz,1H),8.40(s,1H),8.26(d,J＝5.5Hz,1H),8.07-8.01(m,1H),7.94(d,J＝2.9Hz,1H),7.87-7.86(m,1H),7.49-7.40(m,1H),5.00-4.91(m,1H),3.81-3.77(m,4H),3.76-3.69(m,1H),3.55-3.36(m,3H),3.17-3.13(m,4H),2.47-2.37(m,1H),2.33-2.23(m,1H)。MS＝470(MH)+。

EXAMPLE 358 {2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (115.0mg, 0.2694mmol) and 2-methoxy-4-morpholin-4-yl-aniline (58.0mg, 0.278mmol) [ prepared as described in WO2008/051547]Preparation of {2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as an orange-brown lyophilizate (0.155g, 93%).¹HNMR(400MHz,d6-DMSO,,ppm):10.25(br s,1H),9.27(s,1H),9.08(br s,2H),8.87(d,J＝5.1Hz,1H),8.77(d,J＝5.6Hz,1H),8.30(d,J＝5.3Hz,1H),8.16(s,1H),7.98(d,J＝6.5Hz,1H),7.81(dd,J＝6.6,1.3Hz,1H),7.31(d,J＝8.5Hz,1H),6.76(d,J＝2.3Hz,1H),6.64(dd,J＝8.8,2.4Hz,1H),4.94-4.85(m,1H),3.82(s,3H),3.80-3.75(m,4H),3.73-3.63(m,1H),3.55-3.33(m,3H),3.25-3.20(m,4H),2.43-2.34(m,1H),2.31-2.22(m,1H)。MS＝499(MH)+。

Example 359 (2-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -2-methoxy-4-morpholin-4-yl-aniline (55.0mg, 0.264mmol) and tert-butyl-piperazine-1-carboxylate (115.0mg, 0.2517mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as trifluoroacetate salt as an orange-brown lyophilizate (0.150g, 92%).¹HNMR(400MHz,d6-DMSO,,ppm):10.25(br s,1H),9.05(br s,2H),8.93(s,1H),8.47(s,1H),8.13(s,1H),8.00(d,J＝6.6Hz,1H),7.76(dd,J＝6.5,1.3Hz,1H),7.31(d,J＝8.5Hz,1H),6.76(d,J＝2.4Hz,1H),6.64(dd,J＝8.7,2.4Hz,1H),4.11(s,3H),3.91-3.86(m,4H),3.81(s,3H),3.80-3.76(m,4H),3.32(br s,4H),3.25-3.21(m,4H)。MS＝529(MH)+。

EXAMPLE 360 { 5-methoxy-2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of { 5-methoxy-2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -aniline (100.0mg, 0.2188mmol) and 2-methoxy-4-morpholin-4-yl-aniline (55.0mg, 0.264mmol) with-pyrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as an orange-brown lyophilizate (0.057g, 40%).¹HNMR(400MHz,d6-DMSO,,ppm):10.13(br s,1H),9.21-9.00(m,2H),8.86(s,1H),8.46(s,1H),8.26(d,J＝6.2Hz,1H),8.10(s,1H),7.99(d,J＝6.4Hz,1H),7.74(dd,J＝6.4,1.2Hz,1H),7.33(d,J＝8.2Hz,1H),6.76(d,J＝2.4Hz,1H),6.63(dd,J＝8.7,2.4Hz,1H),5.01-4.91(m,1H),4.17(s,3H),3.81(s,3H),3.80-3.75(m,4H),3.69-3.59(m,1H),3.53-3.40(m,2H),3.37-3.26(m,1H),3.25-3.20(m,4H),2.51-2.41(m,1H),2.26-2.16(m,1H)。MS＝529(MH)+。

EXAMPLE 361 (5-methoxy-2- {2- [4- (tetrahydro-pyran-4-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of (5-methoxy-2- {2- [4- (tetrahydro-pyran-4-yl) -phenylamino ] p reparation of (5-methoxy-2- {2- [4- (tetrahydro-pyran-4-yl) -phenylamino ] p yrrolidine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4- (tetrahydro-pyran-4-yl) -phenylamine (43.0mg, 0.243mmol)]-pyridin-4-yl } -pyrido [3,4-d]Pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine. The product was isolated as a salt of trifluoroacetic acid as a yellow lyophilizate (0.109g, 81%).¹HNMR(400MHz,d6-DMSO,,ppm):9.41(br s,1H),8.99(br s,1H),8.88(br s,1H),8.83(s,1H),8.41(s,1H),8.28(d,J＝5.5Hz,1H),8.16(d,J＝6.2Hz,1H),7.93(s,1H),7.69(dd,J＝5.5,1.2Hz,1H),7.64d,J＝8.5Hz,2H),7.20(d,J＝8.5Hz,2H),5.05-4.95(m,1H),4.16(s,3H),3.98-3.92(m,2H),3.72-3.63(m,1H),3.50-3.28(m,5H),2.76-2.68(m,1H),2.50-2.43(m,1H),2.27-2.17(m,1H),1.73-1.60(m,4H)。MS＝498(MH)+。

EXAMPLE 362[ 4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [4- (tetrahydro-pyran-4-yl) -phenyl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4- (tetrahydro-pyran-4-yl) -aniline (43.0mg, 0.243mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- [4- (tetrahydro-pyran-4-yl) -phenyl]-an amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.099g, 74%).¹HNMR(400MHz,d6-DMSO,,ppm,):9.43(br s,1H),8.95-8.83(m,3H),8.42(s,1H),8.28(d,J＝5.5Hz,1H),7.93(s,1H),7.68(dd,J＝5.4,1.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.20(d,J＝8.5Hz,2H),4.10(s,3H),3.98-3.92(m,2H),3.90-3.85(m,4H),3.44(ddd,J＝11.2,11.2,3.0Hz,2H),3.35-3.29(m,4H),2.76-2.68(m,1H),1.72-1.60(m,4H)。MS＝498(MH)+。

EXAMPLE 363 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4-methyl-pyridin-2-ylamine (27.0mg, 0.250mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4-methyl-pyridin-2-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.100g, 84%).¹HNMR(400MHz,d6-DMSO,,ppm):11.72(br s,1H),9.03-8.90(m,3H),8.55(d,J＝5.5Hz,1H),8.46(s,1H),8.37(s,1H),8.27(d,J＝6.1Hz,1H),8.12(d,J＝5.2Hz,1H),7.27(s,1H),7.14(d,J＝4.5Hz,1H),4.12(s,3H),3.94-3.88(m,4H),3.37-3.30(m,4H),2.47(s,3H)。MS＝429(MH)+。

EXAMPLE 364 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (110.0mg, 0.2407mmol) piperazine-1-carboxylate and 5-methyl-pyridin-2-ylamine (27.0mg, 0.250mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-methyl-pyridin-2-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.122g, 93%).¹HNMR(400MHz,d6-DMSO,,ppm):11.73(br s,1H),8.98(br s,2H),8.94(s,1H),8.54(d,J＝5.7Hz,1H),8.46(s,1H),8.37(s,1H),8.22(s,1H),8.12-8.08(m,1H),8.00-7.94(m,1H),7.42(d,J＝7.6Hz,1H),4.12(s,3H),3.94-3.88(m,4H),3.37-3.30(m,4H),2.34(s,3H)。MS＝429(MH)+。

EXAMPLE 365 (4-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4-chloro-pyridin-2-ylamine (32.0mg, 0.249mmol) preparation of (4-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.107g, 86%).¹HNMR(400MHz,d6-DMSO,,ppm):10.56(br s,1H),9.00-8.85(m,3H),8.63(s,1H),8.46(d,J＝5.4Hz,1H),8.43(s,1H),8.29(d,J＝5.6Hz,1H),7.99(s,1H),7.92(dd,J＝5.4,1.2Hz,1H),7.10(dd,J＝5.6,1.8Hz,1H),4.10(s,1H),3.94-3.88(m,4H),3.37-3.29(m,4H)。MS＝449(MH)+。

EXAMPLE 366 (5-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (110.0mg, 0.2407mmol) and 2-amino-5-chloropyridine (32.0mg, 0.249mmol) to prepare (5-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.134g, 98%).¹HNMR(400MHz,d6-DMSO,,ppm):10.45(br s,1H),8.93(s,1H),8.87(brs,2H),8.67(s,1H),8.44-8.41(m,2H),8.34-8.32(s,1H),7.90(d,J＝5.4Hz,1H),7.88-7.81(m,2H),4.10(s,3H),3.94-3.87(m,4H),3.37-3.30(m,4H)。MS＝449(MH)+。

EXAMPLE 367 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4-trifluoromethyl-pyridin-2-ylamine (40.0mg, 0.247mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine. The product was isolated as the trifluoroacetate salt as a yellow solid (0.116g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):10.49(br s,1H),8.93(s,1H),8.87(br s,2H),8.70(s,1H),8.54(d,J＝5.3Hz,1H),8.47(d,J＝5.3Hz,1H),8.42(s,1H),8.30(s,1H),7.91(dd,J＝5.3,1.3Hz,1H),7.25(d,J＝4.4Hz,1H),4.11(s,3H),3.94-3.88(m,4H),3.37-3.30(m,4H)。MS＝483(MH)+。

EXAMPLE 368 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 5-trifluoromethyl-pyridin-2-ylamine (40.0mg, 0.247mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-trifluoromethyl-pyridin-2-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.116g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):10.56(br s,1H),8.94(s,1H),8.88(br s,2H),8.78(s,1H),8.64(s,1H),8.47(d,J＝5.3Hz,1H),8.43(s,1H),8.07(dd,J＝9.0,2.3Hz,1H),8.01(d,J＝9.0Hz,1H),7.94(dd,J＝5.3,1.3Hz,1H),4.11(s,3H),3.94-3.88(m,4H),3.37-3.30(m,4H)。MS＝483(MH)+。

Example 369.2- (4-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

369a) 2- (4-chloro-phenyl) -acetamide was prepared in analogy to example 313a from (4-chloro-phenyl) -acetic acid (1.0g, 5.9 mmol). The product was isolated as a white solid (0.97g, 97%).¹HNMR(400MHz,d6-DMSO,,ppm):7.47(br s,1H),7.35(d,J＝8.5Hz,2H),7.27(d,J＝8.5Hz,2H),6.90(br s,1H),3.37(s,2H)。MS＝170,172(MH)+。

369b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- (4-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and (42.0mg, 0.248mmol) 2- (4-chloro-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.101g, 76%).¹HNMR(400MHz,d6-DMSO,,ppm):10.92(s,1H),9.08(s,1H),8.91(s,1H),8.85(br s,2H),8.51(dd,J＝5.1,0.5Hz,1H),8.41(s,1H),8.05(dd,J＝5.1,1.5Hz,1H),7.43-7.37(m,4H),4.09(s,3H),3.88-3.83(m,4H),3.79(s,2H),3.35-3.28(m,4H)。MS＝490(MH)+。

Example 370.2- (3-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

370a) 2- (3-chloro-phenyl) -acetamide was prepared in analogy to example 313a from (3-chloro-phenyl) -acetic acid (1.0g, 5.9 mmol). The product was isolated as a white solid (0.82g, 82%).¹HNMR(400MHz,d6-DMSO,,ppm):7.50(br s,1H),7.35-7.27(m,3H),7.23-7.19(m,1H),6.93(br s,1H),3.39(s,2H)。MS＝170,172(MH)+。

370b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.218)8mmol) and 2- (3-chloro-phenyl) -acetamide (42.0mg, 0.248mmol) to prepare 2- (3-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.103g, 77%).¹HNMR(400MHz,d6-DMSO,,ppm):10.94(s,1H),9.08(s,1H),8.91(s,1H),8.88(br s,2H),8.51(dd,J＝5.0,0.5Hz,1H),8.41(s,1H),8.06(dd,J＝5.1,1.5Hz,1H),7.47-7.45(m,1H),7.41-7.32(m,3H),4.09(s,3H),3.88-3.83(m,4H),3.81(s,2H),3.35-3.29(m,4H)。MS＝490(MH)+。

Example 371N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and phenylacetamide (34.0mg, 0.252mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-2-phenyl-acetamide. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.120g, 96%).¹HNMR(400MHz,d6-DMSO,,ppm):10.90(s,1H),9.09(s,1H),8.91(s,1H),8.87(br s,2H),8.51(d,J＝5.2Hz,1H),8.41(s,1H),8.05(dd,J＝5.0,1.3Hz,1H),7.40-7.32(m,4H),7.29-7.23(m,1H),4.09(s,3H),3.88-3.83(m,4H),3.78(s,2H),3.35-3.28(m,4H)。MS＝456(MH)+。

Example 372.2- (3-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- (3-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (43.0mg, 0.260mmol) 2- (3-methoxy-phenyl) -acetamide]Pyrimidine-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.056g, 42%).¹HNMR(400MHz,d6-DMSO,,ppm):10.87(s,1H),9.09(s,1H),8.91(s,1H),8.87(br s,2H),8.51(dd,J＝5.1,0.6Hz,1H),8.41(s,1H),8.05(dd,J＝5.1,1.4Hz,1H),7.25(t,J＝7.8Hz,1H),6.97-6.93(m,2H),6.86-6.82(m,1H),4.09(s,3H),3.88-3.83(m,4H),3.78(s,3H),3.74(s,2H),3.35-3.29(m,4H)。MS＝486(MH)+。

Example 373N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2- (3-trifluoromethyl-phenyl) -acetamide

373a) 2- (3-trifluoromethyl-phenyl) -acetamide was prepared in analogy to example 313a from (3-trifluoromethyl-phenyl) -acetic acid (1.0g, 4.9 mmol). The product was isolated as a white solid (0.88g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):7.63-7.51(m,5H),6.96(br s,1H),3.50(s,2H)。MS＝204(MH)+。

373b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (53.0mg, 0.261mmol) 2- (3-trifluoromethyl-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-2- (3-trifluoromethyl-phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.037g, 26%).¹HNMR(400MHz,d6-DMSO,,ppm):10.98(s,1H),9.07(s,1H),8.91(s,1H),8.87(br s,2H),8.52(dd,J＝5.1,0.4Hz,1H),8.41(s,1H),8.06(dd,J＝5.1,1.4Hz,1H),7.75(s,1H),7.70-7.57(m,3H),4.09(s,3H),3.92(s,2H),3.88-3.83(m,4H),3.35-3.28(m,4H)。MS＝524(MH)+。

Example 374.2- (4-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

In a similar way to the embodiments303c and manner of example 1501c starting from 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 4-methoxyphenylacetamide (43.0mg, 0.260mmol) 2- (4-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.067g, 50%).¹HNMR(400MHz,d6-DMSO,,ppm):10.83(s,1H),9.08(s,1H),8.91(s,1H),8.85(br s,2H),8.50(dd,J＝5.1,0.6Hz,1H),8.41(s,1H),8.04(dd,J＝5.1,1.4Hz,1H),7.29(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),4.09(s,3H),3.88-3.83(m,4H),3.73(s,3H),3.69(s,2H),3.35-3.29(m,4H)。MS＝486(MH)+。

EXAMPLE 375 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-morpholin-4-yl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (106.0mg, 0.2320mmol) piperazine-1-carboxylate and 6-morpholin-4-yl-pyridin-3-ylamine (48.0mg, 0.268mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-morpholin-4-yl-pyridin-3-yl) -amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.148g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):9.52(br s,1H),8.98-8.85(m,3H),8.59(br s,1H),8.43(s,1H),8.26(d,J＝5.3Hz,1H),8.01-7.96(m,1H),7.90(s,1H),7.70(d,J＝5.2Hz,1H),7.09(br s,1H),4.10(s,3H),3.90-3.85(m,4H),3.77-3.72(m,4H),3.48-3.42(m,4H),3.36-3.29(m,4H)。MS＝500(MH)+。

EXAMPLE 376 {2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -pyrido in a similar manner to example 303c and example 1501c[3,4-d]Pyrimidin-4-ylamino]Preparation of {2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (103.0mg, 0.2413mmol) and 3-aminopyridine (27.0mg, 0.287mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as bis-trifluoroacetate as a pale yellow lyophilizate (0.141g, 95%).¹HNMR(400MHz,d6-DMSO,,ppm):10.25(br s,1H),9.39(s,1H),9.24(d,J＝0.6Hz,1H),8.97(br s,2H),8.76(d,J＝5.5Hz,1H),8.73(d,J＝5.6Hz,1H),8.51-8.45(m,2H),8.38(d,J＝5.2Hz,1H),8.28(dd,J＝5.6,0.7Hz,1H),8.07(s,1H),7.93(dd,J＝5.3,1.2Hz,1H),7.81(dd,J＝8.2,5.34Hz,1H),5.02-4.93(m,1H),3.78-3.69(m,1H),3.55-3.34(m,3H),2.47-2.37(m,1H),2.32-2.22(m,1H)。MS＝385(MH)+。

EXAMPLE 377 { 5-methoxy-2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of { 5-methoxy-2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (107.0mg, 0.2342mmol) and 3-aminopyridine (25.0mg, 0.266mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as bis-trifluoroacetate as a pale yellow lyophilizate (0.063g, 41%).¹HNMR(400MHz,d6-DMSO,,ppm):10.15(br s,1H),9.31(s,1H),9.05(br s,1H),8.92(br s,1H),8.84(s,1H),8.48-8.41(m,3H),8.34(d,J＝5.0Hz,1H),8.20(d,J＝6.3Hz,1H),8.03(s,1H),7.87(d,J＝5.3Hz,1H),7.74-7.71(m,1H),5.09-5.00(m,1H),4.17(s,3H),3.74-3.65(m,1H),3.52-3.29(m,3H),2.54-2.44(m,1H),2.27-2.17(m,1H)。MS＝415(MH)+。

EXAMPLE 378 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-3-yl-amine

In a manner similar to that of example 303c and example 1501cOf the formula (I) from 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 3-aminopyridine (25.0mg, 0.266mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyridin-3-yl-amine. The product was isolated as bistrifluoroacetate salt as a yellow lyophilizate (0.123g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):10.17(br s,1H),9.33(s,1H),9.02-8.88(m,3H),8.49-8.42(m,3H),8.34(d,J＝4.6Hz,1H),8.03(s,1H),7.87(dd,J＝5.2,1.3Hz,1H),7.74(dd,J＝8.3,5.2Hz,1H),4.11(s,3H),3.92-3.86(m,4H),3.37-3.30(m,4H)。MS＝415(MH)+。

Example 379.2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2-amino-isonicotinamide (36.0mg, 0.262mmol)]Pyrimidin-2-yl) -pyridin-2-ylamino]-isonicotinamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.004g, 2%).¹HNMR(400MHz,d6-DMSO,,ppm):8.94(s,1H),8.86(br s,2H),8.69(s,1H),8.46(d,J＝5.5Hz,1H),8.44(s,1H),8.41(d,J＝5.3Hz,1H),8.19(br s,1H),8.09(br s,1H),7.95-7.91(m,1H),7.71(br s,1H),7.36-7.33(m,1H),4.11(s,3H),3.93-3.89(m,4H),3.37-3.30(m,4H)。MS＝458(MH)+。

Example 380.6- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -nicotinamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 6- [4- (5, 0.262mmol) from-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-amino-nicotinamide (36.0mg, 0.262mmol)-methoxy-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-ylamino]-nicotinamide. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.047g, 37%).¹HNMR(400MHz,d6-DMSO,,ppm):9.08(br s,2H),8.94(s,1H),8.83(s,1H),8.72(s,1H),8.50(d,J＝5.4Hz,1H),8.45(s,1H),8.26(br s,1H),8.10-7.99(m,2H),7.72(br s,1H),7.47(br s,1H),4.11(s,3H),3.96-3.92(m,4H),3.36-3.29(m,4H)。MS＝458(MH)+。

EXAMPLE 382 (3-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (3-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -piperazine-1-carboxylic acid tert-butyl ester (110.0mg, 0.2407mmol) and 3-methoxy-4-morpholin-4-yl-aniline (55.0mg, 0.264mmol) (prepared as described in WO 2008/051547)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.147g, 95%).¹HNMR(400MHz,d6-DMSO,,ppm):9.71(br s,1H),9.12-8.95(m,2H),8.91(s,1H),8.43(s,1H),8.25(d,J＝5.3Hz,1H),7.99(s,1H),7.72(d,J＝4.9Hz,1H),7.44(br s,1H),7.25(d,J＝7.5Hz,1H),7.06(br s,1H),4.11(s,3H),3.92-3.86(m,4H),3.84(s,3H),3.82-3.76(m,4H),3.35-3.29(m,4H),3.17-3.00(m,4H)。MS＝529(MH)+。

EXAMPLE 383 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-4-morpholin-4-yl-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2-methyl-4-morpholin-4-yl-aniline (50.0mg, 0.260mmol) [ preparation as described in WO2008/051547]Preparation of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2-methyl-4-morpholin-4-yl-phenyl) -amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.125g, 91%).¹HNMR(400MHz,d6-DMSO,,ppm):10.06(br s,1H),9.07-8.95(m,2H),8.92(s,1H),8.46(s,1H),8.01(d,J＝5.9Hz,1H),7.74(dd,J＝6.3,1.1Hz,1H),7.27(d,J＝8.7Hz,1H),7.00(d,J＝2.5Hz,1H),6.92(dd,J＝8.8,2.7Hz,1H),4.11(s,3H),3.89-3.84(m,4H),3.79-3.75(m,4H),3.34-3.27(m,4H),3.20-3.16(m,4H),2.20(s,3H)。MS＝513(MH)+。

Example 384.5- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -pyridine-2-carbonitrile

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 5- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] using (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (32.0mg, 0.269mmol) 5-amino-pyridine-2-carbonitrile]Pyrimidin-2-yl) -pyridin-2-ylamino]-pyridine-2-carbonitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.093g, 76%).¹HNMR(400MHz,d6-DMSO,,ppm):10.24(s,1H),8.95(d,J＝2.4Hz,1H),8.91(s,1H),8.88(br s,2H),8.56(dd,J＝8.7,2.6Hz,1H),8.47(d,J＝5.4Hz,1H),8.43(s,1H),8.05(s,1H),7.93(d,J＝8.6Hz,1H),7.90(dd,J＝5.4,1.4Hz,1H),4.11(s,3H),3.91-3.87(m,4H),3.36-3.30(m,4H)。MS＝440(MH)+。

EXAMPLE 385 { 5-methoxy-2- [2- (pyrimidin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of { 5-methoxy-2- [2- (pyrimidin-5-ylamino) -pyridine ] using tert-butyl-pyrrolidine-1-carboxylate (108.0mg, 0.2364mmol) and pyrimidin-5-ylamine (25.0mg, 0.263mmol)-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.029g, 22%).¹HNMR(400MHz,d6-DMSO,,ppm):9.77(s,1H),9.22-9.21(m,2H),9.00-8.80(m,3H),8.74(s,1H),8.43-8.40(m,2H),8.18(d,J＝6.3Hz,1H),7.99(s,1H),7.83(dd,J＝5.3,1.4Hz,1H),5.08-4.98(m,1H),4.17(s,3H),3.74-3.64(m,1H),3.50-3.30(m,3H),2.52-2.44(m,1H),2.28-2.18(m,1H)。MS＝416(MH)+。

EXAMPLE 386 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-5-yl-amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and pyrimidin-5-ylamine (25.0mg, 0.263mmol) of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyrimidin-5-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.073g, 62%).¹HNMR(400MHz,d6-DMSO,,ppm):9.79(s,1H),9.22-9.21(m,2H),8.98-8.95(m,3H),8.74(s,1H),8.43-8.40(m,2H),7.99(s,1H),7.82(dd,J＝5.3,1.4Hz,1H),4.11(s,3H),3.92-3.86(m,4H),3.37-3.29(m,4H)。MS＝416(MH)+。

EXAMPLE 387 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-2-yl-amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (102.0mg, 0.2232mmol) piperazine-1-carboxylate and 2-pyridylamine (25.0mg, 0.266mmol) of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyridin-2-yl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.056g, 47%).¹HNMR(400MHz,d6-DMSO,,ppm):11.54(br s,1H),9.05-8.90(m,3H),8.53(d,J＝4.9Hz,1H),8.50-8.45(m,2H),8.39(d,J＝5.2Hz,1H),8.11-8.00(m,2H),7.54(s,1H),7.21(s,1H),4.12(s,3H),3.94-3.89(m,4H),3.37-3.30(m,4H)。MS＝415(MH)+。

Example 388.2- [4- (5-methoxy-4-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile

388a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 2- (2-chloro-pyridin-4-yl) -5-methoxy-4-morpholin-4-yl-pyrido [3, 4-d) from pyrimidin-4-ol (0.25g, 0.86mmol) and morpholine (0.10mL, 1.1mmol)]A pyrimidine. The product was isolated as a dark brown solid (0.269g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):8.87(s,1H),8.60(dd,J＝5.0,0.9Hz,1H),8.38(s,1H),8.33-8.30(m,2H),4.08(s,3H),3.81-3.71(m,8H)。MS＝358(MH)+。

388b) From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4-morpholin-4-yl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of 2- [4- (5-methoxy-4-morpholin-4-yl-pyrido [3, 4-d) using pyrimidine (100.0mg, 0.2795mmol) and 2-amino-isonicotinonitrile (40.0mg, 0.336mmol)]Pyrimidin-2-yl) -pyridin-2-ylamino]-isonicotinic acid nitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.014g, 9%).¹HNMR(400MHz,d6-DMSO,,ppm):10.63(br s,1H),8.87(s,1H),8.58(s,1H),8.51(d,J＝5.0Hz,1H),8.47(d,J＝5.4Hz,1H),8.37(s,1H),8.29(s,1H),7.92(d,J＝5.4Hz,1H),7.35(d,J＝4.9Hz,1H),4.09(s,3H),3.82-3.74(m,8H)。MS＝441(MH)+。

Example 389.2- (3-cyano-phenyl) -N- [4- (5-methoxy-4-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4-morpholin-4-yl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of 2- (3-cyano-phenyl) -N-, [2- (3-cyano-phenyl ] -acetamide (54.0mg, 0.337mmol) from pyrimidine (110.0mg, 0.3074mmol)4- (5-methoxy-4-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.082g, 44%).¹HNMR(400MHz,d6-DMSO,,ppm):10.96(s,1H),9.03(s,1H),8.85(s,1H),8.49(dd,J＝5.1,0.6Hz,1H),8.35(s,1H),8.04(dd,J＝5.1,1.5Hz,1H),7.84-7.82(m,1H),7.77-7.74(m,1H),7.73-7.70(m,1H),7.57(t,J＝7.8Hz,1H),4.07(s,3H),3.89(s,2H),3.79-3.69(m,8H)。MS＝482(MH)+。

EXAMPLE 390 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,4, 5-trimethoxy-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (106.0mg, 0.2320mmol) piperazine-1-carboxylate and 3,4, 5-trimethoxyaniline (48.0mg, 0.262mmol) to [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (3,4, 5-trimethoxy-phenyl) -amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.074g, 52%).¹HNMR(400MHz,d6-DMSO,,ppm):9.45(br s,1H),8.98-8.84(m,3H),8.42(s,1H),8.30(d,J＝5.4Hz,1H),7.94(s,1H),7.70(d,J＝5.6Hz,1H),7.13-7.10(m,2H),4.10(s,3H),3.90-3.85(m,4H),3.79(s,6H),3.64(s,3H),3.36-3.29(m,4H)。MS＝504(MH)+。

Example 391.N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2- (4-trifluoromethyl-phenyl) -acetamide

391a) 2- (4-trifluoromethyl-phenyl) -acetamide was prepared in analogy to example 313a from (4-trifluoromethyl-phenyl) -acetic acid (1.0g, 4.9 mmol). The product was isolated as a white solid (0.92g, 92%).¹HNMR(400MHz,d6-DMSO,,ppm):7.66(d,J＝8.1Hz,2H),7.54(br s,1H),7.47(d,J＝8.0Hz,2H),6.96(brs,1H),3.49(s,2H)。MS＝204(MH)+。

391b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (54.0mg, 0.266mmol) 2- (4-trifluoromethyl-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-2- (4-trifluoromethyl-phenyl) -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.051g, 36%).¹HNMR(400MHz,d6-DMSO,,ppm):10.99(s,1H),9.08(s,1H),8.91(s,1H),8.84(br s,2H),8.52(dd,J＝5.1,0.5Hz,1H),8.41(s,1H),8.06(dd,J＝5.1,1.4Hz,1H),7.72(d,J＝8.1Hz,2H),7.60(d,J＝8.0Hz,2H),4.09(s,3H),3.92(s,2H),3.87-3.83(m,4H),3.34-3.28(m,4H)。MS＝524(MH)+。

EXAMPLE 392 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-phenyl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-phenyl-pyridin-3-ylamine (45.0mg, 0.264mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-phenyl-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.086g, 65%).¹HNMR(400MHz,d6-DMSO,,ppm):9.82(s,1H),9.01(d,J＝2.3Hz,1H),8.95-8.85(m,3H),8.46-8.40(m,3H),8.06-7.95(m,4H),7.80(dd,J＝5.3,1.3Hz,1H),7.49(t,J＝7.4Hz,2H),7.42-7.37(m,1H),4.11(s,3H),3.92-3.87(m,4H),3.37-3.30(m,4H)。MS＝491(MH)+。

EXAMPLE 393[ 4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methyl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [2- (2-chloro-pyridin-4-yl) -2 ] in a similar manner to example 303c and example 1501c3,4-d]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-methyl-pyridin-3-ylamine (29.0mg, 0.268mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-methyl-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.068g, 56%).¹HNMR(400MHz,d6-DMSO,,ppm):10.22(s,1H),9.34(s,1H),8.96(br s,2H),8.91(s,1H),8.46(d,J＝5.4Hz,1H),8.43(s,1H),8.38(dd,J＝8.8,2.4Hz,1H),8.02(s,1H),7.88(dd,J＝5.3,1.4Hz,1H),7.73(d,J＝8.8Hz,1H),4.11(s,3H),3.91-3.87(m,4H),3.36-3.30(m,4H),2.61(s,3H)。MS＝429(MH)+。

EXAMPLE 394 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 5-amino-2-methoxypyridine (33.0mg, 0.266mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-methoxy-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.091g, 74%).¹HNMR(400MHz,d6-DMSO,,ppm):9.43(s,1H),9.00-8.85(m,3H),8.48(d,J＝2.8Hz,1H),8.42(s,1H),8.26(d,J＝5.4Hz,1H),8.06(dd,J＝8.8,2.7Hz,1H),7.89(s,1H),7.69(dd,J＝5.3,1.1Hz,1H),6.83(d,J＝8.8Hz,1H),4.10(s,3H),3.90-3.86(m,4H),3.84(s,3H),3.35-3.29(m,4H)。MS＝445(MH)+。

Example 395 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-trisFluoromethyl-pyridin-3-ylamine (43.0mg, 0.265mmol) preparation of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-trifluoromethyl-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.084g, 64%).¹HNMR(400MHz,d6-DMSO,,ppm):10.09(s,1H),8.96(d,J＝2.5Hz,1H),8.94-8.84(m,3H),8.61(dd,J＝8.7,2.3Hz,1H),8.46-8.42(m,2H),8.04(s,1H),7.86(dd,J＝5.3,1.3Hz,1H),7.81(d,J＝8.9Hz,1H),4.11(s,3H),3.93-3.86(m,4H),3.37-3.30(m,4H)。MS＝483(MH)+。

Example 396. N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-pyridin-3-yl-acetamide

From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -acetamide from tert-butyl-pyrrolidine-1-carboxylate (100.0mg, 0.2188mmol) and 2-pyridin-3-yl-acetamide (35.0mg, 0.257mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -2-pyridin-3-yl-acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.008g, 6%).¹HNMR(400MHz,d6-DMSO,,ppm):10.99(s,1H),9.09(s,1H),8.95-8.75(m,3H),8.64(s,1H),8.56(d,J＝4.7Hz,1H),8.51(d,J＝5.1Hz,1H),8.40(s,1H),8.15(d,J＝6.1Hz,1H),8.07(dd,J＝5.2,1.4Hz,1H),7.93(d,J＝7.7Hz,1H),7.54-7.48(m,1H),4.98-4.90(m,1H),4.15(s,3H),3.49(s,2H),3.70-3.60(m,1H),3.48-3.28(m,3H),2.53-2.43(m,1H),2.25-2.15(m,1H)。MS＝457(MH)+。

Example 397.2- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

397a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy) -pyrido [3,4-d]Preparation of 2- (2-chloro-Pyridin-4-yl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d]A pyrimidine. The product was isolated as dark brown needles (0.283g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):8.85(s,1H),8.60(d,J＝5.1Hz,1H),8.37(s,1H),8.33-8.29(m,2H),4.07(s,3H),3.75-3.70(m,4H),2.52-2.48(m,4H),2.24(s,3H)。MS＝371,373(MH)+。

397b) From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of 2- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] using pyrimidine (100.0mg, 0.2697mmol) and 2-amino-isonicotinonitrile (39.0mg, 0.327mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -isonicotinonitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.123g, 80%).¹HNMR(400MHz,d6-DMSO,,ppm):10.46(s,1H),9.83(s,1H),8.94(s,1H),8.64(s,1H),8.51(dd,J＝5.0,0.6Hz,1H),8.49(d,J＝5.3Hz,1H),8.44(s,1H),8.35(s,1H),7.93(dd,J＝5.3,1.4Hz,1H),7.33(dd,J＝5.1,1.4Hz,1H),4.43(d,J＝13.4,2H),4.12(s,3H),3.60(d,J＝11.8Hz,2H),3.46(t,J＝12.9Hz,2H),3.30-3.20(m,2H),2.97-2.85(m,3H)。MS＝454(MH)+。

Example 398.2- (3-chloro-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of 2- (3-chloro-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] using pyrimidine (100.0mg, 0.2697mmol) and 2- (3-chloro-phenyl) -acetamide (55.1mg, 0.325mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as an orange lyophilizate (0.050g, 29%).¹HNMR(400MHz,d6-DMSO,,ppm):10.94(s,1H),9.89(br s,1H),9.09(s,1H),8.92(s,1H),8.52(dd,J＝5.1,0.6Hz,1H),8.42(s,1H),8.07(dd,J＝5.2,1.5Hz,1H),7.47-7.75(m,1H),7.41-7.32(m,3H),4.37(d,J＝13.9Hz,2H),4.11(s,3H),3.81(s,2H),3.59(d,J＝11.8Hz,2H),3.41(t,J＝13.1Hz,2H),3.29-3.17(m,2H),2.89(s,3H)。MS＝504,506(MH)+。

Example 399N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-pyridin-3-yl-acetamide

N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-pyridin-3-yl-acetamide was prepared in analogy to example 303c and example 1501c from 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2-pyridin-3-yl-acetamide (36.0mg, 0.264 mmol). The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.115g, 91%). HNMR (400MHz, d6-DMSO, ppm):11.03(s,1H),9.07(s,1H),8.92-8.83(m,3H),8.71(d, J ═ 1.5Hz,1H),8.64(dd, J ═ 5.1,1.2Hz,1H),8.52(dd, J ═ 5.1,0.6Hz,1H),8.41(s,1H),8.11-8.05(m,2H),7.68-7.63(m,1H),4.09(s,3H),3.96(s,2H),3.87-3.82(m,4H),3.34-3.28(m, 4H). MS ═ 457(MH) +.

EXAMPLE 400N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-pyridin-4-yl-acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (35.0mg, 0.257mmol) 2-pyridin-4-yl-acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-2-pyridin-4-yl-acetamide. The product was isolated as trifluoroacetate salt as an orange lyophilizate resin (0.113g, 90%).¹HNMR(400MHz,d6-DMSO,,ppm):11.06(s,1H),9.07(s,1H),8.90(s,1H),8.86(br s,2H),8.71(s,2H),8.53(dd,J＝5.1,0.6Hz,1H),8.41(s,1H),8.08(dd.J＝5.2,1.5Hz,1H),7.71(br s,2H),4.09(s,3H),4.03(s,2H),3.87-3.83(m,4H),3.34-3.28(m,4H)。MS＝457(MH)+。

EXAMPLE 401 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methoxy-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 4-methoxy-pyridin-2-ylamine (33.0mg, 0.266mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4-methoxy-pyridin-2-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.098g, 79%).¹HNMR(400MHz,d6-DMSO,,ppm):9.00-8.90(m,3H),8.55(d,J＝5.4Hz,1H),8.45(s,1H),8.31(s,1H),8.24(d,J＝6.9Hz,1H),8.12-8.08(m,1H),6.92(br s,2H),4.11(s,3H),4.00(s,3H),3.93-3.88(m,4H),3.37-3.30(m,4H)。MS＝445(MH)+。

Example 402.2- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

402a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (0.40g, 1.4mmol) and piperidin-4-ol (0.17g, 1.7mmol)]Pyrimidin-4-yl]-piperidin-4-ol. The product was isolated as an orange solid (0.317g, 62%).¹HNMR(400MHz,d6-DMSO,,ppm):8.84(s,1H),8.60(dd,J＝4.9,0.7Hz,1H),8.36(s,1H),8.32-8.29(m,2H),4.81(d,J＝4.1Hz,1H),4.08(s,3H),4.05-3.97(m,2H),3.85-3.77(m,1H),3.45-3.37(m,2H),1.96-1.88(m,2H),1.61-1.51(m,2H)。MS＝372,374(MH)+。

402b) From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using piperidin-4-ol (100.0mg, 0.2689mmol) and 2-amino-isonicotinic acid nitrile (39.0mg, 0.327mmol)]Pyrimidin-2-yl]-pyridin-2-ylAmino } -isonicotinic acid nitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.082g, 53%).¹HNMR(400MHz,d6-DMSO,,ppm):10.76(br s,1H),8.84(s,1H),8.58(s,1H),8.52(d,J＝5.2Hz,1H),8.47(d,J＝5.6Hz,1H),8.36(s,1H),8.23(s,1H),7.93(d,J＝5.6Hz,1H),7.37(d,J＝4.3Hz,1H),4.09(s,3H),4.08-4.00(m,2H),3.87-3.80(m,1H),3.50-3.40(m,2H),1.97-1.89(m,2H),1.64-1.54(m,2H)。MS＝455(MH)+。

Example 403.2- (3-cyano-phenyl) -N- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- (3-cyano-phenyl) -N- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using piperidin-4-ol (100.0mg, 0.2689mmol) and 2- (3-cyano-phenyl) -acetamide (52.0mg, 0.325mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.072g, 43%).¹HNMR(400MHz,d6-DMSO,,ppm):10.95(s,1H),9.03(s,1H),8.82(s,1H),8.49(dd,J＝5.2,0.6Hz,1H),8.34(s,1H),8.03(dd,J＝5.2,1.6Hz,1H),7.84-7.82(m,1H),7.77-7.74(m,1H),7.73-7.70(m,1H),7.57(t,J＝7.8Hz,1H),4.07(s,3H),4.03-3.95(m,2H),3.89(s,2H),3.85-3.77(m,1H),3.45-3.36(m,2H),1.94-1.86(m,2H),1.60-1.50(m,2H)。MS＝496(MH)+。

Example 404.2- (3-cyano-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide

From 2- (2-cyano-pyridin-4-yl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of 2- (3-cyano-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3, 4] using pyrimidine (100.0mg, 0.2697mmol) and 2- (3-cyano-phenyl) -acetamide (52.0mg, 0.325mmol)-d]Pyrimidin-2-yl]-pyridin-2-yl } -acetamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.044g, 26%).¹HNMR(400MHz,d6-DMSO,,ppm):10.97(s,1H),9.79(br s,1H),9.08(s,1H),8.92(s,1H),8.52(dd,J＝5.1,0.6Hz,1H),8.42(s,1H),8.08(dd,J＝5.1,1.5Hz,1H),7.84-7.82(m,1H),7.78-7.75(m,1H),7.73-7.70(m,1H),7.58(t,J＝7.8Hz,1H),4.37(d,J＝13.9Hz,2H),4.11(s,3H),3.89(s,2H),3.59(d,J＝11.0Hz,2H),3.45-3.35(m,2H),3.28-3.18(m,2H),2.91-2.87(m,3H)。MS＝495(MH)+。

EXAMPLE 405 (6-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (6-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) using (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and 6-chloro-pyridin-3-ylamine (34.0mg, 0.264mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as a free base as a yellow solid (0.010g, 9%). MP 206-.¹HNMR(400MHz,d6-DMSO,,ppm):9.71(s,1H),8.81(s,1H),8.74(d,J＝2.8Hz,1H),8.37-8.32(m,3H),7.92(s,1H),7.75(dd,J＝5.4,1.1Hz,1H),7.42(d,J＝8.7Hz,1H),4.07(s,3H),3.68-3.63(m,4H),2.90-2.85(m,4H)。MS＝449,451(MH)+。

EXAMPLE 406 (R) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-phenyl-propionamide

406a) (R) -2-phenyl-propionamide was prepared in a similar manner to example 313a from (R) -2-phenyl-propionic acid (0.941g, 6.27 mmol). The product was isolated as a white solid (0.457g, 48%).¹HNMR(400MHz,d6-DMSO,,ppm):7.35(s,1H),7.33-7.18(m,5H),6.79(s,1H),3.55(q,J＝7.0Hz,1H),1.30(d,J＝7.0Hz,3H)。MS＝150(MH)+。

406b) From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 4501c]Pyrimidin-4-ylamino]Preparation of (R) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyridino [3,4-d ] using (R) -2-phenyl-propionamide (45.0mg, 0.302mmol) and tert-butyl-pyrrolidine-1-carboxylate (100.0mg, 0.2188mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -2-phenyl-propionamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.100g, 78%).¹HNMR(400MHz,d6-DMSO,,ppm):10.79(s,1H),9.12(s,1H),8.97-8.77(m,3H),8.47(dd,J＝5.3,0.6Hz,1H),8.41(s,1H),8.15(d,J＝6.0Hz,1H),8.03(dd,J＝5.2,1.5Hz,1H),7.47-7.43(m,2H),7.37-7.32(m,2H),7.27-7.22(m,1H),5.00-4.90(m,1H),4.16(s,3H),4.09(q,J＝6.9Hz,1H),3.72-3.62(m,1H),3.50-3.30(m,3H),2.53-2.47(m,1H),2.27-2.17(m,1H),1.46(d,J＝7.0,3H)。MS＝470(MH)+。

EXAMPLE 407 (S) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-phenyl-propionamide

407a) (S) -2-phenyl-propionamide was prepared in a similar manner to example 313a from (S) -2-phenyl-propionic acid (1.25g, 8.32 mmol). The product was isolated as a white solid.¹HNMR(400MHz,d6-DMSO,,ppm):7.35(s,1H),7.33-7.18(m,5H),6.79(s,1H),3.55(q,J＝7.1Hz,1H),1.30(d,J＝7.1Hz,3H)。

407b) From (R) -3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of (S) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3, 4-d) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyridino- [3,4-d ] using (S) -2-phenyl-propionamide (45.0mg, 0.302mmol) and tert-butyl-pyrrolidine-1-carboxylate (100.0mg, 0.2188mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -2-phenyl-propionamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.100g, 78%).¹HNMR(400MHz,d6-DMSO,,ppm):10.79(s,1H),9.12(s,1H),8.99-8.79(m,3H),8.47(dd,J＝5.2,0.6Hz,1H),8.41(s,1H),8.15(d,J＝5.9Hz,1H),8.04(dd,J＝5.2,1.5Hz,1H),7.47-7.43(m,2H),7.37-7.32(m,2H),7.27-7.22(m,1H),5.00-4.90(m,1H),4.16(s,3H),4.09(q,J＝6.8Hz,1H),3.72-3.62(m,1H),3.50-3.30(m,3H),2.53-2.47(m,1H),2.27-2.17(m,1H),1.46(d,J＝7.0Hz,3H)。MS＝470(MH)+。

EXAMPLE 408 (R) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-propionamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (R) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] using (100.0mg, 0.2188mmol) of tert-butyl-piperazine-1-carboxylate and (R) -2-phenyl-propionamide (45.0mg, 0.302mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-2-phenyl-propionamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.115g, 89%).¹HNMR(400MHz,d6-DMSO,,ppm):10.82(s,1H),9.11(s,1H),8.93(s,1H),8.88(br s,2H),8.48(dd,J＝5.1,0.7Hz,1H),8.42(s,1H),8.04(dd,J＝5.1,1.4Hz,1H),7.46-7.43(m,2H),7.37-7.33(m,2H),7.27-7.22(m,1H),4.12-4.05(m,4H),3.90-3.86(m,4H),3.36-3.29(m,4H),1.45(d,J＝7.0Hz,3H)。MS＝470(MH)+。

EXAMPLE 409 (S) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-propionamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (S) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] using (100.0mg, 0.2188mmol) of tert-butyl-piperazine-1-carboxylate and (S) -2-phenyl-propionamide (45.0mg, 0.302mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-2-phenyl-propionamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.104g, 81%).¹HNMR(400MHz,d6-DMSO,,ppm):10.81(s,1H),9.11(s,1H),8.93(s,1H),8.88(br s,2H),8.48(dd,J＝5.1,0.5Hz,1H),8.42(s,1H),8.04(d,J＝5.1,1.4Hz,1H),7.47-7.41(m,2H),7.37-7.32(m,2H),7.27-7.22(m,1H),4.12-4.05(m,4H),3.89-3.84(m,4H),3.36-3.29(m,4H),1.45(d,J＝7.0Hz,3H)。MS＝470(MH)+。

EXAMPLE 410 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (90.0mg, 0.197mmol) and 3-methyl-pyridin-2-ylamine (30.0mg, 0.277mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (3-methyl-pyridin-2-yl) -amine. The product was isolated as a free base as a yellow foam (0.062g, 73%).¹HNMR(400MHz,d6-DMSO,,ppm):8.97(s,1H),8.81(s,1H),8.52(s,1H),8.35(dd,J＝5.2,0.5Hz,1H),8.32(s,1H),8.15(dd,J＝4.7,1.4Hz,1H),7.80(dd,J＝5.2,1.4Hz,1H),7.59-7.55(m,1H),6.94(dd,J＝7.3,5.0Hz,1H),4.07(s,3H),3.68-3.64(m,4H),2.90-2.85(m,4H),2.32(s,3H)。MS＝429(MH)+。

EXAMPLE 411 (3-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (3-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) using (90.0mg, 0.197mmol) tert-butyl piperazine-1-carboxylate and (31.0mg, 0.276mmol) 3-fluoro-pyridin-2-ylamine]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.110g, 84%).¹HNMR(400MHz,d6-DMSO,,ppm):10.34(br s,1H),8.97-8.79(m,4H),8.48-8.44(m,2H),8.27(d,J＝4.8Hz,1H),8.04(dd,J＝5.6,1.2Hz,1H),7.86-7.80(m,1H),7.21-7.16(m,1H),4.11(s,3H),3.94-3.88(m,4H),3.37-3.30(m,4H)。MS＝433(MH)+。

EXAMPLE 412 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-piperazin-1-ylpyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -piperazine-1-carboxylic acid tert-butyl ester (106mg, 0.232mmol) and 4- (5-amino-pyridin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester (73.0mg, 0.262mmol)]Pyrimidin-2-yl) -pyridin-2-yl]- (6-piperazin-1-yl-pyridin-3-yl) -amine. The product was isolated as bis-trifluoroacetate as a brown lyophilizate (0.107g, 63%).¹HNMR(400MHz,d6-DMSO,,ppm):9.28(s,1H),8.95-8.85(m,3H),8.73(br s,2H),8.51(d,J＝2.8Hz,1H),8.42(s,1H),8.25(d,J＝5.4Hz,1H),8.03(dd,J＝9.1,2.8Hz,1H),7.59(s,1H),7.66(dd,J＝5.4,1.2Hz,1H),6.97(d,J＝9.2Hz,1H),4.10(s,3H),3.90-3.85(m,4H),3.65-3.60(m,4H),3.36-3.29(m,4H),3.25-3.19(m,4H)。MS＝499(MH)+。

EXAMPLE 413 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ 2-methyl-4- (4-methyl-piperazin-1-yl) -phenyl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (102.0mg, 0.2232mmol) and 2-methyl-4- (4-methyl-piperazin-1-yl) -aniline (54.0mg, 0.263mmol) [ preparation as described in WO2008/051547]Preparation of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- [ 2-methyl-4- (4-methyl-piperazin-1-yl) -phenyl]-an amine. The product was isolated as bis-trifluoroacetate as a brown lyophilizate (0.128g, 75%).¹HNMR(400MHz,d6-DMSO,,ppm):10.00-9.30(m,2H),9.07(br s,2H),8.90(s,1H),8.44(s,1H),8.06(d,J＝5.9Hz,1H),7.95(s,1H),7.70(d,J＝5.7Hz,1H),7.34(d,J＝8.7Hz,1H),7.02(d,J＝2.3Hz,1H),6.94(dd,J＝8.7,2.4Hz,1H),4.11(s,3H),3.95-3.80(m,6H),3.55(d,J＝11.5Hz,2H),3.35-3.28(m,4H),3.23-3.12(m,2H),2.99(t,J＝13.8Hz,2H),2.89(s,3H),2.21(s,3H)。MS＝526(MH)+。

EXAMPLE 414 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-piperidin-4-yl-1H-pyrazol-4-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and tert-butyl (4-amino-pyrazol-1-yl) -piperidine-1-carboxylate (70.0mg, 0.263mmol) 4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]- (1-piperidin-4-yl-1H-pyrazol-4-yl) -amine. The product was isolated as bis-trifluoroacetate as a brown lyophilizate (0.123g, 78%).¹HNMR(400MHz,d6-DMSO,,ppm):9.40(br s,1H),9.00(br s,2H),8.90(s,1H),8.75-8.65(m,1H),8.50-8.37(m,2H),8.25(d,J＝5.6Hz,1H),8.10(s,1H),7.84(s,1H),7.62(d,J＝5.5Hz,1H),7.55(s,1H),4.54-4.44(m,1H),4.10(s,3H),3.90-3.85(m,4H),3.47-3.40(m,2H),3.36-3.30(m,4H),3.15-3.02(m,2H),2.23-2.06(m,4H)。MS＝487(MH)+。

EXAMPLE 415 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-methyl-pyridin-2-ylamine (30.0mg, 0.277mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-methyl-pyridin-2-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.095g, 80%).¹HNMR(400MHz,d6-DMSO,,ppm):8.96-8.87(m,3H),8.56(br s,1H),8.53(d,J＝5.6Hz,1H),8.45(s,1H),8.05-8.00(m,1H),7.85(br s,1H),7.45-7.39(m,1H),7.04-6.99(m,1H),4.11(s,3H),3.93-3.88(m,4H),3.37-3.30(m,4H)。MS＝429(MH)+。

EXAMPLE 416 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methyl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (104.0mg, 0.2276mmol) piperazine-1-carboxylate and 5-methyl-pyridin-3-ylamine (30.0mg, 0.277mmol) of [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-methyl-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.123g, 99%).¹HNMR(400MHz,d6-DMSO,,ppm):10.13(br s,1H),9.17(br s,1H),8.95-8.85(m,3H),8.46(d,J＝5.4Hz,1H),8.43(s,1H),8.30(s,1H),8.24(s,1H),8.02(s,1H),7.87(dd,J＝5.4,1.3Hz,1H),4.11(s,3H),3.91-3.86(m,4H),3.36-3.30(m,4H),2.43(s,3H)。MS＝429(MH)+。

Example 417 (5-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (5-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) using (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and 5-chloro-pyridin-3-ylamine (35.0mg, 0.272mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as trifluoroacetate salt as a pale yellow lyophilizate (0.112g, 90%).¹HNMR(400MHz,d6-DMSO,,ppm):9.88(s,1H),8.91(s,1H),8.84(br s,2H),8.69(d,J＝2.3Hz,1H),8.64(t,J＝2.2Hz,1H),8.45-8.42(m,2H),8.13(d,J＝2.2Hz,1H),7.99(s,1H),7.82(dd,J＝5.3,1.3Hz,1H),4.11(s,3H),3.91-3.86(m,4H),3.36-3.30(m,4H)。MS＝406,408(MH)+。

EXAMPLE 418 (2-fluoro-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

418a) In a similar manner to example 10b was prepared from 4- (3-fluoro-4-nitro-phenyl) -morpholine (0.52g, 2.3mmol) [ as in Quan, m.l.; et al, J.Med.chem.2005,48,1729-1744]Preparation of 2-fluoro-4-morpholin-4-yl-aniline. The product was isolated as a pale pink solid (0.40g, 88%).¹HNMR 400MHz,d6-DMSO,,ppm):6.71-6.63(m,2H),6.53(dd,J＝8.5,2.3Hz,1H),4.56(br s,2H),3.71-3.67(m,4H),2.93-2.89(m,4H)。MS＝197(MH)+。

418b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-fluoro-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -2-fluoro-4-morpholin-4-yl-aniline (105.0mg, 0.2298mmol) and tert-butyl piperazine-1-carboxylate (105.0mg, 0.2298mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as the bis-trifluoroacetate salt as an orange lyophilizate (0.120g, 70%).¹HNMR(400MHz,d6-DMSO,,ppm):9.27(br s,1H),8.96-8.89(m,3H),8.43(s,1H),8.16(d,J＝5.7Hz,1H),7.94(s,1H),7.70(dd,J＝5.6,1.1Hz,1H),7.61(t,J＝9.2Hz,1H),6.93(dd,J＝14.1,2.5Hz,1H),6.82(dd,J＝8.9,2.3Hz,1H),4.10(s,3H),3.90-3.85(m,4H),3.77-3.73(m,4H),3.34-3.28(m,4H),3.17-3.08(m,4H)。MS＝517(MH)+。

Example 419.3-fluoro-4- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 3-fluoro-4- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (36.0mg, 0.264mmol) 4-amino-3-fluoro-benzonitrile]Pyrimidin-2-yl) -pyridin-2-ylamino]-benzonitrile. The yellow solid is isolated asThe product was the free base (0.019g, 19%).¹HNMR(400MHz,d6-DMSO,,ppm):9.58(d,J＝2.5Hz,1H),8.91(s,1H),8.85-8.70(m,2H),8.45(m,2H),8.30(s,1H),7.89(dd,J＝5.3,1.3Hz,1H),7.83(dd,J＝11.7,1.9Hz,1H),7.66-7.62(m,1H),4.10(s,3H),3.91-3.87(m,4H),3.33-3.30(m,4H)。MS＝457(MH)+。

Example 420.4-fluoro-3- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile

420a) A100 mL round bottom flask equipped with a large magnetic stir bar, reflux condenser, and nitrogen inlet adapter was charged with 4-fluoro-3-nitrobenzonitrile (1.0g, 6.0mmol), ammonium chloride (1.6g, 30mmol), ethanol (20mL, 300mmol), and water (10mL, 600 mmol). Iron powder (1.1g, 20mmol) was added to the suspension. The suspension was stirred vigorously, allowing iron to disperse into the suspension without adhering to the stir bar. The mixture was maintained under a nitrogen atmosphere. An induction period (20 min) was observed, after which the reaction began to darken to russet, maintaining a mild exotherm from 23 ℃ to 26 ℃ over the course of three hours. After 3 hours, the reaction was completed by HPLC. The reaction was filtered through a plug of celite. The filter pad was rinsed with methanol (100 mL). The filtrate was evaporated to dryness. The solid was triturated with dichloromethane (-100 mL) and filtered. The filtrate was evaporated. 3-amino-4-fluoro-benzonitrile (0.78g, 95%) was isolated as a brown solid.¹HNMR(400MHz,d6-DMSO,,ppm):7.19(dd,J＝11.5,8.3Hz,1H),7.09(dd,J＝8.3,2.1Hz,1H),6.96(ddd,J＝8.3,4.3,2.1Hz,1H),5.69(br s,2H)。MS＝137(MH)+。

420b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 4-fluoro-3- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2188mmol) tert-butyl-piperazine-1-carboxylate and (36.0mg, 0.264mmol) 3-amino-4-fluoro-benzonitrile]Pyrimidin-2-yl) -pyridin-2-ylamino]-benzonitrile. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.096 g).¹HNMR(400MHz,d6-DMSO,,ppm):9.41(d,J＝2.0Hz,1H),8.99-8.85(m,1H),8.93-8.84(m,3H),8.44-8.41(m,2H),8.22(s,1H),7.84(dd,J＝5.3,1.4Hz,1H),7.53-7.46(m,2H),4.11(s,3H),3.92-3.87(m,4H),3.36-3.30(m,4H)。MS＝457(MH)+。

EXAMPLE 421 (2, 6-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2, 6-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -based on (100.0mg, 0.2188mmol) of piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2, 6-difluoro-aniline (30.0 μ L, 0.279mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.132g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):8.91-8.80(m,4H),8.41(s,1H),8.18(d,J＝5.6Hz,1H),7.82(s,1H),7.69-7.66(m,1H),7.33-7.25(m,1H),7.21-7.12(m,2H),4.10(s,3H),3.89-3.84(m,4H),3.35-3.27(m,4H)。MS＝450(MH)+。

EXAMPLE 422 (2-fluoro-6-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-fluoro-6-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2-fluoro-6-methyl-aniline (33.0mg, 0.264mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.099g, 67%).¹HNMR(400MHz,d6-DMSO,,ppm):8.98-8.83(m,4H),8.42(s,1H),8.14(d,J＝5.5Hz,1H),7.75(br s,1H),7.65(d,J＝5.3Hz,1H),7.26-7.10(m,3H),4.10(s,3H),3.88-3.82(m,4H),3.36-3.27(m,4H),2.25(s,3H)。MS＝446(MH)+。

EXAMPLE 423 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-2-yl-amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 2-amino-pyrimidine (25.0mg, 0.263mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyrimidin-2-yl-amine. The product was isolated as a free base as a yellow solid (0.009g, 10%). MP 200-.¹HNMR(400MHz,d6-DMSO,,ppm):9.94(s,1H),9.31(s,1H),8.39(s,1H),8.59(d,J＝4.8Hz,2H),8.44-8.41(m,1H),8.33(s,1H),7.90(dd,J＝5.2,1.5Hz,1H),7.00(t,J＝4.8Hz,1H),4.07(s,3H),3.71-3.66(m,4H),2.92-2.87(m,4H)。MS＝416(MH)+。

EXAMPLE 424 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methoxy-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (108.0mg, 0.2364mmol) piperazine-1-carboxylate and 5-methoxy-pyridin-3-ylamine (33.0mg, 0.266mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-methoxy-pyridin-3-yl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.104g, 99%).¹HNMR(400MHz,d6-DMSO,,ppm):9.84(s,1H),8.91(s,1H),8.85(br s,2H),8.62(s,1H),8.44-8.41(m,2H),8.10(t,J＝2.2Hz,1H),7.99(s,2H),7.81(d,J＝5.3Hz,1H),4.11(s,3H),3.91-3.86(m,7H),3.36-3.30(m,4H)。MS＝445(MH)+。

EXAMPLE 425 (S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ol

425a) To be similar to [ B016]OfOf the formula (I) from 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1000.0mg, 3.4639mmol) and (S) -piperidin-3-ol hydrochloride (570.0mg, 4.142mmol)]Pyrimidin-4-yl]-piperidin-3-ol. The product was isolated as a yellow foam (0.747g, 58%).¹HNMR(400MHz,d6-DMSO,,ppm):8.83(s,1H),8.60(dd,J＝5.0,0.6Hz,1H),8.35(s,1H),8.32-8.29(m,2H),4.88(d,J＝3.9Hz,1H),4.14-4.05(m,4H),3.95-3.89(m,1H),3.69-3.61(m,1H),3.48-3.38(m,1H),3.09(dd,J＝12.4,8.3Hz,1H),1.96-1.84(m,2H),1.62-1.40(m,2H)。MS＝372,374(MH)+。

425b) From (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] -piperidin-3-ol (101.0mg, 0.2716mmol) and aniline (30.0. mu.L, 0.329mmol)]Pyrimidin-4-yl]-piperidin-3-ol. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.102g, 69%).¹HNMR(400MHz,d6-DMSO,,ppm):9.60(br s,1H),8.81(s,1H),8.35(s,1H),8.27(d,J＝5.6Hz,1H),7.94(s,1H),7.72-7.68(m,3H),7.33(t,J＝7.7Hz,2H),6.99(t,J＝6.8Hz,1H),4.11-4.04(m,5H),3.97-3.90(m,1H),3.70-3.62(m,1H),3.49-3.40(m,1H),3.11(dd,J＝12.8,8.3Hz,1H),1.98-1.85(m,2H),1.65-1.43(m,2H)。MS＝429(MH)+。

Example 426.2- {4- [4- ((S) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

From (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- {4- [4- ((S) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using-piperidin-3-ol (109.0mg, 0.2932mmol) and 2-amino-isonicotinonitrile (39.0mg, 0.327mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -isonicotinonitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.121g, 72%).¹HNMR(400MHz,d6-DMSO,,ppm):10.60(br s,1H),8.83(s,1H),8.61(s,1H),8.52(d,J＝5.2Hz,1H),8.46(d,J＝5.4Hz,1H),8.35(s,1H),8.26(s,1H),7.91(d,J＝5.1Hz,1H),7.34(d,J＝4.9Hz,1H),4.15-4.05(m,5H),4.00-3.92(m,1H),3.70-3.62(m,1H),3.52-3.40(m,1H),3.11(dd,J＝12.7,8.3Hz,1H),1.98-1.87(m,2H),1.67-1.43(m,2H)。MS＝455(MH)+。

Example 427.1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol

From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl ] -L-pyrido [ 10, 4-d ] -L-piperidin-4-ol (104.0mg, 0.2797mmol) and aniline (30.0. mu.L, 0.329mmol)]Pyrimidin-4-yl]-piperidin-4-ol. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.093g, 61%).¹HNMR(400MHz,d6-DMSO,,ppm):9.66(br s,1H),8.82(s,1H),8.36(s,1H),8.25(d,J＝5.6Hz,1H),7.96(s,1H),7.72-7.67(m,3H),7.34(t,J＝7.8Hz,2H),7.02(t,J＝7.2Hz,1H),4.08(s,3H),4.05-3.97(m,2H),3.87-3.79(m,1H),3.47-3.39(m,2H),1.96-1.88(m,2H),1.63-1.52(m,2H)。MS＝429(MH)+。

EXAMPLE 428 (R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ol

428a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (R) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1000.0mg, 3.4639mmol) and (R) -piperidin-3-ol hydrochloride (570.0mg, 4.142mmol)]Pyrimidin-4-yl]-piperidin-3-ol. The product was isolated as a dark brown solid (0.561g, 44%).¹HNMR(400MHz,d6-DMSO,,ppm):8.83(s,1H),8.60(dd,J＝5.0,0.5Hz,1H),8.35(s,1H),8.32-8.29(m,2H),4.88(d,J＝3.9Hz,1H),4.15-4.05(m,4H),3.95-3.88(m,1H),3.70-3.60(m,1H),3.47-3.37(m,1H),3.09(dd,J＝12.7,8.3Hz,1H),1.96-1.84(m,2H),1.60-1.40(m,2H)。MS＝372,374(MH)+。

Example 429.2- {4- [4- ((R) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

From (R) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- {4- [4- ((R) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using-piperidin-3-ol (105.0mg, 0.2824mmol) and 2-amino-isonicotinonitrile (39.0mg, 0.327mmol)]Pyrimidin-2-yl]-pyridin-2-ylamino } -isonicotinonitrile. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.013g, 8%).¹HNMR(400MHz,d6-DMSO,,ppm):10.60(br s,1H),8.83(s,1H),8.61(s,1H),8.52(d,J＝5.1Hz,1H),8.46(d,J＝5.7Hz,1H),8.35(s,1H),8.26(s,1H),7.91(d,J＝5.4Hz,1H),7.34(d,J＝5.3Hz,1H),4.14-4.04(m,4H),4.00-3.92(m,1H),3.70-3.62(m,1H),3.51-3.41(m,1H),3.12(dd,J＝12.9,8.2Hz,1H),1.98-1.88(m,2H),1.65-1.43(m,2H)。MS＝455(MH)+。

EXAMPLE 430 [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (S) -1-pyrrolidin-2-ylmethyl-amine

430a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (S) -2- { [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol (1000.0mg, 3.4639mmol) and (S) -2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (840.0mg, 4.194mmol)]Pyrimidin-4-ylamino]-methyl } -pyrrolidine-1-carboxylic acid tert-butyl ester. The product was isolated as a yellow foam (0.817g, 50%).¹HNMR(400MHz,d6-DMSO,,ppm):8.87-8.25(m,6H),4.30-4.22(m,1H),4.14(s,3H),4.01-3.91(m,1H),3.72-3.50(m,1H),3.37-3.27(m,1H),2.03-1.78(m,5H),1.45-1.10(m,9H)。MS＝471,473(MH)+。

430b) From (S) -2- { [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyridine in a similar manner to example 303c and example 1501cAnd [3,4-d ]]Pyrimidin-4-ylamino]Preparation of tert-butyl (108.0mg, 0.2293mmol) methyl } -pyrrolidine-1-carboxylate and aniline (25.0. mu.L, 0.274mmol) [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ]]Pyrimidin-4-yl]- (S) -1-pyrrolidin-2-ylmethyl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.109g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):9.42(br s,1H),8.97(br s,1H),8.82(s,1H),8.64(t,J＝5.7Hz,1H),8.54(br s,1H),8.40(s,1H),8.31(d,J＝5.4Hz,1H),7.94(s,1H),7.75-7.70(m,3H),7.31(t,J＝7.7Hz,2H),6.95(t,J＝7.4Hz,1H),4.15(s,3H),4.12-3.85(m,3H),3.34-3.14(m,2H),2.20-1.74(m,4H)。MS＝428(MH)+。

EXAMPLE 431 [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -1-pyrrolidin-2-ylmethyl-amine

431a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (R) -2- { [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol (1000.0mg, 3.4639mmol) and (R) -2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (840.0mg, 4.194mmol)]Pyrimidin-4-ylamino]-methyl } -pyrrolidine-1-carboxylic acid tert-butyl ester. The product was isolated as a yellow foam (0.869g, 53%).¹HNMR(400MHz,d6-DMSO,,ppm):8.86-8.25(m,6H),4.31-4.21(m,1H),4.14(s,3H),4.00-3.90(m,1H),3.72-3.50(m,1H),3.36-3.28(m,1H),2.02-1.78(m,5H),1.45-1.10(m,9H)。LC/MS＝471,473(MH)+。

431b) From (R) -2- { [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of tert-butyl (105.0mg, 0.2230mmol) methyl } -pyrrolidine-1-carboxylate and aniline (25.0. mu.L, 0.274mmol) [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ]]Pyrimidin-4-yl]- (R) -1-pyrrolidin-2-ylmethyl-amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.117g, 97%).¹HNMR(400MHz,d6-DMSO,,ppm):9.42(br s,1H),8.97(br s,1H),8.82(s,1H),8.64(t,J＝5.9Hz,1H),8.53(br s,1H),8.40(s,1H),8.31(d,J＝5.4Hz,1H),7.94(s,1H),7.75-7.70(m,3H),7.31(t,J＝7.5Hz,2H),6.95(t,J＝7.4Hz,1H),4.15(s,3H),4.12-3.85(m,3H),3.34-3.15(m,2H),2.20-1.74(m,4H)。MS＝428(MH)+。

Example 432.2- {4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-1-yl } -ethanol

432a) From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c ]Preparation of 2- {4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1000.0mg, 3.4639mmol) and 2-piperazin-1-yl-ethanol (550.0mg, 4.225mmol)]Pyrimidin-4-yl]-piperazin-1-yl } -ethanol. The product was isolated as a yellow solid (0.414g, 30%).¹HNMR(400MHz,d6-DMSO,,ppm):8.84(s,1H),8.60(dd,J＝5.1,0.7Hz,1H),8.36(s,1H),8.32-8.29(m,2H),4.46(t,J＝5.4Hz,1H),4.07(s,3H),3.75-3.70(m,4H),3.58-3.52(m,2H),2.63-2.58(m,4H),2.46(t,J＝6.2Hz,2H)。LC/MS＝401,403(MH)+。

EXAMPLE 433 {1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -azetidin-3-yl } -methanol

433a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of {1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1000.0mg, 3.4639mmol) and azetidin-3-yl-methanolic hydrochloride (550.0mg, 4.450mmol)]Pyrimidin-4-yl]-azetidin-3-yl } -methanol. The product was isolated as a dark brown solid (0.925g, 75%).¹HNMR(400MHz,d6-DMSO,,ppm):8.80(s,1H),8.59(dd,J＝4.8,1.1Hz,1H),8.33-8.29(m,3H),4.83(t.J＝5.5Hz,1H),4.60-4.53(m,1H),4.41-4.34(m,1H),4.27-4.21(m,1H),4.16-4.10(m,1H),4.06(s,3H),3.59(t,J＝5.7Hz,2H),2.85-2.75(m,1H)。MS＝358,360(MH)+。

433b) In a similar manner to example 303c and example 1501cFrom {1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (E) -azetidin-3-yl } -methanol (114.0mg, 0.3186mmol) and aniline (31.0. mu.L, 0.340mmol) {1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ]]Pyrimidin-4-yl]-azetidin-3-yl } -methanol. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.117g, 69%).¹HNMR(400MHz,d6-DMSO,,ppm):9.65(br s,1H),8.79(s,1H),8.33(s,1H),8.25(d,J＝5.5Hz,1H),7.97(s,1H),7.72-7.67(m,3H),7.34(t,J＝7.8Hz,2H),7.01(t,J＝7.3Hz,1H),4.61-4.11(m,4H),4.07(s,3H),3.60(d,J＝6.2Hz,2H),2.87-2.76(m,1H)。MS＝415(MH)+。

Example 434 { (R) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -methanol

434a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (R) -4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1.00g, 3.46mmol) and (R) -2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.90g, 4.2mmol)]Pyrimidin-4-yl]-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester. The product was isolated as an off-white solid (1.23g, 72%).¹HNMR(400MHz,d6-DMSO,,ppm):8.86(s,1H),8.60(d,J＝5.4Hz,1H),8.38(s,1H),8.36-8.32(m,2H),4.78(t,J＝5.2Hz,1H),4.48(d,J＝12.7Hz,1H),4.17-4.11(m,1H),4.09(s,3H),4.06-3.99(m,1H),3.88-3.80(m,1H),3.47-3.35(m,3H),3.29-3.21(m,2H),1.42(s,9H)。LC/MS＝487,489(MH)+。

434b) From (R) -4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (104.0mg, 0.2136mmol) and aniline (23.0 μ L, 0.252mmol) { (R) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d { (R) }]Pyrimidin-4-yl]-piperazin-2-yl } -methanol. The product was isolated as a free base as a yellow foam (0.033g, 34%).¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.81(s,1H),8.33(s,1H),8.30(d,J＝5.3Hz,1H),7.89(s,1H),7.77-7.73(m,2H),7.66(dd,J＝5.3,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.71(t,J＝5.5Hz,1H),4.24-4.15(m,2H),4.07(s,3H),3.44-3.36(m,2H),3.16-3.02(m,2H),2.88-2.78(m,3H)。MS＝444(MH)+。

EXAMPLE 435 (R) -7- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-Azolo [3,4-a ] s]Pyrazin-3-ones

(R) -7- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-Azolo [3,4-a ] s]Pyrazin-3-one is the by-product from example 434. The product was isolated as a free base as a yellow foam (0.023g, 23%).¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.87(s,1H),8.38(s,1H),8.32(d,J＝5.2Hz,1H),7.91(s,1H),7.77-7.74(m,2H),7.69(dd,J＝5.3,1.4Hz,1H),7.31-7.26(m,2H),6.93-6.88(m,1H),4.50-4.39(m,2H),4.29(d,J＝13.1Hz,1H),4.12-4.03(m,6H),3.77(dd,J＝13.2,2.1Hz,1H),3.17-3.06(m,2H)。MS＝470(MH)+。

EXAMPLE 436 (. + -.) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

436a) To benzyl 3, 6-dihydro-2H-pyridine-1-carboxylate (1.16g, 5.34mmol) in acetone (4mL) and water (4mL) [ as in Solares, f.l.; et al, Tetrahedron2006,62,3284-3291]To the solution of (3) was added N-methylmorpholine N-oxide (0.88g, 7.5mmol) followed by 2.5 wt% (w/v) OsO4 (2.5: 97.5, osmium tetroxide: t-butanol, 0.8mL, 0.06mmol) in t-butanol. The mixture was stirred at room temperature for 1 hour. The reaction was completed by LC/MS. Saturated aqueous sodium thiosulfate (5) was added0mL), the mixture was stirred for 5 minutes and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a red-brown oil. The recovered oil was purified by chromatography (silica gel column (24g) and 2:1 ethyl acetate: hexane) using an ISCO instrument. Benzyl (. + -.) -cis-3, 4-dihydroxy-piperidine-1-carboxylate (1.13g, 84%) was isolated as a pale yellow oil.¹HNMR(400MHz,d6-DMSO,,ppm):7.43-7.27(m,5H),5.05(s,2H),4.66(d,J＝4.1Hz,1H),4.55(d,J＝3.7Hz,1H),3.75-3.64(m,1H),3.51-3.18(m,5H),1.69-1.60(m,1H),1.52-1.43(m,1H)。MS＝274(M+Na)+。

436b) A parr bottle (500mL) was charged with 10% palladium on carbon (50% wet) (5:45:50, palladium: carbon black: water, 1.0g, 0.47mmol) followed by the addition of a solution of (+ -) -cis-3, 4-dihydroxy-piperidine-1-carboxylic acid benzyl ester (1.13g, 4.50mmol) in 2:1 ethyl acetate: methanol (50 mL). The reaction mixture was degassed and charged with hydrogen (50 psi). The mixture was shaken on a parr (Paar) instrument for 4 hours. The reaction mixture was degassed and maintained under a nitrogen atmosphere. The mixture was filtered through a plug of celite and rinsed with dichloromethane. The filtrate was evaporated. (. + -.) -cis-piperidine-3, 4-diol was isolated as a pale yellow oil (0.569g, 100%).¹HNMR(400MHz,d6-DMSO,,ppm):4.11(br s,3H),3.57-3.53(m,1H),3.46-3.42(m,1H),2.79-2.67(m,2H),2.57-2.49(m,1H),2.47-2.37(m,1H),1.61-1.51(m,1H),1.47-1.39(m,1H)。MS＝118(MH)+。

436c) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (+ -) -cis-1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using (+ -) -cis-piperidine-3, 4-diol (0.56g, 4.8mmol) and pyrimidin-4-ol (1.00g, 3.46mmol)]Pyrimidin-4-yl]Piperidine-3, 4-diol. The product was isolated as a pale yellow solid (0.927g, 69%).¹HNMR(400MHz,d6-DMSO,,ppm):8.82(s,1H),8.60(dd,J＝5.0,0.5Hz,1H),8.35(s,1H),8.32-8.29(m,2H),4.65-4.61(m,2H),4.07(s,3H),3.94(br s,1H),3.83-3.74(m,2H),3.65-3.53(m,3H),1.94-1.85(m,1H),1.73-1.65(m,1H)。MS＝388,390(MH)+。

436d) From (. + -.) cis-1- [2- (2-chloro-pyridin-4-yl) -5-methyl in a similar manner to example 303cOxy-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (. + -.) cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] using (100.0mg, 0.2578mmol) piperidine-3, 4-diol and (29.0. mu.L, 0.318mmol) aniline]Pyrimidin-4-yl]Piperidine-3, 4-diol. The product was isolated as the free base as a yellow solid (0.039g, 34%). MP 241-.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.79(s,1H),8.32-8.29(m,2H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.3,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.64-4.60(m,2H),4.07(s,3H),3.98-3.88(m,1H),3.85-3.72(m,2H),3.66-3.53(m,3H),1.97-1.87(m,1H),1.76-1.66(m,1H)。MS＝445(MH)+。

EXAMPLE 437 (. + -.) -trans-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

437a) From (±) -trans-3, 4-dihydroxy-piperidine-1-carboxylic acid benzyl ester (1.0g, 4.0mmol) [ as in Solares, f.l.; et al, Tetrahedron2006,62,3284-3291]Preparation of (+ -) -trans-piperidine-3, 4-diol. The product was isolated as a pale yellow oil (0.451g, 97%).¹HNMR(400MHz,d6-DMSO,,ppm):4.59(br s,2H),4.09(br s,1H),3.20-3.13(m,1H),3.11-3.04(m,1H),2.88(ddd,J＝4.4,12.1,1.2Hz,1H),2.77(dddd,J＝12.6,4.1,4.1,1.2Hz,1H),2.35(dddd,J＝14.1,11.3,2.9Hz,1H),2.15(dd,J＝12.2,9.1Hz,1H),1.71(dddd,J＝12.6,3.8,3.8,3.8Hz,1H),1.25-1.15(m,1H)。MS＝118(MH)+。

437b) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of (+ -) -trans-1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using (+ -) -trans-piperidine-3, 4-diol (0.46g, 3.9mmol) and (+ -) -trans-4-ol (1.00g, 3.46mmol)]Pyrimidin-4-yl]Piperidine-3, 4-diol. The product was isolated as a dark brown solid (0.700g, 52%). MP 213-.¹HNMR(400MHz,d6-DMSO,,ppm):8.83(s,1H),8.61(dd,J＝5.0,0.6Hz,1H),8.36(s,1H),8.32-8.29(m,2H),5.00(d,J＝4.1Hz,1H),4.94(d,J＝4.2Hz,1H),4.11-4.03(m,4H),4.00-3.90(m,1H),3.59-3.47(m,2H),3.44-3.37(m,1H),3.16(dd,J＝13.1,7.9Hz,1H),2.07-1.99(m,1H),1.54-1.44(m,1H)。MS＝388,390(MH)+。

437c) From (. + -.) -trans-1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of the desired (. + -.) -trans-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] from piperidine-3, 4-diol (100.0mg, 0.2578mmol) and aniline (29.0. mu.L, 0.318mmol)]Pyrimidin-4-yl]Piperidine-3, 4-diol. The product was isolated as the free base as a dark brown foam (0.1126g, 98%).¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.80(s,1H),8.33(s,1H),8.30(d,J＝5.4Hz,1H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.3,1.3Hz,1H),7.40-7.36(m,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),5.00(d,J＝4.1Hz,1H),4.94(d,J＝4.2Hz,1H),4.10-4.04(m,4H),3.98(d,J＝13.4Hz,1H),3.55-3.46(m,1H),3.40(dddd,J＝7.7,7.7,4.2,4.2Hz,1H),3.13(dd,J＝13.0,7.7Hz,1H),2.09-2.00(m,1H),1.57-1.46(m,1H)。MS＝445(MH)+。

Example 438.4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-one

438a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1.0g, 3.5mmol) and piperazin-2-one (0.42g, 4.2mmol)]Pyrimidin-4-yl]-piperazin-2-one. The product was isolated as a dark brown solid (1.12g, 87%).¹HNMR(400MHz,d6-DMSO,,ppm):8.89(s,1H),8.63-8.60(m,1H),8.41(s,1H),8.34-8.32(m,2H),8.15(s,1H),4.23(s,2H),4.10(s,3H),3.95-3.90(m,2H),3.43-3.39(m,2H)。LC/MS＝371,373(MH)+。

438b) From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] from (100.0mg, 0.2697mmol) and aniline (30.0. mu.L, 0.329mmol)]Pyrimidine-4-Base of]-piperazin-2-one. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.022g, 19%).¹HNMR(400MHz,d6-DMSO,,ppm):9.66(br s,1H),8.87(s,1H),8.40(s,1H),8.27(d,J＝5.5Hz,1H),8.18(s,1H),7.97(s,1H),7.74-7.69(m,3H),7.34(t,J＝7.7Hz,2H),7.00(t,J＝7.0Hz,1H),4.23(s,2H),4.10(s,3H),3.92-3.87(m,2H),3.46-3.41(m,2H)。MS＝428(MH)+。

Example 439 (2, 3-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2, 3-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -based on (100.0mg, 0.2188mmol) of piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2, 3-difluoro-aniline (27.0 μ L, 0.266mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.125g, 84%).¹HNMR(400MHz,d6-DMSO,,ppm):9.24(s,1H),8.91(s,1H),8.86(br s,2H),8.42(s,1H),8.33(d,J＝5.4Hz,1H),8.10(s,1H),8.07-8.03(m,1H),7.78(dd,J＝5.3,1.4Hz,1H),7.19-7.11(m,1H),7.06-6.98(m,1H),4.10(s,3H),3.91-3.86(m,4H),3.36-3.29(m,4H)。MS＝450(MH)+。

EXAMPLE 440 (2, 5-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2, 5-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -based on (100.0mg, 0.2188mmol) of piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2, 5-difluoro-aniline (27.0 μ L, 0.268mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.036g, 24%).¹HNMR(400MHz,d6-DMSO,,ppm):9.25(s,1H),8.91(s,1H),8.89(br s,2H),8.45-8.38(m,3H),8.21(s,1H),7.81(dd,J＝5.3,1.4Hz,1H),7.31-7.24(m,1H),6.80-6.74(m,1H),4.11(s,3H),3.92-3.87(m,4H),3.36-3.30(m,4H)。MS＝450(MH)+。

EXAMPLE 441[ 4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,4, 6-trifluoro-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 2,4, 6-trifluoro-aniline (39.0mg, 0.265mmol) to [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2,4, 6-trifluoro-phenyl) -amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.092g, 60%).¹HNMR(400MHz,d6-DMSO,,ppm):8.93(br s,2H),8.90(s,1H),8.82(s,1H),8.42(s,1H),8.17(dd,J＝5.4,0.5Hz,1H),7.83(s,1H),7.68(dd,J＝5.3,1.4Hz,1H),7.34-7.23(m,2H),4.10(s,3H),3.90-3.84(m,4H),3.35-3.29(m,4H)。MS＝468(MH)+。

EXAMPLE 442 ((R) -4- {2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -piperazin-2-yl) -methanol

From (R) -4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (R) -4- {2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2054mmol) and 2, 6-difluoro-aniline (32.0mg, 0.248mmol)]-5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl } -piperazin-2-yl) -methanol. The product was isolated as a free base as a dark brown foam (0.066g, 66%).¹HNMR(400MHz,d6-DMSO,,ppm):8.80(s,1H),8.76(s,1H),8.32(s,1H),8.15(d,J＝5.3Hz,1H),7.77(s,1H),7.64(d,J-5.2,1.3Hz,1H),7.31-7.10(m,3H),4.70(t,J＝5.5Hz,1H),4.21-4.12(m,2H),4.06(s,3H),3.42-3.35(m,2H),3.15-3.00(m,2H),2.86-2.77(m,3H)。MS＝480(MH)+。

Example 443.3-hydroxymethyl-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol

443a) To a cooled solution of 4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride (5.0g, 24mmol) and sodium bicarbonate (4.40g, 52.4mmol) in water (50mL) at 5 deg.C was added dropwise benzyl chloroformate (3.40mL, 23.8 mmol). The mixture was stirred at room temperature overnight. Saturated aqueous sodium carbonate (10mL) was added and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography (silica gel column 120g and 10% → 50% ethyl acetate: hexane) using an ISCO apparatus. 1-benzyl 4-oxo-piperidine-1, 3-dicarboxylate 3-ethyl ester (7.30g, 100%) was isolated as a clear oil.¹HNMR(400MHz,CDCl3,,ppm):12.07(s,1H),7.43-7.29(m,5H),5.20-5.15(m,2H),4.24(q,J＝7.2Hz,2H),4.14(br s,2H),3.65(t,J＝5.9Hz,2H),2.39(br s,2H),1.31(t,J＝7.2Hz,3H)。MS＝328(M+Na)+。

443b) To a stirred solution of 4-oxo-piperidine-1, 3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (3.0g, 9.8mmol) in methanol (30mL) under nitrogen at room temperature was added sodium borohydride (4.5g, 120mmol) 0.5g each over 1 hour. Gas evolution and an exotherm were noted at each addition. During the addition process, slow batch addition maintained the reaction temperature below 25 ℃. The mixture was stirred at room temperature for 1 hour, then slowly warmed. The reaction was refluxed for 4 hours, cooled to room temperature and stirred overnight. Water was added dropwise to the reaction over 1 hour: methanol 1:1 mixture (100 mL). No exotherm or gas evolution was noted. The mixture was stirred for 4 hours. Methanol was evaporated under reduced pressure. Methanol (50mL) was added and the white suspension was heated to reflux for 30 min. Methanol was evaporated under reduced pressure. This was repeated twice. The mixture was evaporated to a white oily solid. The solid was triturated with dichloromethane (3 × 50mL) and decanted. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Is divided intoBenzyl 4-hydroxy-3-hydroxymethyl-piperidine-1-carboxylate (0.655g, 25%) was isolated as a clear oil.¹HNMR(400MHz,d6-DMSO,,ppm):7.41-7.28(m,5H),5.13-5.00(m,2H),4.70-4.56(m,1H),4.50-4.39(m,1H),4.09-3.60(m,3H),3.47-2.58(m,4H),1.80-1.20(m,3H)。MS＝288(M+Na)+。

443c) 3-hydroxymethyl-piperidin-4-ol was prepared in analogy to example 436b from 4-hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (0.655g, 2.47 mmol). The product was isolated as a viscous oil (0.324g, 100%).¹HNMR(400MHz,d6-DMSO,,ppm):4.60-3.18(m,7H),3.3-2.78(m,1H),2.70-2.56(m,1H),2.43-2.10(m,1H),1.74-1.18(m,3H)。

443d) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (0.70g, 2.4mmol) and 3-hydroxymethyl-piperidin-4-ol (0.324g, 2.47mmol)]Pyrimidin-4-yl]-3-hydroxymethyl-piperidin-4-ol. The product was isolated as a pale yellow foam (0.342g, 35%).¹HNMR(400MHz,d6-DMSO,,ppm):8.83(d,J＝5.4Hz,1H),8.61-5.85(m,1H),8.35(d,J＝6.2Hz,1H),8.33-8.29(m,2H),4.78-4.69(m,1H),4.58-4.46(m,1H),4.36-3.70(m,6H),3.56-3.12(m,4H),2.02-1.45(m,3H)。MS＝402,404(MH)+。

443e) From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 3-hydroxymethyl-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] using (100.0mg, 0.2488mmol) 3-hydroxymethyl-piperidin-4-ol and aniline (28.0. mu.L, 0.307mmol)]Pyrimidin-4-yl]-piperidin-4-ol. The product was isolated as the free base of the enantiomeric mixture as a yellow foam (0.071g, 62%).¹HNMR(400MHz,d6-DMSO,,ppm):9.31(d,J＝3.0Hz,1H),8.80(d,J＝4.5Hz,1H),8.34-8.29(m,2H),7.90(s,1H),7.75(d,J＝7.7H,2H),7.68(dd,J＝5.3,1.2Hz,1H),7.31-7.25(m,2H),6.92-6.87(m,1H),4.79-4.69(m,1H),4.55-4.43(m,1H),4.30-3.70(m,6H),3.56-3.25(m,3H),3.19-2.91(m,1H),2.04-1.50(m,3H)。MS＝459(MH)+。

EXAMPLE 444 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 6-trifluoro-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (121.0mg, 0.2648mmol) piperazine-1-carboxylate and 2,3, 6-trifluoro-aniline (33.9 μ L, 0.320mmol) to [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2,3, 6-trifluoro-phenyl) -amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.155g, 84%).¹HNMR(400MHz,d6-DMSO,,ppm):9.07(s,1H),8.94-8.84(m,3H),8.42(s,1H),8.21(d,J＝5.3Hz,1H),7.89(s,1H),7.72(dd,J＝5.3,1.4Hz,1H),7.33(dddd,J＝9.7,9.7,9.7,4.9Hz,1H),7.21(dddd,J＝9.6,4.7,4.7,2.2Hz,1H),4.10(s,3H),3.91-3.84(m,4H),3.36-3.28(m,4H)。MS＝468(MH)+。

EXAMPLE 445[ 4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-trifluoromethyl-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (124.0mg, 0.2714mmol) piperazine-1-carboxylate and 2- (trifluoromethyl) -aniline (40.0 μ L, 0.318mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2-trifluoromethyl-phenyl) -amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.134g, 69%).¹HNMR(400MHz,d6-DMSO,,ppm):9.00-8.85(m,4H),8.42(d,J＝2.3Hz,1H),8.19(dd,J＝5.4,1.4Hz,1H),7.99(s,1H),7.80-7.66(m,4H),7.44-7.37(m,1H),4.11(s,3H),3.90-3.84(m,4H),3.35-3.28(m,4H)。MS＝482(MH)+。

EXAMPLE 446 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-trifluoromethyl-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (140.0mg, 0.3064mmol) piperazine-1-carboxylate and 3- (trifluoromethyl) -aniline (46.2 μ L, 0.370mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (3-trifluoromethyl-phenyl) -amine. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.179g, 98%).¹HNMR(400MHz,d6-DMSO,,ppm):9.76(s,1H),8.93-8.83(m,3H),8.42(s,1H),8.41(d,J＝5.4Hz,1H),8.34(s,1H),7.97(s,1H),7.92(d,J＝8.3Hz,1H),7.78(dd,J＝5.3,1.3Hz,1H),7.52(t,J＝7.9Hz,1H),7.23(d,J＝7.6Hz,1H),4.11(s,3H),3.91-3.86(m,4H),3.36-3.30(m,4H)。MS＝482(MH)+。

EXAMPLE 447 (6-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (6-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) using (100.0mg, 0.2188mmol) tert-butyl piperazine-1-carboxylate and 6-fluoro-pyridin-2-ylamine (30.0mg, 0.268mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as the free base as an off-white solid (0.003g, 2%).¹HNMR(400MHz,d6-DMSO,,ppm):10.15(s,1H),8.81(s,1H),8.74(s,1H),8.40(d,J＝5.1Hz,1H),8.32(s,1H),7.88-7.81(m,2H),7.75(dd,J＝8.1,2.6Hz,1H),6.59(dd,J＝7.7,2.3Hz,1H),4.07(s,3H),3.71-3.66(m,4H),2.90-2.85(m,4H)。MS＝433(MH)+。

EXAMPLE 448 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-in a similar manner to example 303c and example 1501cRadical-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of tert-butyl (124.0mg, 0.2714mmol) piperazine-1-carboxylate and 6-methoxy-pyridin-2-ylamine (40.0mg, 0.322mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-methoxy-pyridin-2-yl) -amine. The product was isolated as a free base as an off-white solid (0.098g, 80%). MP 189-.¹HNMR(400MHz,d6-DMSO,,ppm):9.79(s,1H),9.04(s,1H),8.73(s,1H),8.37(d,J＝5.2Hz,1H),8.31(s,1H),7.79(dd,J＝5.2,1.4Hz,1H),7.58(t,J＝7.9Hz,1H),7.16(d,J＝7.8Hz,1H),6.30(d,J＝7.7Hz,1H),4.07(s,3H),4.04(s,3H),3.67-3.62(m,4H),2.89-2.84(m,4H)。MS＝445(MH)+。

Example 449 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-2-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 6-trifluoromethyl-pyridin-2-ylamine (43.0mg, 0.265mmol) [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-trifluoromethyl-pyridin-2-yl) -amine. The product was isolated as the free base as an off-white solid (0.005g, 5%).¹HNMR(400MHz,d6-DMSO,,ppm):10.34(s,1H),8.80-8.78(m,2H),8.42(d,J＝4.7Hz,1H),8.32(s,1H),8.08(d,J＝8.1Hz,1H),7.94(t,J＝8.1Hz,1H),7.89(dd,J＝5.1,1.3Hz,1H),7.36(d,J＝7.4Hz,1H),4.07(s,3H),3.68-3.63(m,4H),2.90-2.85(m,4H)。MS＝483(MH)+。

EXAMPLE 450 (2-fluoro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (124.0mg, 0.2714mmol) and 2-fluoro-pyridine-3Preparation of (2-fluoro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) with (40.0mg, 0.357mmol) of (methylamine]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.156g, 86%).¹HNMR(400MHz,d6-DMSO,,ppm):9.26(s,1H),8.91(br s,3H),8.86(ddd,J＝10.0,8.0,1.7Hz,1H),8.42(s,1H),8.36(dd,J＝5.5Hz,1H),8.19(s,1H),7.81(dd,J＝5.3,1.3Hz,1H),7.77(ddd,J＝4.6,1.5,1.5Hz,1H),7.32(ddd,J＝7.9,4.8,0.9Hz,1H),4.11(s,3H),3.93-3.87(m,4H),3.36-3.30(m,4H)。MS＝433(MH)+。

Example 451 (2-fluoro-3-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-fluoro-3-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -based on (111.0mg, 0.2429mmol) of piperazine-1-carboxylic acid tert-butyl ester (111.0mg, 0.2429mmol) and 2-fluoro-3-methyl-aniline (36.0mg, 0.288mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as the tris-trifluoroacetate salt as a yellow lyophilizate (0.146g, 76%).¹HNMR(400MHz,d6-DMSO,,ppm):9.04(br s,1H),8.90(s,1H),8.87(br s,2H),8.42(s,1H),8.28(d,J＝5.3Hz,1H),8.06(s,1H),7.98(t,J＝7.8Hz,1H),7.73(dd,J＝5.3,1.3Hz,1H),7.05(t,J＝7.8Hz,1H),6.93(t,J＝7.2Hz,1H),4.10(s,3H),3.91-3.86(m,4H),3.35-3.29(m,4H),2.28(d,J＝1.8Hz,3H)。MS＝446(MH)+。

EXAMPLE 452 (2-fluoro-3-trifluoromethyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-fluoro-3-trifluoro-2-methyl-aniline from (i) -piperazine-1-carboxylic acid tert-butyl ester (102.0mg, 0.2232mmol) and 2-fluoro-3-trifluoromethyl-aniline (48.0mg, 0.268mmol)Methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.050g, 30%).¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.91(s,1H),8.85(br s,2H),8.63(ddd,J＝7.8,7.8,2.3Hz,1H),8.42(s,1H),8.35(d,J＝5.3Hz,1H),8.14(s,1H),7.81(dd,J＝5.3,1.4Hz,1H),7.39-7.30(m,2H),4.11(s,3H),3.92-3.86(m,4H),3.36-3.29(m,4H)。MS＝500(MH)+。

Example 453 (2, 4-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2, 4-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2188mmol) and 2, 4-difluoro-aniline (27.0 μ L, 0.265mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.059g, 39%).¹HNMR(400MHz,d6-DMSO,,ppm):9.03(s,1H),8.90(s,1H),8.87(br s,2H),8.42(s,1H),8.27(d,J＝5.3Hz,1H),8.10(ddd,J＝9.3,9.3,6.3Hz,1H),8.00(s,1H),7.72(dd,J＝5.4,1.3Hz,1H),7.31(ddd,J＝11.5,9.0,2.9Hz,1H),7.11-7.04(m,1H),4.10(s,3H),3.90-3.85(m,4H),3.35-3.29(m,4H)。MS＝450(MH)+。

EXAMPLE 454 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 4-trifluoro-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 2,3, 4-trifluoro-aniline (28.0 μ L, 0.265mmol) to [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2,3, 4-trifluoro-phenyl) -amine. Separating yellow lyophilized powderProduct as bis-trifluoroacetate (0.104g, 68%).¹HNMR(400MHz,d6-DMSO,,ppm):9.21(s,1H),8.95-8.85(m,3H),8.42(s,1H),8.30(d,J＝5.3Hz,1H),8.04(s,1H),7.99-7.91(m,1H),7.77(dd,J＝5.3,1.3Hz,1H),7.33-7.24(m,1H),4.10(s,1H),3.91-3.86(m,4H),3.36-3.29(m,4H)。MS＝468(MH)+。

EXAMPLE 455 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,4, 5-trifluoro-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of tert-butyl (100.0mg, 0.2188mmol) piperazine-1-carboxylate and 2,4, 5-trifluoro-aniline (39.0mg, 0.265mmol) to [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2,4, 5-trifluoro-phenyl) -amine. The product was isolated as bis-trifluoroacetate as a yellow lyophilizate (0.027g, 17%).¹HNMR(400MHz,d6-DMSO,,ppm):9.21(s,1H),8.91(s,1H),8.86(br s,2H),8.54(ddd,J＝13.6,8.5,8.5Hz,1H),8.42(s,1H),8.36(d,J＝5.4Hz,1H),8.14(s,1H),7.79(dd,J＝5.3,1.4Hz,1H),7.60(ddd,J＝10.9,10.9,7.7Hz,1H),4.10(s,3H),3.91-3.86(m,4H),3.36-3.29(m,4H)。MS＝468(MH)+。

EXAMPLE 456 (3S,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol or (3R,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

From (±) -trans-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (3S,4S) -or (3R,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] by supercritical fluid chiral chromatography of (67.52mg) piperidine-3, 4-diol]Pyrimidin-4-yl]Piperidine-3, 4-diol, using a Chiralcel OJ-H (10x250mm) column with 30% methanol (weight/0.1% diethylamine modifier): 70 percent ofCO₂The eluate was injected 4 times at 6.0 mL/min in 150 μ L, T35 ℃, P120 bar, UV 220 nm. The product was isolated as a yellow solid as the initial peak (0.0166g, 24%). Purity: > 99% ee @ 100% purity. The RT time is 8.6min,¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.80(s,1H),8.33(s,1H),8.31(d,J＝5.4Hz,1H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.3,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),5.01-4.98(m,1H),4.94(d,J＝4.1Hz,1H),4.11-3.94(m,5H),3.55-3.38(m,3H),3.16-3.10(m,1H),2.08-2.00(m,1H),1.57-1.47(m,1H)。MS＝445(MH)+。

EXAMPLE 457 (3R,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol or (3S,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

From (±) -trans-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (3R,4R) -or (3S,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] by supercritical fluid chiral chromatography of (67.52mg) piperidine-3, 4-diol]Pyrimidin-4-yl]Piperidine-3, 4-diol, using a Chiralcel OJ-H (10x250mm) column with 30% methanol (weight/0.1% diethylamine modifier): 70% CO₂The eluate was injected 4 times at 6.0 mL/min in 150 μ L, T35 ℃, P120 bar, UV 220 nm. The product was isolated as a yellow solid with a second peak (0.0209g, 31%). Purity: > 97.6% ee @ 98% purity. RT:12.98min.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.80(s,1H),8.33(s,1H),8.31(d,J＝5.2Hz,1H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.4,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),5.02-4.98(m,2H),4.11-3.93(m,5H),3.55-3.37(m,3H),3.16-3.10(m,1H),2.08-2.00(m,1H),1.57-1.47(m,1H)。MS＝445(MH)+。

Example 458.3- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -propionamide

458a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1.00g, 3.46mmol) and 3-amino-propionamide hydrochloride (0.52g, 4.2mmol)]Pyrimidin-4-ylamino]-propionamide. The product was isolated as a dark brown solid (0.303g, 24%).¹HNMR(400MHz,d6-DMSO,,ppm):8.93(t,J＝5.5Hz,1H),8.79(s,1H),8.61-8.58(m,1H),8.35(s,1H),8.34-8.32(m,2H),7.50(br s,1H),7.00(br s,1H),4.11(s,3H),3.94-3.87(m,2H),2.57-2.52(m,2H)。MS＝359,361(MH)+。

458b) From 3- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-ylamino]Preparation of 3- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] with propionamide (100.0mg, 0.2787mmol) and aniline (30.0. mu.L, 0.329mmol)]Pyrimidin-4-ylamino]-propionamide. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.043g, 28%).¹HNMR(400MHz,d6-DMSO,,ppm):9.55(br s,1H),8.88(t,J＝5.4Hz,1H),8.77(s,1H),8.34(s,1H),8.26(d,J＝5.4Hz,1H),7.96(s,1H),7.74-7.69(m,3H),7.50(s,1H),7.33(t,J＝7.9Hz,2H),7.04-6.95(m,2H),4.12(s,3H),3.95-3.89(m,2H),2.58-2.53(m,2H)。MS＝416(MH)+。

EXAMPLE 459 [4- (5-methoxy-4-piperidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine

459a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 2- (2-chloro-pyridin-4-yl) -5-methoxy-4-piperidin-1-yl-pyrido [3,4-d ] using pyrimidin-4-ol (1.0g, 3.5mmol) and piperidine (0.41mL, 4.2mmol)]A pyrimidine. The product was isolated as a yellow-orange solid (0.61g, 49%).¹HNMR(400MHz,d6-DMSO,,ppm):8.83(s,1H),8.59(d,J＝5.0Hz,1H),8.35(s,1H),8.31-8.28(m,2H),4.08(s,3H),3.71-3.65(m,4H),1.75-1.65(m,6H)。MS＝356,358(MH)+。

459b) From 2- (2-chloro-pyridin-4-yl) -5-methoxy-4-piperidin-1-yl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of [4- (5-methoxy-4-piperidin-1-yl-pyrido [3,4-d ] using pyrimidine (100.0mg, 0.2810mmol) and aniline (31.0. mu.L, 0.340mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-phenyl-amines. The product was isolated as a free base as a yellow solid (0.075g, 64%). MP 221-.¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.80(s,1H),8.32(s,1H),8.30(d,J＝5.2Hz,1H),7.90(s,1H),7.77-7.73(m,2H),7.66(dd,J＝5.2,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.08(s,3H),3.70-3.65(m,4H),1.75-1.67(m,6H)。MS＝413(MH)+。

EXAMPLE 460 {4- [4- (4, 4-difluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine

460a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 2- (2-chloro-pyridin-4-yl) -4- (4, 4-difluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1.0g, 3.5mmol) and 4, 4-difluoro-piperidine hydrochloride (0.66g, 4.2mmol)]A pyrimidine. The product was isolated as an orange solid (0.806g, 59%).¹HNMR(400MHz,d6-DMSO,,ppm):8.90(s,1H),8.61(dd,J＝4.9,0.8Hz,1H),8.41(s,1H),8.34-8.31(m,2H),4.10(s,3H),3.84-3.79(m,4H),2.26-2.14(m,4H)。MS＝392,394(MH)+。

460b) From 2- (2-chloro-pyridin-4-yl) -4- (4, 4-difluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of {4- [4- (4, 4-difluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidine (100.0mg, 0.2552mmol) and aniline (28.0 μ L, 0.307mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -phenyl-amine. The product was isolated as the free base as an orange solid (0.027g, 23%).¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.87(s,1H),8.38(s,1H),8.32(d,J＝5.2Hz,1H),7.92(s,1H),7.78-7.74(m,2H),7.68(dd,J＝5.3,1.4Hz,1H),7.31-7.25(m,2H),6.93-6.88(m,1H),4.10(s,3H),3.82-3.78(m,4H),2.27-2.15(m,4H)。MS＝449(MH)+。

Example 461.1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-4-carbonitrile

461a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidin-4-ol (1.0g, 3.5mmol) and piperidine-4-carbonitrile (0.46g, 4.2mmol)]Pyrimidin-4-yl]-piperidine-4-carbonitrile. The product was isolated as an orange solid (0.80g, 61%).¹HNMR(400MHz,d6-DMSO,,ppm):8.87(s,1H),8.61(dd,J＝5.0,0.7Hz,1H),8.39(s,1H),8.34-8.31(m,2H),4.10(s,3H),3.96-3.88(m,2H),3.57-3.49(m,2H),3.25-3.17(m,1H),2.14-2.05(m,2H),1.96-1.86(m,2H)。MS＝381,383(MH)+。

461b) From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl ] -n-propylphenyl ] -4-carbonitrile (100.0mg, 0.2626mmol) and aniline (29.0. mu.L, 0.318mmol)]Pyrimidin-4-yl]-piperidine-4-carbonitrile. The product was isolated as the free base as a yellow solid (0.090g, 77%). MP 242-.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.84(s,1H),8.36(s,1H),8.31(d,J＝5.2Hz,1H),7.91(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.4,1.4Hz,1H),7.31-7.26(m,2H),6.93-6.88(m,1H),4.09(s,3H),3.96-3.88(m,2H),3.56-3.48(m,2H),3.26-3.19(m,1H),2.15-2.06(m,2H),1.98-1.88(m,2H)。MS＝438(MH)+。

EXAMPLE 462 {4- [4- (4-fluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine

462a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Preparation of 2- (2-chloro-pyridin-4-yl) -4- (4-fluoro-piperidin-1-yl) -5-methoxy-pyrido [3, 4-d) using pyrimidin-4-ol (1.0g, 3.5mmol) and 4-fluoro-piperidine hydrochloride (0.58g, 4.2mmol)]A pyrimidine. Separating out orangeProduct as a colored solid (0.61g, 47%).¹HNMR(400MHz,d6-DMSO,,ppm):8.87(s,1H),8.61(dd,J＝4.9,0.7Hz,1H),8.38(s,1H),8.33-8.30(m,2H),5.08-4.90(m,1H),4.09(s,3H),3.83-3.68(m,4H),2.16-2.00(m,2H),1.97-1.85(m,2H)。MS＝374,376(MH)+。

462b) From 2- (2-chloro-pyridin-4-yl) -4- (4-fluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Preparation of {4- [4- (4-fluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] using pyrimidine (100.0mg, 0.2675mmol) and aniline (30.0 μ L, 0.329mmol)]Pyrimidin-2-yl]-pyridin-2-yl } -phenyl-amine. The product was isolated as a free base as a yellow solid (0.057g, 49%). MP 202-.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.83(s,1H),8.35(s,1H),8.31(d,J＝5.3Hz,1H),7.91(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.3,1.3Hz,1H),7.31-7.25(m,2H),6.92-6.87(m,1H),5.10-4.90(m,1H),4.09(s,3H),3.84-3.67(m,4H),2.17-2.02(m,2H),1.98-1.85(m,2H)。MS＝431(MH)+。

EXAMPLE 463 (3R,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol or (3S,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

From (±) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (3R,4S) -or (3S,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] by supercritical fluid chiral chromatography of (3R,4S) -piperidine-3, 4-diol]Pyrimidin-4-yl]Piperidine-3, 4-diol, using a Chiralpak AD-H (10 × 250mm) column, using 40% methanol (weight/0.1% diethylamine modifier): 60% CO₂The eluate was injected 2 times at 6.0 mL/min with 400 μ L, T35 ℃, P120 bar, UV 220 nm. The product was isolated as a yellow solid as the initial peak (0.0254g, 38%). Purity: > 99% ee @ 100% purity. RT:9.4min.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.79(s,1H),8.32-8.29(m,2H),7.90(s,1H),7.77-7.73(m,2H),7.67(dd,J＝5.3,1.4Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.63(brs,2H),4.07(s,3H),4.00-3.88(m,1H),3.84-3.72(m,2H),3.65-3.52(m,3H),1.97-1.88(m,1H),1.75-1.68(m,1H)。MS＝445(MH)+。

EXAMPLE 464 (3S,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol or (3R,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol

From (±) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]Preparation of (3S,4R) -or (3R,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] by supercritical fluid chiral chromatography of (3S,4R) -piperidine-3, 4-diol]Pyrimidin-4-yl]Piperidine-3, 4-diol, using a Chiralpak AD-H (10 × 250mm) column, using 40% methanol (weight/0.1% diethylamine modifier): 60% CO₂The eluate was injected 2 times at 6.0 mL/min with 400 μ L, T35 ℃, P120 bar, UV 220 nm. The product was isolated as a yellow solid as the second peak (0.0255g, 38%). Purity: > 99% ee @ 100% purity. RT:8.6min.¹HNMR(400MHz,d6-DMSO,,ppm):9.32(s,1H),8.79(s,1H),8.32-8.29(m,2H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.2,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.64(brs,2H),4.07(s,3H),3.99-3.73(m,3H),3.65-3.54(m,3H),1.97-1.87(m,1H),1.76-1.66(m,1H)。MS＝445(MH)+。

EXAMPLE 465 { (R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -pyrrolidin-3-yl } -methanol

465a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol (0.50g, 1.7mmol) and (R) -3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.42g, 2.1mmol) [ prepared with 1:1 trifluoroacetic acid: methylene dichloride deprotection]Preparation of { (R) -1- [2- (2-chloro-pyridin-4-yl) -5-methylOxy-pyrido [3,4-d]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol. The product was isolated as a yellow foam (0.186g, 28%).¹HNMR(400MHz,d6-DMSO,,ppm):8.78(s,1H),8.59(dd,J＝5.0,0.6Hz,1H),8.34(s,1H),8.32-8.29(m,2H),4.72(br s,1H),4.07(s,3H),3.90-3.37(m,6H),2.37(br s,1H),1.99(br s,1H),1.68(br s,1H)。MS＝372,374(MH)+。

465b) From { (R) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] -pyrrolidin-3-yl } -methanol (186.0mg, 0.5002mmol) and aniline (55.0. mu.L, 0.604mmol)]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol. The product was isolated as a free base as a yellow solid (0.091g, 42%). MP 208-.¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.75(s,1H),8.30(s,1H),8.29(d,J＝5.2Hz,1H),7.90(s,1H),7.78-7.74(m,2H),7.68(dd,J＝5.3,1.3Hz,1H),7.30-7.25(m,2H),6.91-6.86(m,1H),4.73(br s,1H),4.07(s,3H),3.88-3.35(m,6H),2.37(br s,1H),2.00(br s,1H),1.70(br s,1H)。MS＝429(MH)+。

EXAMPLE 466 { (S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -pyrrolidin-3-yl } -methanol

466a) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol (0.50g, 1.7mmol) and (S) -3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.42g, 2.1mmol) [ prepared with 1:1 trifluoroacetic acid: methylene dichloride deprotection]Preparation of the desired { (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol. The product was isolated as a yellow resin (0.185g, 29%).¹HNMR(400MHz,d6-DMSO,,ppm):8.78(s,1H),8.59(d,J＝5.0Hz,1H),8.34(s,1H),8.32-8.29(m,2H),4.72(br s,1H),4.07(s,3H),3.90-3.35(m,6H),2.42(br s,1H),1.99(br s,1H),1.70(br s,1H)。MS＝372,374(MH)+。

466b) In a similar manner asEXAMPLE 303c and manner of example 1501c starting from { (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]Preparation of { (S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] using (185.0mg, 0.4976mmol) and aniline (55.0. mu.L, 0.604mmol)]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol. The product was isolated as a free base as a yellow foam (0.093g, 43%). MP 210-.¹HNMR(400MHz,d6-DMSO,,ppm):9.31(s,1H),8.75(s,1H),8.30(s,1H),8.29(d,J＝5.3Hz,1H),7.90(s,1H),7.78-7.74(m,2H),7.68(dd,J＝5.3,1.4Hz,1H),7.30-7.25(m,2H),6.92-6.86(m,1H),4.73(br s,1H),4.07(s,1H),3.88-3.35(m,6H),2.37(br s,1H),2.00(br s,1H),1.71(br s,1H)。MS＝429(MH)+。

Example 467 (meso) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -azepane-4, 5-diol

467a) To a round bottom flask equipped with a stir bar and reflux condenser, containing but-3-enylamine (0.58g, 8.1mmol) and tetrahydrofuran (50mL) was added 4-bromo-but-1-ene (1.0g, 7.4mmol) and the mixture was heated at 60 ℃ for 18 h. The mixture was cooled to room temperature. Triethylamine (1.1mL, 8.1mmol) was added followed by di-tert-butyl dicarbonate (1.8g, 8.1 mmol). The suspension was stirred at room temperature for 1 hour. The suspension was filtered through a plug of celite and the filtrate was evaporated to a yellow suspension. Methanol (40mL) was added to the residue, followed by 1N aqueous sodium hydroxide solution (5 mL). The mixture was stirred for 1 hour. The resulting suspension was filtered through a plug of celite. The filtrate was evaporated. The residue was purified by chromatography (silica gel column 24g, 0% → 5% ethyl acetate: hexane) using an ISCO apparatus. Di-but-3-enyl-carbamic acid tert-butyl ester (0.304g, 18%) was isolated as a clear oil.¹HNMR(400MHz,CDCl3,,ppm):5.83-5.70(m,2H),5.10-4.99(m,4H),3.23(br s,4H),2.31-2.24(m,4H),1.46(s,9H)。MS＝248(M+Na)+。

467b) To a solution of di-but-3-enyl-carbamic acid tert-butyl ester (0.30g, 1.3mmol) in dry toluene (30mL) under nitrogen was added(1, 3-bis- (2,4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxyphenylmethylene) ruthenium (45.0mg, 0.0717mmol) was added. The mixture was heated at 50 ℃ for 5 hours. The mixture was cooled to room temperature and stirred overnight. The volatiles were evaporated. The residue was triturated with hexanes (30mL) and the suspension filtered through a plug of celite. The filtrate was evaporated. The residue was purified by chromatography (silica gel column 24g, 0% → 5% ethyl acetate: hexane) using an ISCO apparatus. Separating the 2,3,6, 7-tetrahydro-azepine as a clear oil-1-carboxylic acid tert-butyl ester (0.166g, 63%).¹HNMR(400MHz,CDCl3,,ppm):5.79-5.66(m,2H),3.50-3.38(m,4H),2.28(br s,4H),1.47(s,9H)。MS＝220(M+Na)+。

467c) From 2,3,6, 7-tetrahydro-azepine in a similar manner to example 436aTert-butyl-1-carboxylate (0.166g, 0.841mmol) to prepare tert-butyl (meso) -cis-4, 5-dihydroxy-azepane-1-carboxylate. The product was isolated as an off-white solid (0.151g, 77%).¹HNMR(400MHz,d6-DMSO,,ppm):4.48(d,J＝4.3Hz,2H),3.67-3.60(m,2H),3.45-3.32(m,2H),3.19-3.05(m,2H),1.84-1.73(m,2H),1.64-1.52(m,2H),1.38(s,9H)。MS＝254(M+Na)+。

467d) To be similar to [ B016]From 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-ol (0.20g, 0.69mmol) and (meso) -cis-4, 5-dihydroxy-azepane-1-carboxylic acid tert-butyl ester (0.15g, 0.65mmol) [ prepared with 1:1 trifluoroacetic acid: methylene dichloride deprotection]Preparation of (meso) -cis-1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]-azepane-4, 5-diol. The product was isolated as an orange resin (0.115g, 44%).¹HNMR(400MHz,d6-DMSO,,ppm):8.77(s,1H),8.59(dd,J＝4.8,1.0Hz,1H),8.32-8.28(m,3H),4.45-4.42(m,2H),4.04(s,3H),3.88-3.60(m,6H),2.10-2.00(m,2H),1.86-1.77(m,2H)。MS＝402,404(MH)+。

467e) From (meso) -cis-1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (meso) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] using (115.0mg, 0.2862mmol) azepane-4, 5-diol and aniline (33.0. mu.L, 0.362mmol)]Pyrimidin-4-yl]-azepane-4, 5-diol. The product was isolated as a free base as a yellow foam (0.033g, 25%).¹HNMR(400MHz,d6-DMSO,,ppm):9.29(s,1H),8.74(s,1H),8.29(d,J＝5.2Hz,1H),8.26(s,1H),7.90(s,1H),7.77-7.74(m,2H),7.67(dd,J＝5.3,1.3Hz,1H),7.30-7.25(m,2H),6.92-6.87(m,1H),4.45(d,J＝4.2Hz,2H),4.05(s,3H),3.87-3.60(m,6H),2.12-2.02(m,2H),1.87-1.78(m,2H)。MS＝459(MH)+。

Example 468.1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol

From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -piperidin-4-ol (90.0mg, 0.242mmol) and 6-fluoro-pyridin-2-ylamine (33.0mg, 0.294mmol)]-5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl } -piperidin-4-ol. The product was isolated as a free base as a yellow foam (0.048g, 35%).¹HNMR(400MHz,d6-DMSO,,ppm):10.43(br s,1H),8.83(s,1H),8.71(s,1H),8.43(d,J＝5.3Hz,1H),8.36(s,1H),7.92-7.85(m,2H),7.69-7.65(m,1H),6.65(dd,J＝7.9,2.2Hz,1H),4.11-4.01(m,5H),3.87-3.80(m,1H),3.51-3.42(m,2H),1.97-1.89(m,2H),1.64-1.54(m,2H)。MS＝448(MH)+。

Example 469.1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol

From 1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyridine in a similar manner to example 303c and example 1501cAnd [3,4-d ]]Pyrimidin-4-yl]Preparation of 1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl ] -1- { 5-methoxy-2-amine (90.0mg, 0.242mmol) and 6-methoxy-pyridin-2-ylamine (36.0mg, 0.290mmol)]-pyrido [3,4-d]Pyrimidin-4-yl } -piperidin-4-ol. The product was isolated as a free base as a yellow foam (0.031g, 27%).¹HNMR(400MHz,d6-DMSO,,ppm):10.45(br s,1H),8.86(s,1H),8.78(s,1H),8.43(d,J＝5.6Hz,1H),8.36(s,1H),7.90(d,J＝6.0Hz,1H),7.69(t,J＝7.9Hz,1H),7.05(d,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),4.10-3.98(m,8H),3.87-3.80(m,1H),3.48-3.39(m,2H),1.97-1.89(m,2H),1.63-1.53(m,2H)。MS＝460(MH)+。

EXAMPLE 470 ((S) -1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol

From { (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol (90.0mg, 0.242mmol) and 6-fluoro-pyridin-2-ylamine (40.0mg, 0.357mmol) preparation ((S) -1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl]-5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.026g, 19%).¹HNMR(400MHz,d6-DMSO,,ppm):10.43(br s,1H),8.79(s,1H),8.68(s,1H),8.43(d,J＝5.5Hz,1H),8.37(s,1H),7.92-7.85(m,2H),7.68(d,J＝7.9Hz,1H),6.65(d,J＝8.0Hz,1H),4.09(s,3H),3.92-3.40(m,6H),2.45-2.30(m,1H),2.08-1.98(m,1H),1.80-1.65(m,1H)。MS＝448(MH)+。

EXAMPLE 471 ((S) -1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol

From { (S) -1- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-pyrrolidin-3-yl } -methanol(90.0mg, 0.242mmol) and 6-methoxy-pyridin-2-ylamine (45.0mg, 0.362mmol) prepared ((S) -1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl]-pyrido [3,4-d]Pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol. The product was isolated as trifluoroacetate salt as a yellow lyophilizate (0.044g, 31%).¹HNMR(400MHz,d6-DMSO,,ppm):10.44(br s,1H),8.86(s,1H),8.73(s,1H),8.43(d,J＝5.6Hz,1H),8.36(s,1H),7.91(d,J＝5.0Hz,1H),7.68(t,J＝8.2Hz,1H),7.03(d,J＝8.0Hz,1H),6.44(d,J＝7.8Hz,1H),4.08(s,3H),4.04(s,3H),3.90-3.35(m,6H),2.45-2.30(m,1H),2.05-1.95(m,1H),1.77-1.64(m,1H)。MS＝460(MH)+。

Example 473.2- (4-cyano-phenyl) -N- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of 2- (4-cyano-phenyl) -N- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2141mmol) tert-butyl piperazine-1-carboxylate and (50.0mg, 0.312mmol) 2- (4-cyano-phenyl) -acetamide]Pyrimidin-2-yl) -pyridin-2-yl]-an acetamide. The product was isolated as a free base (0.094g, 89%) as a dark brown solid. MP 200-.¹HNMR(400MHz,d6-DMSO,,ppm):9.05(s,1H),8.97(s,1H),8.49(dd,J＝5.1,0.6Hz,1H),8.09(s,1H),8.04(dd,J＝5.2,1.4Hz,1H),7.84-7.81(m,2H),7.60-7.57(m,2H),3.91(s,2H),3.85-3.45(m,4H),2.83(m,4H),2.63-2.55(m,1H),1.28-1.22(m,2H),1.04-0.99(m,2H)。LC/MS＝491(MH)+。

EXAMPLE 474[ 4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-4-morpholin-4-yl-phenyl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2141mmol)Preparation of 2-methyl-4-morpholin-4-yl-aniline (61.0mg, 0.317mmol) [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2-methyl-4-morpholin-4-yl-phenyl) -amine. The product was isolated as a free base as an orange-brown solid (0.085g, 75%). MP 214-.¹HNMR(400MHz,d6-DMSO,,ppm):8.93(s,1H),8.23(s,1H),8.14(d,J＝5.3Hz,1H),8.07(s,1H),7.58(s,1H),7.52(dd,J＝5.2,1.3Hz,1H),7.28(d,J＝8.6Hz,1H),6.86(d,J＝2.7Hz,1H),6.79(dd,J＝8.6,2.8Hz,1H),3.80-3.50(m,8H),3.10-3.06(m,4H),2.81(br s,4H),2.64-2.56(m,1H),2.19(s,3H),1.27-1.21(m,2H),1.04-0.99(m,2H)。LC/MS＝523(MH)+。

EXAMPLE 475 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-morpholin-4-yl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (107.0mg, 0.2291mmol) and 6-morpholin-4-yl-pyridin-3-ylamine (57.0mg, 0.318mmol) [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (6-morpholin-4-yl-pyridin-3-yl) -amine. The product was isolated as a free base as a yellow solid (0.103g, 87%). MP 217-.¹HNMR(400MHz,d6-DMSO,,ppm):9.08(s,1H),8.96(s,1H),8.45(d,J＝2.6Hz,1H),8.24(d,J＝5.4Hz,1H),8.09(s,1H),7.99(dd,J＝9.1,2.7Hz,1H),7.81(s,1H),7.62(dd,J＝5.3,1.3Hz,1H),6.85(d,J＝9.1Hz,1H),3.90-3.50(m,8H),3.37-3.34(m,4H),2.86(br s,4H),2.66-2.58(m,1H),1.29-1.23(m,2H),1.05-1.00(m,2H)。LC/MS＝510(MH)+。

EXAMPLE 476 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-3-yl-amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]-piperazine-1-carboxylic acidTert-butyl ester (100.0mg, 0.2141mmol) and 3-aminopyridine (30.0mg, 0.319mmol) was prepared [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-pyridin-3-yl-amine. The product was isolated as the free base as a pale yellow solid (0.067g, 74%). MP 226-.¹HNMR(400MHz,d6-DMSO,,ppm):9.55(s,1H),8.98(s,1H),8.87(d,J＝2.5Hz,1H),8.35(d,J＝5.4Hz,1H),8.32-8.28(m,1H),8.12-8.09(m,2H),7.95(s,1H),7.75(dd,J＝5.3,1.2Hz,1H),7.30(dd,J＝8.4,4.7Hz,1H),3.96-3.46(m,4H),2.87(br s,4H),2.66-2.58(m,1H),1.30-1.23(m,2H),1.06-1.01(m,2H)。LC/MS＝425.0(MH)+。

Example 477 (2-chloro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [34-d ] in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (2-chloro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3, 4-d) from (100.0mg, 0.2141mmol) of tert-butyl piperazine-1-carboxylate and o-chloroaniline (52.0uL, 0.315mmol)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine. The product was isolated as a free base as an orange foam (0.086g, 88%).¹HNMR(400MHz,d6-DMSO,,ppm):8.97(s,1H),8.68(s,1H),8.26(d,J＝5.3Hz,1H),8.09(s,1H),8.04-8.00(m,2H),7.72(dd,J＝5.3,1.4Hz,1H),7.48(dd,J＝8.0,1.5Hz,1H),7.34-7.29(m,1H),7.09-7.04(m,1H),3.96-3.46(m,4H),2.86(br s,4H),2.65-2.57(m,1H),1.29-1.23(m,2H),1.05-1.00(m,2H)。LC/MS＝458.0(MH)+。

EXAMPLE 478 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-3-yl) -amine

From 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d in a similar manner to example 303c and example 1501c]Pyrimidin-4-yl]Preparation of (E) -piperazine-1-carboxylic acid tert-butyl ester (100.0mg, 0.2141mmol) and 4-methyl-pyridin-3-ylamine (34.0mg, 0.314mmol) [4- (5-Cyclo)Propyl-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]- (4-methyl-pyridin-3-yl) -amine. The product was isolated as the free base as a pale yellow foam (0.070g, 74%).¹HNMR(400MHz,d6-DMSO,,ppm):8.98(s,1H),8.81(s,1H),8.64(s,1H),8.22(d,J＝5.4Hz,1H),8.16(d,J＝4.9Hz,1H),8.11(s,1H),7.87(s,1H),7.67(dd,J＝5.2,1.3Hz,1H),7.25(d,J＝4.9Hz,1H),3.95-3.45(m,4H),2.93(br s,4H),2.65-2.59(m,1H),2.28(s,3H),1.29-1.23(m,2H),1.06-1.01(m,2H)。LC/MS＝439.2(MH)+。

EXAMPLE 481 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine

481a) 3-bromo-5-fluoro-isonicotinic acid tert-butyl ester (1.9g, 6.9mmol), cyclopropyl trifluoroborate (1.18g, 7.97mmol), palladium acetate (81.3mg, 0.36mmol), butyl-ditricyclo [3.3.1.1(3,7)]Dec-1-yl-phosphine (194.8mg, 0.54mmol), and cesium carbonate (7g, 21.7mmol) were heated in toluene (35 mL)/water (4mL) at 85 ℃ overnight. Cooled and partitioned between ether and water. The organic extract was dried (MgSO)₄) Filtering and evaporating the solvent; the product was purified by flash chromatography (ISCO, silica gel, EtOAc/hexanes 0-10%; second fraction is product): 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester (50% yield).

481b) 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester (700.0mg, 2.95mmol) was treated with trifluoroacetic acid (2.0mL, 26.0mmol) in methylene chloride (5mL) at 25 ℃ overnight. The solvent was evaporated and the crude residue was dried in high vacuum, then used without further purification: 3-cyclopropyl-5-fluoro-isonicotinic acid; complexing with trifluoroacetic acid (quantitation).

481c) 3-cyclopropyl-5-fluoro-isonicotinic acid and 2-chloro-isonicotinamidi-dine hydrochloride (1.3g, 6.7mmol) complexed with trifluoroacetic acid (995mg, 3.37mmol) were treated with N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (1.35g, 3.54mmol) and N, N-diisopropylethylamine (3.5mL, 20.2mmol) in N, N-dimethylformamide (14mL) at room temperature overnight. Mixing the reactionThe mixture was partitioned between DCM and water, the organic layer was washed well with water and dried (MgSO)₄) The solvent is evaporated when a precipitate is formed. Trituration with diethyl ether followed by filtration gave N- [ (2-chloro-pyridin-4-yl) -imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide, which was used in the next step without further purification.

481d) N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -3-cyclopropyl-5-fluoro-isonicotinamide (solid product from step C) and cesium carbonate (1.4g, 4.2mmol) were mixed in N, N-dimethylacetamide (17 mL). The reaction was microwaved at 120 ℃ for 20 minutes at 300 watts. The reaction mixture was diluted with ice/water, neutralized with acetic acid to pH 5 at 0 ℃, and the precipitate was collected by filtration, washed with water and dried: 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-3H-pyrido [3,4-d ] pyrimidin-4-one (2 steps, 33% yield).

481e) Treatment of 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-3H-pyrido [3,4-d ] in N, N-dimethylformamide (10mL, 100mmol) with 2,4, 6-triisopropylbenzenesulfonyl chloride (0.98g, 3.2mmol)]A suspension of pyrimidin-4-one (0.85g, 2.8mmol), triethylamine (1.3mL, 9.3mmol) and 4-dimethylaminopyridine (43.0mg, 0.352mmol) was stirred at room temperature for 1 hour. Tert-butyl-1-piperazinecarboxylate (0.65g, 3.5mmol) was added and the mixture was stirred at room temperature overnight. Water (40mL) was added and the mixture was stirred vigorously for 1 hour. The suspension was filtered, rinsed with water and dried. The solid was dissolved in DCM and the solution was dried (MgSO₄) Filtered and the solvent evaporated under vacuum. The product was isolated by flash chromatography (Isco, silica gel, 20% → 100% ethyl acetate/hexanes): 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester, dark brown solid (1.03 g).

481f) The reaction tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] in 1, 4-dioxane (2mL)]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.428mmol), aniline (43.9 μ L, 0.482mmol), palladium acetate (16mg, 0.07mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (38.8mg, 0.067mmol), and cesium carbonate (366mg, 1.125 mmol). The tube was evacuated and inverted with nitrogenFlushed 3 times, then purged with argon, capped, and heated at 100 ℃ for 3 hours. The reaction mixture was cooled to room temperature and partitioned between ether and water. The organic extract was dried (MgSO)₄) And then the solvent was evaporated under reduced pressure. The product was used in the next step without further purification. The crude product obtained in step 1 was treated with trifluoroacetic acid (1.48mL, 19.2mmol) in methylene chloride (5.92mL) at room temperature until the reaction was complete after about 1 hour (by HPLC). The volatiles were evaporated under reduced pressure, the product was isolated by reverse phase chromatography (Gilson), followed by neutralization through a cation exchange column (Strata, from Phenomenex), filtration and liberation with methanolic ammonia: [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]-phenyl-amine (133mg, 73% yield over 2 steps); a bright yellow solid; MP 221-226C;¹H-NMR(CDCl₃) 9.11(s,1H),8.36(d, J ═ 5.2Hz,1H),8.04(s,1H),8.00(s,1H),7.80(dd, J ═ 5.2; 1.3Hz,1H),7.45(d, J ═ 8.3Hz,2H),7.37(dd, J ═ 8.4; 8.4Hz,2H),7.07(t, J ═ 8.4Hz,1H),6.68(br s,1H),3.75(br s,4H),3.01(m,4H),269(m,1H),1.59 (water and exchangeable NH),1.26(m,2H),1.00(m, 2H); LC/MS (ESI +):424.17(M + H).

Example 482.2- {4- [ 5-cyclopropyl-4- (4-hydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

Following a procedure analogous to example 481e, f from 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-3H-pyrido [3,4-d]Pyrimidin-4-one preparation of this product: a white solid;¹H NMR(dmso-d₆):10.40(s,1H),8.98(s,1H),8.64(br s,1H),8.49(dd,J＝6.0；0.4Hz,1H),8.45(d,J＝5.2Hz,1H),8.37(br s,1H),8.10(s,1H),7.88(dd,J＝5.2；1.4Hz,1H),7.30(dd,J＝6.0；1.4Hz,1H),7.81(br s,1H),4.11(m,2H),3.80(br s,1H),3.50(br s,2H),2.60(br s,1H),1.90(m,2H),1.52(br s,1H),1.26(m,2H),1.04(m,2H)；LC/MS(ESI+):465.2(M+H)。

EXAMPLE 483 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridin-2-yl) -amine

Following a procedure analogous to example 481e, f from 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-3H-pyrido [3,4-d]Pyrimidin-4-one preparation of this product: yellow lyophilizate;¹H NMR(dmso-d₆):10.40(s,1H),9.08(s,1H),9.03(br s,2H),8.81(s,1H),8.45(d,J＝5.3Hz,1H),8.20(s,1H),7.92(m,1H),7.86(m,1H),7.69(m,1H),6.65(m,1H),3.97(br s,4H),3.34(br s,4H),2.69(m,1H),1.27(m,2H),1.09(m,2H)；LC/MS(ESI+):443.2(M+H)。

EXAMPLE 484 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine

Prepared in analogy to example 481f from 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester preparation of the product: an off-white foam;¹H-NMR(CDCl₃) 9.12(s,1H),8.39(d, J ═ 5.3Hz,1H),8.23(m,1H),8.05(s,1H),7.93(s,1H),7.85(m,1H),7.14(m,2H),6.97(m,2H),6.86(br s,1H),3.76(br s,4H),3.03(m,4H),2.69(m,1H),1.93(br s, water and exchangeable protons), 1.27(m,2H),1.01(m, 2H); LC/MS (ESI +):442.1(M + H).

EXAMPLE 485 (. + -.) -2- {4- [ 5-cyclopropyl-4-cis-3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

Following a procedure analogous to example 481e, f from 2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-3H-pyrido [3,4-d]Pyrimidin-4-one preparation of this product: a dark brown solid;¹H-NMR(CDCl₃) 9.18(s,1H),8.52(s,1H),8.44(d, J ═ 5.2Hz,1H),8.39(m,2H),8.15(m,2H),7.93(m,1H),7.04(m,1H),3.95(m,7H),2.78(br s,1H),2.60(m,1H),1.87(m,2H),1.63(br s, water), 1.27(m,2H),1.01(m, 2H); LC/MS (ESI +):481.0(M + H).

EXAMPLE 486 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -o-tolyl-amine

Prepared in analogy to example 481f from 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester preparation of the product: yellow foam;¹H-NMR(CDCl₃):9.08(s,1H),8.33(d,J＝5.2Hz,1H),8.02(s,1H),7.81(s,1H),7.76(m,1H),7.60(m,1H),7.24(m,2H),7.08(m,1H),6.54(br s,1H),3.72(br s,4H),2.97(m,4H),2.67(m,1H),3.04(s,3H),1.95(br s,NH),1.25(m,2H),0.99(m,2H)；LC/MS(ESI+):438.1(M+H)。

example 487.2- {4- [ 5-cyclopropyl-4- ((3R,4S) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

The product was obtained by separation of the racemic enantiomer of example 485 (SCF chiral chromatography).

Example 488.2- {4- [ 5-cyclopropyl-4- ((3S,4R) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile

The product was obtained by separation of the racemic enantiomer of example 485 (SCF chiral chromatography). It is the optical antipode of example 487.

Example 489.4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -N- (1-phenylpyrazol-4-yl) pyridin-2-amine: the tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (131.4mg, 0.2877mmol), 1-phenyl-1H-pyrazol-4-ylamine (55.0mg, 0.346mmol), palladium acetate (7.9mg, 0.035mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (21.0mg, 0.0364mmol), cesium carbonate (144.6mg, 0.4438mmol), and 1, 4-dioxane (1 mL). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The suspension was stirred for 15 minutes, filtered, rinsed with water and dried by suction to give a dark solid.

The dark solid was suspended in methylene chloride (3mL) and stirred at room temperature. Trifluoroacetic acid (1mL, 20mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. Reverse phase chromatography using a Gilson instrument with 5% → 30% acetonitrile: the residue was purified by solvent gradient with water (wt/0.1% TFA as modifier). The desired fractions were combined, frozen and lyophilized. The recovered lyophilisate corresponds to the desired 4- (5-methoxy-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -N- (1-phenylpyrazol-4-yl) pyridin-2-amine (14mg, 10%).¹H NMR(DMSO-d₆):-8.91(bs,1H),8.71(bs,3H),8.41(s,1H),8.34(d,1H,J＝5.43Hz),7.88(s,1H),7.84(s,1H),7.83(dd,2H,JJ＝1.09,8.69Hz),7.66(dd,1H,JJ＝1.30,5.65),7.47-7.53(m,2H),7.25-7.31(m,1H),4.10(s,3H),3.88(bs,4H),3.33(bs,4H)。LCMS(ESI+)480.3(M+H)。

EXAMPLE 490 (2, 3-dimethyl-2H-indazol-6-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine the tube was charged with tert-butyl 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylate (131.4mg, 0.2877mmol), 2, 3-dimethyl-2H-indazol-6-ylamine (55.7mg, 0.346mmol), palladium acetate (7.9mg, 0.035mmol), 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (21.0mg, 0.0364mmol), cesium carbonate (144.6mg, 0.4438mmol) and 1, 4-dioxane (1 mL). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The suspension was stirred for 15 minutes, filtered, rinsed with water and dried by suction to give a dark solid.

The dark solid was suspended in methylene chloride (3mL,40mmol) and stirred at room temperature. Trifluoroacetic acid (1mL, 20mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. Reverse phase chromatography using a Gilson instrument with 5% → 30% acetonitrile: the residue was purified by solvent gradient with water (wt/0.1% TFA as modifier). The desired fractions were combined, frozen and lyophilized. The recovered lyophilizate corresponded to the desired (2, 3-dimethyl-2H-indazol-6-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine (38mg, 27%).

¹H NMR(DMSO-d₆):-9.509bs,1H),8.91(bs,3H),8.42(s,1H),8.36(d,1H,J＝5.19Hz),8.24(bs,1H),8.01(bs,1H),7.72(dd,1H,J＝1.20,5.28Hz),7.58(d,1H,J＝9.07Hz),7.06(dd,1H,JJ＝1.65,8.87Hz),4.10(s,3H),3.99(s,3H0,3.89(bs,4H),3.33(bs,3H),2.57(s,3H)。LCMS(ESI+)482.1(M+H)。

EXAMPLE 491 [1- (2-fluoro-phenyl) -1H-pyrazol-4-yl ] - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine

The tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (131.4mg, 0.2877mmol), 1- (2-fluoro-phenyl) -1H-pyrazol-4-ylamine (61.2mg, 0.346mmol), palladium acetate (7.9mg, 0.035mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (21.0mg, 0.0364mmol), cesium carbonate (144.6mg, 0.4438mmol), and 1, 4-dioxane (1 mL). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The suspension was stirred for 15 minutes, filtered, rinsed with water and dried by suction to give a dark solid.

The dark solid was suspended in methylene chloride (3mL) and stirred at room temperature. Trifluoroacetic acid (1mL, 20mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. Reverse phase chromatography using a Gilson instrument with 5% → 30% acetonitrile: the residue was purified by solvent gradient with water (wt/0.1% TFA as modifier). The desired fractions were combined, frozen and lyophilized. The recovered lyophilizate corresponded to the desired [1- (2-fluoro-phenyl) -1H-pyrazol-4-yl ] - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine (12mg, 8.4%).

¹H NMR(DMSO-d₆) 9.51(bs,1H),8.90(bs,3H),8.59(d,1H, J ═ 3.17Hz),8.41(s,1H),8.33(d,1H, J ═ 5.50Hz),7.83 to 7.88(m,3H),7.69(dd,1H, J ═ 1.33,5.50Hz),7.33 to 7.51(m,3H),4.10(s,3H),3.88(bs,4H),3.33(bs, 4H). LCMS (ESI +)490.1(M + H). HPLC > 95% pure (retention time 1.7 min in G method).

EXAMPLE 492 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-phenyl-1H-pyrazol-4-yl) -amine

The tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (403.0mg, 0.8631mmol), 1-phenyl-1H-pyrazol-4-ylamine (165.0mg, 1.036mmol), palladium acetate (24mg, 0.10mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (63.1mg, 0.109mmol), cesium carbonate (433.8mg, 1.331mmol), and 1, 4-dioxane (1 mL). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The suspension was stirred for 15 minutes, filtered, rinsed with water and dried by suction to give a dark solid.

The dark solid was suspended in methylene chloride (8mL) and stirred at room temperature. Trifluoroacetic acid (4mL, 50mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. Reverse phase chromatography using a Gilson instrument with 5% → 30% acetonitrile: the residue was purified by solvent gradient with water (wt/0.1% TFA as modifier). The desired fractions were combined, frozen and lyophilized. The recovered lyophilisate corresponded to the desired [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-phenyl-1H-pyrazol-4-yl) -amine (10mg, 4%).

¹H NMR(DMSO-d₆):-9.40(s,1H),8.97(s,1H),8.7(s,1H)8.35(d,1H, J ═ 5.65Hz),8.09(s,1H),7.78-7.85(m,4H),7.63(dd,1H, J ═ 1.42,5.34Hz),7.49(t,2H, J ═ 8.37Hz),7.27(t,1H, J ═ 7.48Hz),3.52-3.88(bm,4H),2.58-2.85(bm,5H),1.20-1.32(m,2H),1.00-1.06(m, 2H). LCMS (ESI +)490.19(M + H). HPLC > 95% pure (retention time 1.8 min in G method).

EXAMPLE 493 [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dimethyl-2H-indazol-6-yl) -amine

The tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (241.2mg, 0.5166mmol), 2, 3-dimethyl-2H-indazol-6-ylamine (100.0mg, 0.6203mmol), palladium acetate (14mg, 0.063mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (37.8mg, 0.0653mmol), cesium carbonate (259.6mg, 0.7968mmol), and 1, 4-dioxane (2 mL). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The suspension was stirred for 15 minutes, filtered, rinsed with water and dried by suction to give a brown solid.

The dark solid was suspended in methylene chloride (5mL,70mmol) and stirred at room temperature. Trifluoroacetic acid (2mL, 30mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. Reverse phase chromatography using a Gilson instrument with 5% → 30% acetonitrile: the residue was purified by solvent gradient with water (wt/0.1% TFA as modifier). The desired fractions were combined, frozen and lyophilized. The recovered lyophilizate corresponded to the desired [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dimethyl-2H-indazol-6-yl) -amine (60mg, 24%).

¹H NMR(DMSO-d₆):-9.32(s,1H),8.96(s,1H),8.35(d,1H,J＝5.25Hz),8.28(bs,1H),8.08(s,1H),7.95(bs,1H),7.68(dd,1H,J＝1.36,5.45Hz),7.52(d,1H,J＝8.95Hz),7.04(dd,1H,J＝1.56,8.95Hz),3.97(s,3H),2.53-2.70(m,5H),2.45(bs,4H),2.45(s,3H),1.21-1.29(m,2H),100-1.06(m, 2H). LCMS (ESI +)492.20(M + H). HPLC > 95% pure (retention time 1.7 min in G method).

EXAMPLE 494 phenyl- [4- (4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine 4- [2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (180mg, 0.42mmol) and aniline (51.1uL, 0.561mmol) were converted to the title compound 35.28mg, 22% yield following a procedure analogous to 303 c. LC/MS-384.2 (M + H) +

Example 495.[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-pyridin-3-yl) -amine: the tube was charged with 4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.214mmol), 2-fluoro-pyridin-3-ylamine (46.2mg, 0.412mmol), palladium acetate (12.0mg, 0.053mmol), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (34.0mg, 0.058mmol), cesium carbonate (120mg, 0.368mmol), and 1, 4-dioxane (0.7mL, 8 mmol). The tube was evacuated and back flushed with nitrogen. The tube was sealed and the reaction mixture was heated at 100 ℃ for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (10mL) and filtered through celite. The filtrate was evaporated to a dark resin.

The brown resin was dissolved in methylene chloride (0.7mL, 10mmol) and trifluoroacetic acid (0.7mL, 9mmol) was added. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by reverse phase chromatography using a Gilson apparatus. The desired fractions were loaded onto SCX cartridges and rinsed with methanol, releasing the product with 2M ammonia in methanol. The ammonia filtrate was evaporated and placed under high vacuum for 2 hours. The yellow solid recovered (35mg, 37%) corresponded to the title compound. 1H NMR (300MHz, DMSO-d6):9.26(s,1H),8.98(s,1H),8.88(t, J ═ 9Hz,1H),8.34(d, J ═ 5Hz,1H),8.18(s,1H),8.10(s,1H),7.79(d, J ═ 5Hz,1H),7.75(d, J ═ 4Hz,1H),7.31(M,1H),3.72(M,4H),2.88(br s,4H),2.62(M,1H),1.26(d, J ═ 8Hz,2H),1.04(d, J ═ 5Hz,2H), MS:433(M + H).

Example 496 [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-methyl-iso)Azol-3-yl) -amines

Reacting 4- [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d]Pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (75mg, 0.16mmol), 5-methyl-iso-butyl esterOxazol-3-ylamine (32.2mg, 0.3283mmol), bis (dibenzylideneacetone) palladium (0) (5mg, 0.0085mmol), XANTPHOS (10mg, 0.171mmol) and lithium hexamethyl silazide (55mg, 0.328mmol) were combined in tetrahydrofuran (3mL), degassed with argon and reacted in a microwave at 120 ℃ for 6 hours. Adding additional palladium and isoOxazole and silicon azide and the microwave temperature is raised to 150 c for an additional 6 hours. The reaction was concentrated and purified by reverse phase chromatography to give the title compound (2mg, 3%). MS:419.23(M + H).

Example 497.2- [2- (3-piperazin-1-yl-phenylamino-) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol. In analogy to the procedure of example 303c, 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol (67mg, 0.26mmol) and 4- (3-amino-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (1.1 fold equivalent) were converted into the title compound isolated as the bis TFA salt (21mg, 13%). LC/MS M + H + 400.

Example 498.2- [2- (3-piperazin-1-ylmethyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol. In analogy to the procedure of example 303c, 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol (143mg, 0.56mmol) and 4- (3-amino-benzyl) -piperazine-1-carboxylic acid tert-butyl ester (1.1 fold equivalent) were converted into the title compound isolated as the bis TFA salt (51.4mg, 14%). LC/MS M + H + 414.

Example 499.2- [2- (1-piperidin-4-ylmethyl-1H-pyrazol-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol. In analogy to the procedure of example 303c, 2- (2-chloro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol (145mg, 0.56mmol) and 4- (4-amino-pyrazol-1-ylmethyl) -piperidine-1-carboxylic acid tert-butyl ester (1.1-fold equivalent) were converted into the title compound isolated as the bis TFA salt (20.56mg, 6%). LC/MS M + H + 403.

Example 500 { 5-methoxy-2- [2- (3-piperazin-1-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine. In analogy to the procedure of example 303b, 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol (362mg, 1.25mmol) and methylamine-HCl (1.1 fold equivalent) were converted into [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-amine (64% yield), which was converted using a procedure analogous to example 497 into the title compound isolated as the bis TFA salt (14mg, 5% yield), LC/MS: 443.25 + H +

EXAMPLE 501 (5-methoxy-2- {2- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -methyl-amine. In analogy to the procedure of example 500, 4- (2-pyrrolidin-1-yl-ethoxy) -aniline (44mg, 0.21mmol) was converted into the title compound isolated as bis TFA salt (6.35mg, 5% yield) LC/MS: M + H + ═ 472.

EXAMPLE 502 { 5-methoxy-2- [2- (3-piperidin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine. Following an analogous procedure to example 500, tert-butyl 4- (3-amino-phenyl) -piperidine-1-carboxylate (0.1468g, 0.5312mmol) was converted to the title compound isolated as the bis TFA salt (23.61mg, 7% yield). LC/MS M + H + ═ 442.

EXAMPLE 503 [4- (5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-piperazin-1-yl-phenyl) -amine

503a) 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol (208mg, 0.720mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (221.1mg, 0.7301mmol), triethylamine (0.31mL, 2.2mmol) and 4-dimethylaminopyridine (8.8mg, 0.072mmol) in N, N-dimethylformamide (2mL, 30mmol) were stirred at room temperature for 1 hour, hydrazine hydrate (0.05410g, 1.081mmol) was added and the reaction stirred overnight. The product precipitated and was triturated with ether. It was used without further purification.

503b) [2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] was treated with 1, 4-dioxane (5.0mL, 65mmol) and water (0.6mL, 30mmol) and then with silver (I) oxide (334mg, 1.44mmol)]Pyrimidin-4-yl]Hydrazine (0.218g, 0.720mmol), stirred at room temperature. After 1.5 hours LC/MS showed 273 as the main product (M + H) +. The silver salt is filtered off and concentrated and placed under high vacuum. By ISCO chromatography, 12g SiO₂Gradient elution 0% to 100% EA/hexanes over 13min purification to give 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3, 4-d%]A pyrimidine.

503c) Using a procedure analogous to example 497 for its title compound, 2- (2-chloro-pyridin-4-yl) -5-methoxy-pyrido [3,4-d ] pyrimidine (31mg, 0.11mmol) was converted to the title compound (6.37mg, 13% yield). LC/MS M + H + 414.

The following compounds were synthesized following the general synthesis shown in scheme [ B4 ]:

the following compounds were synthesized following the general synthesis shown in scheme [ B4 ]:

general Synthesis scheme for substituted 2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of the general formula [ H-006]

General formula [ H-002]The amino-isonicotinamide derivative of the general formula [ H-001]Is prepared by reaction of a substituted amino-isonicotinamide derivative of (a) with di-tert-butyl dicarbonate and ammonium carbonate in a polar aprotic solvent containing a basic pyridine, e.g. DMA, DMF, NMP. General formula [ H-003 ]]Substituted 2-mercapto-3H-pyrido [3,4-d ] of]The pyrimidin-4-one derivatives are represented by the general formula [ H-002 [)]With carbon disulphide in a polar aprotic solvent containing a sterically hindered base such as DBU, such as DMA, DMF, NMP. General formula [ H-004]2-chloro-pyrido [3,4-d of (a)]Pyrimidin-4-ol derivatives represented by the general formula [ H-003]Substituted 2-mercapto-3H-pyrido [3,4-d ] of]Pyrimidin-4-one derivatives are prepared by reacting a thiophosgene in a polar aprotic solvent such as 1, 4-dioxane. General formula [ H-005]2-morpholin-4-yl-pyrido [3,4-d]Pyrimidine-alcohol derivatives of the general formula [ H-004 ]]2-chloro-pyrido [3,4-d of (a)]Pyrimidin-4-ol derivatives and their use as herbicidesFormula [ H-007 ]]Is prepared by reaction of substituted morpholine derivatives of (a) in a polar aprotic solvent such as DMA, DMF, NMP at elevated temperatures obtained by heating or using a microwave reactor. General formula [ H-006]2-morpholin-4-yl-pyrido [3,4-d]The pyrimidine derivative is prepared by: general formula [ H-005 ]]2-morpholin-4-yl-pyrido [3,4-d]Reaction of pyrimidine-alcohol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine-containing bases such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP in a polar aprotic solvent such as DMA, DMF, NMP. The intermediate 6, 7-substituted- (2,4, 6-triisopropyl-benzenesulfonic acid) -2-morphin-4-yl-pyrido [3,4-d]Pyrimidin-4-yl esters with the general formula [ H-008 ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme C1

Synthesis of 4- ((S) -3-benzyl-piperazin-1-yl) -2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine [1000]

3-amino-isonicotinamides [ C001]

A slurry of 3-aminoisonicotinic acid (1.00g, 7.24mmol) and CDI (1.76g, 10.85mmol) in DMF (15mL) was heated to 40 ℃ for 0.5 h and then cooled. Concentrated aqueous ammonia (50mL) was added and the mixture was stirred for 15 minutes and then extracted with ethyl acetate. Removing the solventTo give a solid, which was dissolved in ethyl acetate. The organic phase was washed with water and brine over MgSO₄Dried above, filtered, and then concentrated under reduced pressure to obtain the title compound [ C001](780mg, 79%). LCMS method 5, RT 0.54min, MI 138[ M + H]。

2-mercapto-3H-pyrido [3,4-d ] pyrimidin-4-one hydrochloride [ C002]

3-amino-isonicotinamide [ C001] (5g, 36.46mmol) was dissolved in DMF (40 mL). Carbon disulfide (11mL, 183mmol) and DBU (10.9mL, 73mmol) were added and the reaction was heated to 60 ℃ for 2 hours. 2M HCl (40mL) was added, the precipitate was collected, washed with water and dried under vacuum to give the title compound [ C002] as a white solid, which was used without further purification: LCMS method 5, RT:1.55min, MI 180[ M + H ].

2-chloro-3H-pyrido [3,4-d ] pyrimidin-4-one hydrochloride [ C003]

To a mixture of 2-mercapto-pyrido [3,4-d ] pyrimidin-4-ol [ C002] (5.45g, 30.41mmol) in dioxane (100mL) was added thiophosgene (3.5mL, 45.6mmol) dropwise and the mixture was heated at 100 ℃ for 3 hours. The mixture was cooled to room temperature, the resulting solid was diluted with ether (100mL), the precipitate was collected by filtration, and the solid was washed with ether to give the title compound, which was used without further purification: LCMS method 5, RT:2.61min, MI 182[ M + H ].

2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol [ C004]

In a microwave vial, a solution of 2-chloro-pyrido [3,4-d ] pyrimidin-4-ol hydrochloride (300mg, 1.38mmol) and morpholine (0.22mL, 2.48mmol) in DMA (4mL) was heated to 150 ℃ for 20 minutes under microwave irradiation. The solvent was removed under reduced pressure and the resulting solid was washed with diethyl ether and collected to give the title compound [ C004], which was used without further purification. LCMS method 5, RT 2.20min, MI 232[ M + H ].

4- ((S) -3-benzyl-piperazin-1-yl) -2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine [1000]

To 2-morpholin-4-yl-pyrido [3,4-d ] in DMA (3mL)]Pyrimidin-4-ol [ C004](100mg, 0.43mmol) of the solution was added 2,4, 6-triisopropylbenzenesulfonyl chloride (143mg, 0.47mmol), NEt in that order₃(0.12mL, 0.86mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 hour, and (S) -1-Boc-2-benzylpiperazine (154mg, 0.56mmol) was added. The reaction was stirred overnight and the solvent was removed under reduced pressure. Purifying with silica gel column chromatography using CH containing 0-10% methanol₂Cl₂The mixture was purified by elution. The appropriate fractions were combined and the solvent was removed by rotary evaporation. Dissolving the residue in CH₂Cl₂(2mL), TFA (0.5mL) was added. The solution was stirred for 3 hours, then loaded onto an SCX-2 cartridge, washed with methanol (6mL) and eluted with 2M ammonia in methanol. The solvent was removed from the ammonia fraction to give the title compound [ 1000%]: LCMS method 5, RT:2.33min, MI 391[ M + H ]]；NMR:(1H,300MHz,CDCl₃)；8.88(1H,s),8.10(1H,d),7.35–7.21(7H,m),4.31–4.21(2H,m),3.78–3.71(8H,m),3.39–3.30(1H,m),3.18–3.08(2H,m),2.98–2.90(2H,m),2.76(2H,d)。

Synthesis of 2-chloro-5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol hydrochloride [ C-005]

3-amino-5-methoxy-isonicotinamide [ C-006]

A stirred suspension of 3-amino-5-methoxy-isonicotinic acid (1.00g, 5.947mmol) in anhydrous dioxane (10mL) was prepared under nitrogen at room temperature. Pyridine (0.53mL, 6.542mmol) was added followed by di-tert-butyl dicarbonate (1.43g, 6.542mmol) and ammonium carbonate (1.26g, 13.083 mmol). The reaction mixture was stirred at room temperature for 5 hours, then diluted with ether (50mL) and the suspension was stirred at room temperature for 18 hours. The suspension was filtered and the solid was washed with diethyl ether (50mL) then dissolved in methanol and filtered to remove inorganic salts. The filtrate was concentrated by rotary evaporation to give the title compound [ C-006] (690mg, 70%) as a cream solid. LCMS method 5, RT 1.27min, MI 168[ M + H ]; NMR (1H,300MHz, d6-dmso)7.77(s,1H),7.65(br.S,1H),7.58(br.S,1H),7.57(s,1H),6.30(s,2H),3.85(s, 3H).

2-mercapto-5-methoxy-3H-pyrido [3,4-d ] pyrimidin-4-one [ C-007]

A suspension of 3-amino-5-methoxy-isonicotinamide [ C-006] (1.10g, 6.58mmol) in dry DMF (10mL) was prepared under nitrogen. Carbon disulfide (1.97mL, 32.90mmol) was added followed by dropwise addition of DBU (1.96mL, 13.16mmol) and the reaction mixture was heated to 60 ℃ for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with 2M HCl, the precipitate was filtered and washed with water. The precipitate was suspended in toluene (40mL) and the toluene was carefully poured off and this was repeated once. The precipitate was then suspended in toluene (30mL) and concentrated by rotary evaporation to give the title compound [ C-007] (1.05g, 65%) as a yellow solid. LCMS method 5, RT 2.33min, MI 210[ M + H ]; NMR (1H,500MHz, d6-dmso)12.71(1H, s),12.38(1H, s),8.30(1H, s),8.22(1H, s),3.95(3H, s).

2-chloro-5-methoxy-pyrido [3,4-d ] pyrimidin-4-ol hydrochloride [ C-005]

A suspension of 2-mercapto-5-methoxy-3H-pyrido [3,4-d ] pyrimidin-4-one hydrochloride [ C-007] (1.145g, 4.660mmol) in anhydrous dioxane (20mL) was prepared under nitrogen. Thiophosgene (0.54mL, 6.990mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes and then heated to 95 ℃ for 4 hours. Another portion of thiophosgene (0.09mL, 1.165mmol) was added and heating continued for another 1.5 hours, followed by stirring at room temperature overnight. The reaction mixture was diluted with ether, the precipitate was filtered, washed with ether and dried under vacuum to give the title compound [ C-003] (1.16g, 100%) as a pale yellow solid. LCMS method 5, RT2.71min, MI 212[ M + H ]; NMR (1H,500MHz, d6-dmso)8.53(1H, s),8.40(1H, s),3.98(3H, s).

Synthesis of [2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine [1001]

2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol [ C008]

Following the procedure described in scheme C1, 2-chloro-pyrido [3,4-d]Pyrimidine-4-ol hydrochloride (100mg, 0.459mmol) was reacted with 2-benzyl-morpholine (146mg, 0.825mmol) to give the title compound [ C008 mmol ]](114mg, 64%) and then subjected to column chromatography on silica using CH containing 0-10% methanol₂Cl₂And (4) eluting. LCMS method 5, RT 2.37min, MI 323.24[ M + H ]]。

(R) -3- [2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -pyrrolidine-1-carboxylic acid tert-butyl ester [ C009]

To 2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d in DMA (1mL)]Pyrimidin-4-ol [ C008]](70mg，0.21mmol)、NEt₃A stirred solution of (90mL, 0.63mmol) and DMAP (3mg, 0.02mmol) was added 2,4, 6-triisopropylbenzenesulfonyl chloride (77mg, 0.25 mmol). After 4 hours, (R) - (+) -1-Boc-3-aminopyrrolidine (43mL, 0.25mmol) was added and stirred at room temperature overnight. The reaction mixture is added to CH₂Cl₂And H₂Partition between O, separate the organic phase and evaporate. Purifying the residue by column chromatography on silica with 0-5% methanol in CH₂Cl₂And (4) eluting. The appropriate fractions were combined and evaporated to give the title compound as an off-white solid [ C009](43mg, 33%). LCMS method 5, RT 3.59min, MI 491.33[ M + H ]]。

[2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine [1001]

(R) -3- [2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -pyrrolidine-1-carboxylic acid tert-butyl ester [ C009] (34mg, 0.069mmol) was stirred in 4N HCl in dioxane (2mL) for 1 hour. The reaction mixture was diluted with methanol and loaded onto an SCX-cartridge, washed with methanol and eluted with ammonia in methanol. The ammonia phase was evaporated to give the title compound [1001] (21mg, 78%). LCMS method 5, RT 1.97min, MI 391.21[ M + H ]; NMR (1H,300MHz, d4-MeOD)8.66(1H, s),8.14(1H, dd),7.83(1H, ddd),7.35-7.22(5H, m),4.66-4.59(2H, m),4.50-4.48(1H, m),3.98(1H, dd),3.71-3.55(2H, m),3.44-3.41(1H, m),3.16-3.07(2H, m),2.99-2.91(1H, m),2.85-2.74(3H, m),2.34-2.13(3H, m).

General Synthesis scheme for substituted 2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of the general formula [ H006]

General formula [ H-009]2-morpholin-4-yl-pyrido [3,4-d]The pyrimidin-4-yl derivative is prepared by: general formula [ H-004]2-chloro-pyrido [3,4-d of (a)]The pyrimidin-4-ol derivative is reacted with a chlorinating agent such as phosphoryl chloride and then with a compound of the general formula [ H-008 ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the general formula [ H-009]2-morpholin-4-yl-pyrido [3,4-d]Pyrimidine derivatives and their use as herbicides]The substituted morpholine derivatives of (a) are reacted in a polar aprotic solvent such as DMA, DMF, NMP at elevated temperatures obtained by heating or using a microwave reactor. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme C2

(S)-N¹- (5-methoxy-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -3-phenyl-propane-1, 2-diamine [1002]Synthesis of (2)

(S) -2-benzyl-4- (2-chloro-5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C010]

Preparation of 2-chloro-5-methoxy-pyrido [3,4-d in DCE (50mL) under Nitrogen]Pyrimidin-4-ol [ C005 ]](1.04g, 4.911 mmol). DIPEA (1.72mL, 9.822mmol) and POCl were added₃(0.46mL, 4.911mmol), the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was evaporatedUsed directly in the next step. Preparation of 2, 4-dichloro-5-methoxy-pyrido [3,4-d ] in DCM (15mL) under nitrogen]Solution of pyrimidine (280mg of crude residue, 1.228mmol, assuming complete conversion). Triethylamine (0.34mL, 2.456mmol) was added followed by (S) -2-benzyl-piperazine-1-carboxylic acid tert-butyl ester (170mg, 0.614 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure and the residue was purified by chromatography on silica eluting with 0-10% methanol in DCM to give the title compound [ C-010 ]](110mg, 19%): LCMS method 5, RT 2.55min, MI 263[ M + H ]](ii) a NMR (1H,500MHz, d6-dmso)8.69(1H, d, J ═ 3.7Hz),8.39(1H, d, J ═ 3.7Hz),4.10(3H, s),3.63(4H, width s),3.54(4H, width s),1.47(9H, s).

(S)-N¹- (5-methoxy-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -3-phenyl-propane-1, 2-diamine [1002]

A solution of (S) -2-benzyl-4- (2-chloro-5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C010] (100mg, 0.213mmol) in anhydrous DMA (2mL) was prepared. Morpholine (19mg, 0.213mmol) and DIPEA (0.04mL, 0.213mmol) were added and the mixture was heated to 150 ℃ in a microwave for 20 min. The reaction mixture was evaporated under reduced pressure and the crude residue was purified by chromatography on silica eluting with DCM containing 0-10% methanol. The product in 4M HCl in dioxane was stirred at room temperature for 1 hour, the reaction mixture was evaporated under reduced pressure and loaded onto an SCX cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia eluate was evaporated under reduced pressure to give the title compound [1001] (46mg, 51%) as a yellow solid: LCMS method 5, RT 2.51min, MI 421[ M + H ]; NMR (1H,500MHz, d6-dmso)8.34(1H, s),7.82(1H, s),7.35-7.32(2H, m),7.28-7.25(3H, m),4.0-3.97(1H, m),3.80(4H, width s),3.62-3.61(8H, width m),3.08-3.03(1H, m),2.98-2.91(1H, m),2.76-2.57(6H, m).

Synthesis of 5-methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [1003]

4- (2-chloro-5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C011]

Preparation of 2-chloro-5-methoxy-pyrido [3,4-d in DCE (10mL) under Nitrogen]Pyrimidine-4-ol hydrochloride [ C005 ]](200mg, 0.806mmol) of a stirred suspension. DIPEA (0.31mL, 1.773mmol) was added followed by dropwise POCl addition₃(0.08mL, 0.887 mmol). The reaction mixture was stirred at room temperature for 2 hours. Another portion of DIPEA (0.31mL, 1.773mmol) and POCL3(0.08mL, 0.887mmol) was added and stirring continued at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was in CH₂Cl₂(30mL) and saturated NaHCO₃(aqueous solution) (30 mL). Separating the organic phase with CH₂Cl₂The aqueous phase was extracted (2x10 mL). The combined organic fractions were dried (phase separator) and evaporated under reduced pressure to give a mixture containing 2, 4-dichloro-5-methoxy-pyrido [3,4-d]The crude residue of pyrimidine (assumed to be 185mg, 100%) was used without further purification. Preparation under nitrogen at CH₂Cl₂2, 4-dichloro-5-methoxy-pyrido [3,4-d ] in (10mL)]A solution of crude pyrimidine (assumed to be 185mg, 0.806 mmol). Triethylamine (0.17mL, 1.209mmol) was added followed by tert-butyl piperazine-1-carboxylate (120mg, 0.645mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure by chromatography on silica with CH containing 0-10% methanol₂Cl₂The residue was purified by elution. The appropriate fractions were combined and concentrated to give the title compound as a yellow solid [1003]](177mg, 58%). LCMS method 5, RT 5.44min, MI 380[ M + H ]]；NMR:(1H,500MHz,d6-dmso)8.65(s,1H),8.34(s,1H),4.06(s,3H),3.59(br.m,4H),3.49(br.m,4H),1.42(s,9H)。

5-methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [ C012]

To 2, 4-dichloro-5-methoxy-pyrido [3,4-d ] in DMA (2mL)]Pyrimidine [ C011](70mg, 0.19mmol) was added morpholine (20mg, 0.228mmol) and DIPEA (0.04mL, 0.228 mmol). The reaction mixture was heated to 150 ℃ for 20 minutes in a microwave. The reaction mixture was concentrated under reduced pressure by chromatography on silica (with CH containing 0-10% methanol)₂Cl₂Elution) to obtain the title compound [ C012]]. LCMS method 5, RT4.01min, MI 431[ M + H ]]。

5-methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [1003]

5-methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [ C012] in 4M HCl in dioxane (2mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with methanol (to dissolve the precipitate) and loaded onto an SCX cartridge, washed with methanol and eluted with 7M ammonia in methanol. The ammonia fraction was evaporated under reduced pressure and dried under vacuum to give the title compound [1003] (48mg, 83%): LCMS method 5, RT 3.54min, MI 331[ M + H ]; NMR (1H,500MHz, d6-dmso)8.33(1H, width d, J ═ 0.9Hz),7.88(1H, s),3.95(3H, s),3.73-3.71(4H, m),3.64-3.62(4H, m),3.38(4H, width m),2.82-2.80(4H, width t, J ═ 4.5 Hz).

The following intermediate compounds were synthesized following the general synthesis shown in scheme [ C2 ]:

the following compounds were synthesized following the general synthesis shown in scheme [ C2 ]:

synthesis of [ 2-morpholin-4-yl-8- (2H-pyrazol-3-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine [1012]

2, 8-dichloro-pyrido [3,4-d ] pyrimidin-4-ol [ C022]

To a suspension of 3-amino-2-chloro-isonicotinamide (2.00g, 11.65mmol) in dioxane (30mL) was added thiophosgene (2.25mL, 29.13mmol) dropwise and the suspension was stirred for 15 min. The reaction was then heated at 100 ℃ for 3 hours, then cooled to room temperature and diluted with ether. The resulting solid was collected and dried to give the title compound [ C022] (2.41g, 96%) which was used without further purification. LCMS method 5, RT 3.51min, MI 216[ M + H ].

8-chloro-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol [ C023]

2, 8-dichloro-pyrido [3,4-d ] into DMA (2mL)]Pyrimidin-4-ols [ C022](200mg, 0.926mmol) was added morpholine (0.1mL, 1.20 mmol). The solution was stirred at room temperature for 30 minutes and then heated to 40 ℃ for 3 hours. The solvent was removed under reduced pressure and a minimum amount of CH was added₂Cl₂To dissolve the crude residue, diethyl ether was added. The resulting solid was collected and dried to give the title compound [ C022](200mg, 80%) and used without further purification. LCMS method 5, RT3.95min, MI 267[ M + H]。

(R) -3- (8-chloro-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -pyrrolidine-1-carboxylic acid tert-butyl ester [ C024]

To 8-chloro-2-morpholin-4-yl-pyrido [3,4-d in DMA (10mL)]Pyrimidin-4-ols [ C022](500mg, 1.87mmol) of the solution 2,4, 6-triisopropylbenzenesulfonyl chloride (690mg, 2.25mmol), NEt were added in this order₃(0.52mL, 3.75mmol) and DMAP (50mg, 0.41 mmol). The mixture was stirred at 40 ℃ for 1h, then (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (460mg, 2.44mmol) was added. The reaction was stirred at room temperature overnight, and then the solvent was removed under reduced pressure. By column chromatography on silica with 0-10% methanol in CH₂Cl₂The mixture was purified by elution. The appropriate fractions were combined and evaporated under reduced pressure to give the title compound [ C023](310mg, 38%). LCMS method 5, RT 5.77min, MI 435[ M + H ]]。

[ 2-Morpholin-4-yl-8- (2H-pyrazol-3-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine [1012]

Microwave vials were charged with (R) -3- (8-chloro-2-morpholin-4-yl-pyrido [3,4-d]Pyrimidin-4-ylamino) -pyrrolidine-1-carboxylic acid tert-butyl ester [ C024](100mg, 0.23mmol), 1H-pyrazole-5-boronic acid (38mg, 0.35mmol), Pd (Ph)₃P)₄(27mg，0.023mmol)、K₃PO₄Solution of (0.92mL of 0.5M in H)₂O, 0.46mmol) and DMA (3.5 mL). The mixture was heated to 150 ℃ for 10 minutes under microwave irradiation. Removing the solvent under reduced pressure by chromatography on silica with CH containing 0-10% methanol₂Cl₂The residue was purified by elution. The appropriate fractions were combined, the solvent was evaporated under reduced pressure to give the Boc-protected intermediate, which was dissolved in CH₂Cl₂To (2mL) was added TFA (0.5 mL). The solution was stirred for 3 hours and then loaded onto an SCX-2 cartridge, washed with methanol and eluted with 2N ammonia in methanol solution. The solvent was removed from the ammonia fraction under reduced pressure to give the title compound [1012]: LCMS method 5, RT 4.39min, MI 367[ M + H ]]；NMR:(1H,300MHz,d6-dmso)8.28(d,1H),7.96(d,1H),7.60(d,1H),7.33(d,1H),4.61-4.68(m,1H),3.78-3.81(m,4H),3.68-3.74(m,4H),3.33-3.40(m,2H),3.18-3.23(m,1H),3.02-3.07(m,1H),2.15-2.24(m,1H),1.98-2.04(m,1H)。

N⁴- ((S) -2-amino-3-phenyl-propyl) -2-morpholin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamines [1013 ]]Synthesis of (2)

[ (S) -1-benzyl-2- (8-chloro-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -carbamic acid tert-butyl ester [ C025]

Following the procedure described above, 8-chloro-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-ol [ C023] (500mg, 1.87mmol) was reacted with ((S) -1-aminomethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (600mg, 2.44mmol) to give the title compound [ C024] (350mg, 38%). LCMS method 5, RT 5.90min, MI 499[ M + H ].

N⁴- ((S) -2-amino-3-phenyl-propyl) -2-morpholin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamines [1013 ]]

Microwave vials were loaded with [ (S) -1-benzyl-2- (8-chloro-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-ylamino) -ethyl]-carbamic acid tert-butyl ester [ C025](100mg, 0.20mmol), EtOH (2mL) and NH₄OH (2 mL). The reaction mixture was heated to 150 ℃ for 1 hour under microwave irradiation. This process was repeated until reasonable conversion of the desired product was identified by LCMS analysis. Then the solvent is removed under reduced pressure, at CH₂Cl₂BOC protected compound was diluted (2mL) and TFA (0.5mL) was added. The solution was stirred for 3 hours and then loaded onto an SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol solution. The solvent was removed from the ammonia fraction and the residue was purified by preparative HPLC (method a) to give the title compound [1013 ]]: LCMS method 5, RT 2.11min, MI 380[ M + H ]]；NMR:(1H,300MHz,d6-dmso)8.30-8.35(m,1H),8.27(br s,1H),7.49(d,1H),7.22-7.33(m,4H),6.97(d,1H),6.34(br s,2H),3.68-3.78(m,1H),3.61-3.65(m,1H),3.37-3.54(m,8H),3.25-3.35(m,2H),2.91(dd,1H),2.73(dd,1H)。

(S)-N¹- (2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -3-phenyl-propane-1, 2-diamine [1014]Synthesis of (2)

Reacting 2-chloro-pyrido [3,4-d]Pyrimidin-4-ol [ C003]](1.50g, 8.26mmol) was suspended in DMA (30 mL). Triethylamine (2.3mL, 16.52mmol) was added and the reaction mixture was stirred at room temperature. 2,4, 6-Triisopropylbenzenesulfonyl chloride (2.75g, 9.09mmol) and DMAP (50mg, 0.41mmol) were both added and the mixture was cooled at room temperatureThe mixture was stirred for 6 hours. ((S) -1-aminomethyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (3.10g, 12.39mmol) was added to the reaction mixture and stirring continued at room temperature for 18 h. Morpholine (1mL) was added to the crude solution and the mixture was sealed and heated to 150 ℃ for 20 minutes under microwave irradiation. The mixture was dissolved in DCM and washed with water and brine. The layers were separated and the organic layer was over MgSO₄And drying. The solvent was removed under reduced pressure and the crude mixture was purified by flash column chromatography using CH₂Cl₂Eluted with 5% methanol. The appropriate fractions were combined and concentrated, and the residue was stirred in 4M HCl in dioxane for 18 hours. The mixture was concentrated under reduced pressure and the residue was loaded onto an SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. The solvent was removed from the ammonia fraction under reduced pressure to give the title compound [1014](150mg, 22%). LCMS method 5, RT 1.79min, MI 365[ M + H](ii) a NMR (1H,300MHz, d6-dmso)8.73(1H, br s),8.64(1H, s),8.29(2H, br s),8.20(1H, d),8.00(1H, d), 7.38-7.28 (5H, m), 3.90-3.83 (1H, m), 3.62-3.34 (10H overlapping br m), 3.13-3.07 (1H, m), 2.88-2.81 (1H, m).

General Synthesis scheme for substituted 2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine derivatives of the general formula [ H-006]

General formula [ H-011 ]]By reacting a 3-halo-N- (imino-morpholin-4-yl-methyl) -isonicotinamide derivative of the general formula [ H-010 ] with a suitable coupling agent, for example O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)]O-halo-isonicotinic acid derivatives of formula [ H-004]Is prepared by coupling of the appropriately substituted 4-carbamimidoyl-morpholine in a polar aprotic solvent such as DMA or DMF. General formula [ H-011 ]]Cyclizing the isonicotinoyl-amidine derivative to replace the relevant halogen group to give the desired general formula [ H005 [ ]]Morpholin-4-yl-pyrido [3,4-d of]A pyrimidin-4-ol derivative. General formula [ H-006]2-morpholin-4-yl-pyrido [3,4-d]The pyrimidin-4-yl derivative is prepared by: general formula [ H-005 ]]Morpholin-4-yl-pyrido [3,4-d of]The pyrimidin-4-ol derivative is reacted with a chlorinating agent such as phosphoryl chloride or a trifluoromethanesulfonizing agent (triflating agent) such as N-phenyl-bis (trifluoromethanesulfonimide), followed by reaction with a compound of the general formula [ H-008 [ ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme C3

Synthesis of 5-bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [1015]

3-bromo-5-fluoro-N- (imino-morpholin-4-yl-methyl) -isonicotinamide [ C026]

A stirred solution of 3-bromo-5-fluoro-isonicotinic acid hydrochloride (800mg, 3.119mmol) and DIPEA (1.91mL, 10.917mmol) in DMF (11mL) was prepared. HATU (1.186g, 3.119mmol) was added and the reaction mixture was stirred at room temperature for 1 hour, during which time the reaction mixture slowly turned brown. 4-Morpholinylmethamidine hydrobromide (655mg, 3.119mmol) was added and stirring continued at room temperature for 2 h. The reaction mixture was diluted with water (30mL) and stirred at room temperature for 10 min. The reaction mixture was extracted with ethyl acetate (3 × 20mL), the combined organics were dried and evaporated under reduced pressure to give the title compound [ C026] (1.15g, 87%) as a brown gum which was used in the next step without purification: LCMS method 5, RT2.86min, MI 331[ M + H ].

5-bromo-2-morpholin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ C027]

A solution of 3-bromo-5-fluoro-N- (imino-morpholin-4-yl-methyl) -isonicotinamide [ C025] (containing 1.03g, 3.119mmol of crude product, assuming 100% conversion of the starting material) in anhydrous DMA (10mL) was prepared and potassium carbonate (453mg, 3.275mmol) was added. The reaction mixture was heated to 150 ℃ for 1 hour in a microwave. The reaction mixture was poured into water (20mL) and acidified with acetic acid. The resulting beige precipitate was filtered, washed with water and dried in a vacuum oven overnight to give the title compound [ C027] (400mg, 41%): LCMS method 5, RT 1.42min, MI 313[ M + H ].

5-bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [1015]

A solution of 5-bromo-2-morpholin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one (50mg, 0.161mmol) in anhydrous DMF (2mL) was prepared under nitrogen. N-phenyl-bis (trifluoromethanesulfonimide) (60mg, 0.322mmol) was added followed by DIPEA (0.06mL, 0.354mmol) and the reaction mixture was stirred at room temperature overnight. Tert-butyl piperazine-1-carboxylate (60mg, 0.322mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (10mL) and washed with water (3 × 5 mL). The organic phase was dried, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica eluting with 5-50% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated to give tert-butyl 4- (5-bromo-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylate [ C027] (35mg, 45%) as a yellow solid. LCMS method 5, RT 5.92min, MI 479[ M + H ]; NMR (1H,500MHz, d6-dmso)8.67(1H, s),8.29(1H, s),3.78-3.76(4H, m),3.66-3.62(4H, m),3.62(2H, very wide s),3.52-3.47(4H, very wide m),3.24(2H, very wide s),1.40(9H, s).

Boc protected intermediate [ C026]Dissolved in 4M HCl in dioxane (2mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated by rotary evaporation and the residue was loaded onto an SCX-2 cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia fraction was concentrated under reduced pressure to give the title compound as a yellow solid [1015](24mg, 86%). LCMS method 5, RT 2.24min, MI 379[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.76(1H,s),8.28(s,1H),3.89-3.87(4H,m),3.78-3.76(4H,m),3.70(2H,br.s),3.33(2H,br.s),3.09(2H,br.s),3.00(2H,br.s)。

Synthesis of 5-cyclopropyl-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine [1016]

Preparation of 4- (5-bromo-2-morpholin-4-yl-pyrido [3, 4-d) in anhydrous dioxane (2.5mL) in a microwave vial]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C028](100mg, 0.229 mmol). Potassium phosphate (tribasic) (ground, 145mg, 0.687mmol) and cyclopropylboronic acid (30mg, 0.344mmol) were added. The reaction mixture was purged 3 times with argon (vacuum/argon balloon) and then dichloro [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) dichloromethane adduct (9mg, 0.011mmol), the vial was sealed and heated to 95 ℃ for 5 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was evaporated on silica and chromatographed on silica with CH containing 0-8% methanol₂Cl₂And (4) eluting and purifying. The product was not purified with this solvent system, so the appropriate fractions were concentrated and purified repeatedly, eluting with cyclohexane containing 50-100% ethyl acetate. The appropriate fractions were combined and concentrated to give 4- (5-cyclopropyl-2-morpholin-4-yl-pyrido [3, 4-d) as a yellow glassy solid]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester (53mg, 52%). LCMS method 5, RT4.09min, MI 441[ M + H](ii) a NMR (1H,500MHz, d6-dmso)8.50(1H, s),7.68(1H, s),3.79-3.19(8H, a very broad set of signals), 3.79-3.74(4H, m),3.66-3.64(4H,m),2.62-2.59(1H,m),1.40(9H,s),1.18-1.14(2H,m),0.93-0.90(2H,m)。

The Boc-protected intermediate was stirred in dioxane (2mL) in 4M HCl for 2 hours at room temperature. The reaction mixture was concentrated by rotary evaporation, loaded onto an SCX cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia fraction was concentrated by rotary evaporation to give the title compound [1016] (37mg, 90%) as a pale yellow solid. LCMS method 5, RT4.41min, MI 341[ M + H ]; NMR (1H,500MHz, d6-dmso)8.48(1H, s),7.65(1H, s),3.75-3.73(4H, m),3.66-3.62 (overlapping 4H m and 2H very wide s),3.19(2H, very wide s),2.80(4H, br. m),2.63-2.58(1H, m),1.17-1.14(2H, m),0.93-0.90(2H, m).

Synthesis of 4- ((S) -3-benzyl-piperazin-1-yl) -5-cyclopropyl-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine [1017]

(S) -2-benzyl-4- (5-bromo-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C029]

Following the procedure described in scheme C3, 5-bromo-2-morpholin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ C027] (200mg, 0.64mmol) was reacted with (S) -2-benzyl-piperazine-1-carboxylic acid tert-butyl ester (355mg, 1.28mmol) to give (S) -2-benzyl-4- (5-bromo-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C028] (139mg, 38%). LCMS method 5, RT 5.64min, MI 569/571[ M +1 ].

4- ((S) -3-benzyl-piperazin-1-yl) -5-cyclopropyl-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine

Following the procedure described in scheme C3, (S) -2-benzyl-4- (5-bromo-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C029](135mg, 0.24mmol) was reacted with cyclopropylboronic acid (31mg, 0.36mmol) to give 4- ((S) -3-benzyl-piperazin-1-yl) -5-cyclopropyl-2-morpholin-4-yl-pyrido [3, 4-d) as a yellow solid]Pyrimidine [1017]](62mg, 61%). LCMS method 5, RT 2.74min, MI 431[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.66(1H, s),7.65(1H, s),7.33-7.19(5H, m),4.35-2.42(18H, very broad overlapping multiplets), 1.16-1.08(2H, br m),0.90-0.82(2H, br m).

Synthesis of [ (S) -4- (5-cyclopropyl-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazin-2-yl ] -acetonitrile [1018]

3-cyclopropyl-5-fluoro-N- (imino-morpholin-4-yl-methyl) -isonicotinamide [ C030]

Following the procedure described in scheme C3, 4-carboxy-3-cyclopropyl-5-fluoro-pyridineTrifluoro-acetate (1.51g, 5.10mmol) was reacted with 4-morpholinylmethamidine hydrobromide (1.56g, 5.10mmol) to give 3-cyclopropyl-5-fluoro-N- (imino-morpholin-4-yl-methyl) -isonicotinamide [ C029 [](1.23g, 84%) which was used in the next step without purification. LCMS method 5, RT 2.35min, MI 293[ M + H ]]。

Step 2-5-cyclopropyl-2-morpholin-4-yl-3H-pyrido [3,4-d ] pyrimidin-4-one [ C031]

Following the procedure described in scheme C3, with K under microwave irradiation₂CO₃Treatment of 3-cyclopropyl-5-fluoro-N- (imino-morpholin-4-yl-methyl) -isonicotinamide (1.26g, 4.30mmol) to give 5-cyclopropyl-2-morpholin-4-yl-3H-pyrido [3,4-d]Pyrimidin-4-ones[C030](402mg, 34%). LCMS method 5, RT 3.41min, MI 273[ M + H ]]。

[ (S) -4- (5-cyclopropyl-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -piperazin-2-yl]-acetonitrile [1018]]Preparation of 5-cyclopropyl-2-morpholin-4-yl-3H-pyrido [3,4-d in DMF (5mL) at room temperature under nitrogen]Pyrimidin-4-one [ C031]](50mg, 0.184mmol) of the solution. Triethylamine (0.03mL, 0.193mmol) was added followed by 2,4, 6-triisopropylbenzenesulfonyl chloride (56mg, 0.186 mmol). The reaction mixture was stirred at room temperature for 2 hours, then (S) -piperazin-2-yl-acetonitrile (23mg, 0.184mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure by chromatography on silica with CH containing 0-10% methanol₂Cl₂The residue was purified by elution. The appropriate fractions were combined and concentrated to give the title compound as a yellow solid [1018]](30mg, 43%). LCMS method 5, RT5.76min, MI 380[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.69(1H,s),7.70(1H,s),4.46-4.29(1H,br s),3.95-3.93(1H,br m),3.88(4H,t),3.78(4H,t),3.32-3.27(1H,m),3.20-2.66(5H,br m),2.50(2H,br s),1.80(1H,br s),1.16(2H,br s),0.95(2H,br s)。

4PPAZ compounds

Several chemical syntheses of the 4-substituted-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -azaquinazoline compounds of the present invention of the general formula [ I-001] (collectively referred to herein as "4 PPAZ compounds" for convenience) are described herein. These methods and/or other known methods may be modified and/or adapted in known ways to facilitate the synthesis of other compounds within the scope of the invention.

General Synthesis scheme D1 for substituted 4-substituted-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -azaquinazoline derivatives of the general formula [ I-001]

General formula [ I-003 ]]4-substituted-2- (1H-pyrrolo [2, 3-b) of (A)]Pyridin-4-yl) -azaquinazoline derivatives were prepared as follows: the general formula [ I-002, prepared in scheme C2, was catalyzed by a Suzuki-type target-catalyzed cross-coupling reaction]2-chloro-pyrido [3,4-d of (a)]Pyrimidine derivatives and the general formula [ I-004]Boric acid or borate ester derivative of (a), palladium catalyst such as Pd (PPh)₃)₄Bases such as K₂PO₄In a polar aprotic solvent such as DMA or DMF at elevated temperatures obtained by heating or using a microwave reactor to give the general formula [ I-003]4PPAZ derivatives of (1). The intermediates are purified by column chromatography after a post-reaction treatment, usually by liquid-liquid extraction, or after purification by acidic ion exchange capture-release. Then the general formula [ I-003 ]]The intermediate aryl sulfonate protected derivative of (a) is subjected to a deprotection reaction in the presence of a base such as sodium hydroxide in a polar protic solvent such as ethanol. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the intermediate is purified by column chromatography, deprotection of the N-Boc derivative with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1, 4-dioxane under acidic conditions or by capture and release of a sulfonic acid resin such as polymer-supported toluenesulfonic acid, and purification of the crude reaction product by normal phase chromatography or reverse phase preparative HPLC.

Scheme D1

Synthesis of 5-methoxy-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1200]

4- { 5-methoxy-2- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-D ] pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ D001]

Preparation of 4- (2-chloro-5-methoxy-pyrido [3, 4-d) in DMA (7.5mL)]Pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester [ C011 prepared in scheme C2](250mg, 0.671 mmol). Adding 4- (4,4,5, 5-tetramethyl- [1,3,2]]Dioxolan-2-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b]Pyridine [ D002](374mg，0.940mmol)、Pd(PPh₃)₄(77mg, 0.067mmol) and K₃PO₄(2.68mL of a 0.5M aqueous solution). The reaction mixture was heated to 150 ℃ for 10 minutes in a microwave. The reaction mixture was concentrated by rotary evaporation and purified by column chromatography on silica eluting with cyclohexane containing 0-100% ethyl acetate. The appropriate fractions were combined and concentrated to give the title compound [ D001] as a yellow solid](115mg, 28%). LCMS method 5, RT 5.13min, MI 616[ M + H ]]；NMR:(1H,500MHz,d6-dmso)8.92(s,1H),8.53(d,1H),8.37(s,1H),8.26(d,1H),8.05(d,1H),8.02(d,1H),7.77(d,1H),7.64–7.60(m,1H),7.57–7.53(m,1H),7.43(d,2H),4.09(s,3H),3.67(br.m,4H),3.56(br.m,4H),1.43(s,9H)。

5-methoxy-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1200]

A solution of 4- { 5-methoxy-2- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-D ] pyrimidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester [ D001] (100mg, 0.162mmol) in ethanol (4mL) was prepared and NaOH (1mL of a 5M solution) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated by rotary evaporation and the residue was dissolved in DCM (10mL) and water (10 mL). The pH was adjusted to about 7 by addition of ammonium chloride and the mixture was extracted with DCM (3 × 10 mL). The combined organic extracts were dried (phase separator) and concentrated by rotary evaporation. The residue was purified by column chromatography on silica eluting with cyclohexane containing 75-100% ethyl acetate. The appropriate fractions were combined and concentrated to give intermediate 4- [ 5-methoxy-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester, which was stirred in 4M HCl in dioxane (2mL) at room temperature for 1 hour. The reaction mixture was concentrated by rotary evaporation, loaded onto an SCX cartridge, washed with methanol and eluted with 7N ammonia in methanol. The ammonia fraction was concentrated by rotary evaporation to give the title compound [1200] (29mg, 49%) as a yellow solid. LCMS method 5, RT2.23min, MI 362[ M + H ]; NMR (1H,500MHz, d6-dmso)11.81(1H, s),8.89(1H, s),8.37(1H, d, J ═ 5.0Hz),8.31(1H, s),8.09(1H, d, J ═ 5.0Hz),7.63-7.62(1H, m),7.43(1H, dd, J ═ 3.3,1.8Hz),4.07(3H, s),3.66-3.64(4H, m),2.91-2.89(4H, m).

General Synthesis scheme D2 for substituted boronic acid or boronic ester derivatives of general formula [ I-004]

General formula [ I-004]By using a base such as NaH in a polar aprotic solvent such as THF]4-bromo-1H-pyrrolo [2,3-b ] of]Pyridine derivatives and the general formula [ I-008 ]]Is prepared by reacting the arylsulfonyl chloride derivative at low temperature. Then the general formula [ I-006 ]]1-arylsulfonyl-4-bromo-1H-pyrrolo [2,3-b ] of]Pyridine derivatives with strong bases such as LDA in polar aprotic solvents at low temperatures such as THF and the general formula [ I-009]The alkyl halide derivative of (1). Then using a palladium catalyst such as PdCl₂dppf, boron reagents such as bis-pinacoldiboron, potassium acetate, in polar aprotic solvents such as dioxane, at elevated temperatures obtained by heating or using microwave reactors]C2 substituted 4-bromo-1H-pyrrolo [2,3-b ] of (1)]The pyridine derivative is subjected to palladium-catalyzed cross-coupling reaction to obtain the general formula [ I-004]After work-up of the substituted boronic ester derivatives, usually by liquid-liquid extraction, the derivatives are purified by column chromatography.

Scheme D2

Synthesis of 4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] pyridine [ D002]

4-bromo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] pyridine [ D003]

4-bromo-7-azaindole (3g, 15.22mmol) was weighed into a round-bottom flask and dissolved in THF (50mL) under nitrogen. The reaction mixture was cooled to 0 ℃ and treated with sodium hydride (60% in mineral oil, 0.67g, 16.75mmol) in portions, with the addition of hissing sound. After addition, the reaction mixture was stirred at room temperature for 30 minutes, then treated with benzenesulfonyl chloride (2.14mL, 16.75 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure and dissolved in DCM 30mL and the organics washed with 2 × 30mL sodium carbonate 2M, MgSO₄Dried, filtered and evaporated to give an orange oil. Purification by flash column chromatography with 1:9 ethyl acetate: purification was performed eluting with cyclohexane to give the title compound as an off-white solid (92%). LCMS method 5, RT5.36min, MI 337[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.22(d,1H),8.18(d,2H),7.78(d,1H),7.58(t,1H),7.48(t,2H),7.35(d,1H),6.63(d,1H)。

4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] pyridine [ D002]

Reacting 4-bromo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b]Pyridine (1.57g, 4.47mmol), bis (pinacolato) diboron [ D003](2.71g，10.72mmol)，PdCl₂.dppf CH₂Cl₂Adduct (0.365g, 0.45mmol) and acetic acidPotassium (0.876g, 8.94mmol) was weighed into a microwave vial. Dioxane (30mL) was added and the reaction mixture capped and heated in a microwave reactor at 130 ℃ for 30 minutes. The solvent was removed under reduced pressure and the residue partitioned between 20mL of ammonium chloride and 20mL of ethyl acetate. The organic phase was washed with MgSO₄Dried, filtered and evaporated under reduced pressure to give a brown oil. It was passed through a short column of silica eluting with 1:4 ethyl acetate: cyclohexane. The fractions were pooled together and evaporated to give the title compound [ D002 as a pale yellow solid]: LCMS method: 5, RT: 4.77min, MI 317[ boronic acid intermediate M + H]

Synthesis of benzenesulfonyl-2-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxopan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D004]

1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine [ D005]

4-bromo-7-azaindole (3g, 15.22mmol) was weighed into a round-bottom flask and dissolved in THF (50mL) under nitrogen. The reaction mixture was cooled to 0 ℃ and treated with sodium hydride (60% in mineral oil, 0.67g, 16.75mmol) in portions, with the addition of hissing sound. After addition, the reaction mixture was stirred at room temperature for 30 minutes, then treated with benzenesulfonyl chloride (2.14mL, 16.75 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure and dissolved in DCM 30mL and the organics washed with 2 × 30mL sodium carbonate 2M, MgSO₄Dried, filtered and evaporated to give an orange oil. Purification by flash column chromatography with 1:9 ethyl acetate: purification by elution with cyclohexane to give the title compound [ D005] as an off-white solid](92%) LCMS method: 5, RT5.36min, MI 337[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.22(d,1H),8.18(d,2H),7.78(d,1H),7.58(t,1H),7.48(t,2H),7.35(d,1H),6.63(d,1H)。

1-benzenesulfonyl-4-bromo-2-methyl-1H-pyrrolo [2,3-b ] pyridine [ D006]

To 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] in THF (50mL) at-78 deg.C]Pyridine [ D005]](2g, 5.93mmol) solution LDA (2M, 5.9mL, 11.86mmol) was added dropwise. The solution was stirred for 30 minutes. The temperature was raised to 0 ℃, methyl iodide (3.67mL, 59mmol) was then added dropwise, the solution was stirred at 0 ℃ for 3 hours, and allowed to stir at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and extracted with DCM. The combined organic layers were washed with MgSO 2₄Dried and concentrated in vacuo. The crude product was purified by means of SP1 (eluent, gradient: cyclohexane/ethyl acetate: 1/0 to 8/2). The fractions were collected and concentrated under reduced pressure to give the title compound [ D006] as a white solid](87%). LCMS method 5, RT 5.80min, MI 351[ M + H ]]；NMR:(1H,500MHz,CDCl₃)8.12-8.15(m,3H),7.56(t,1H),7.47(t,2H),7.29(d,1H),6.34(s,1H),2.74(s,3H)。

Benzenesulfonyl-2-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D004]

Following the procedure described in scheme D2, with 1-benzenesulfonyl-4-bromo-2-methyl-1H-pyrrolo [2,3-b ]]Substitution of pyridine for 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ]]Pyridine to give the title compound [ D004] as a pale yellow solid](72%). LCMS method 5, RT 6.19min, MI 399[ M + H]；NMR:(1H,500MHz,CDCl₃)8.34(d,1H),8.07(d,2H),7.50(t,1H),7.46(d,1H),7.41(t,2H),6.70(s,1H),2.73(s,3H),1.33(s,12H)。

The following compounds were prepared according to scheme D2:

1-benzenesulfonyl-2-benzyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D007]

1-benzenesulfonyl-2-benzyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine [ D008]

Following the procedure described in scheme D2, 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine was reacted with benzyl bromide to give the title compound [ D008] which was used as crude in the next step. LCMS method 5, RT 6.62min, MI427[ M + H ].

1-benzenesulfonyl-2-benzyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D007]

Following the procedure described in scheme D2, substituting 1-benzenesulfonyl-2-benzyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine for 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine gave the title compound [ D007] LCMS method: 5, RT: 5.59min, MI 392[ M + H, boronic ester hydrolyzed to the corresponding boronic acid under LCMS conditions ]; NMR (1H,500MHz, d6-dmso)8.38(d,1H),7.70(dd,1H),7.49(d,1H),7.42(t,1H),7.23-7.30(m,7H),6.75(s,1H),4.54(d,2H),1.34(s, 12H).

Synthesis of 1-benzenesulfonyl-2- (2-fluoro-benzyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D009]

Step 1-1-benzenesulfonyl-4-bromo-2- (2-fluoro-benzyl) -1H-pyrrolo [2,3-b ] pyridine [ D010]

Following the procedure described in scheme D2, 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine was reacted with 2-fluorobenzyl bromide to give the title compound [ D010] (75%) lcMS method: 5, RT 6.45min, MI 445[ M + H ].

Step 2-benzenesulfonyl-2- (2-fluoro-benzyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D009]

Following the procedure described in scheme D2, 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine was substituted for 1-benzenesulfonyl-4-bromo-2- (2-fluoro-benzyl) -1H-pyrrolo [2,3-b ] pyridine to give the title compound [ D009] as a white solid. LCMS method: 5, RT 5.50min, MI 411[ M +1, boronate hydrolysis to its corresponding boronic acid ].

Synthesis of 1-benzenesulfonyl-2-ethyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D011]

1-benzenesulfonyl-4-bromo-2-ethyl-1H-pyrrolo [2,3-b ] pyridine [ D012]

Following the procedure described in scheme D2, 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine was reacted with iodoethane to give the title compound as a white solid [ D012 ]: LCMS method: 5, RT 6.01min, MI 351[ M + H ]; NMR (1H,500MHz, d6-dmso)8.11-8.15(m,3H),7.56(d,1H),7.45-7.48(m,2H),7.30(d,1H),6.39(s,1H),3.19(q,2H),1.42(t, 3H).

1-benzenesulfonyl-2-ethyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine [ D011]

Following the procedure described in scheme 2, 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine was substituted for 1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] pyridine to give the title compound [ D011] as a pale yellow solid. LCMS method 5, RT 6.42min, MI 413[ M + H ]; LCMS method 1LCMS5,6.42min, MI:413[ M +1 ].

The following compounds were synthesized following the general synthesis shown in scheme [ D1 ]:

general Synthesis scheme D3 for substituted 4-substituted-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -azaquinazoline derivatives of the general formula [ I-001]

General formula [ I-001]4-substituted-2- (1H-pyrrolo [2, 3-b) of (A)]Pyridin-4-yl) -azaquinazoline derivatives were prepared as follows: general formula [ I-010]With a strong base such as LDA in a polar aprotic solvent such as THF, a symmetrical anhydride such as di-tert-butyl dicarbonate at low temperatures to give the general formula [ I-011]Halogen substituted-isonicotinic acid tert-butyl ester derivatives of (a). After work-up of the reaction, usually by liquid-liquid extraction, the intermediates are purified by column chromatography. Then the general formula [ I-011 ]]Halogen substituted-isonicotinic acid tert-butyl ester derivatives of general formula [ I-018]Boric acid or borate ester derivative of (a), palladium catalyst such as Pd (PPh)₃)₄Bases such as K₂PO₄Carrying out a palladium-catalyzed cross-coupling reaction of the Suzuki type in a polar aprotic solvent such as DMA or DMF at elevated temperatures obtained by heating or using a microwave reactor to give the general formula [ I-012]Substituted-isonicotinic acid tert-butyl ester derivatives. After work-up of the reaction, usually by liquid-liquid extraction, the intermediates are purified by column chromatography. Then tert-butyl ester intermediate [ I-012]]The deprotection reaction is carried out in a polar protic solvent such as ethanol in the presence of a base such as sodium hydroxide to give the general formula [ I-013]Followed by the coupling of a substituted-isonicotinic acid derivative of the general formula [ I-013 ] with a suitable coupling agent, e.g. O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)]Substituted-isonicotinic acid derivatives of formula [ I-014]Substituted 1H-pyrrolo [2,3-b ] of]Pyridine-4-carboxamidine derivatives are coupled in polar aprotic solvents such as DMA or DMF. Then the general formula [ I-015 ] can be reacted]Cyclizing the isonicotinyl-amidine derivative so as to replace the relevant halogen group to obtain the general formula [ I-016]To the desired 2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -pyrido [3,4-d]A pyrimidin-4-ol derivative. General formula [ I-001]4-substituted-2- (1H-pyrrolo [2, 3-b) of (A)]Pyridin-4-yl) -azaquinazoline derivatives were prepared as follows: general formula [ I-016]2- (1H-pyrrolo [2, 3-b) of (1)]Pyridin-4-yl) -pyrido [3,4-d]The pyrimidin-4-ol derivative is reacted with a chlorinating agent, such as phosphoryl chloride, to give the compound of formula (la), and then the intermediate 4-chloro derivative is further reacted with the compound of formula [ I-017]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature [ method A ]]. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by normal phase silica gel chromatography or reverse phase preparative HPLC. General formula [ I-001]4-substituted-2- (1H-pyrrolo [2, 3-b) of (A)]Pyridin-4-yl) -azaquinazoline derivatives were prepared as follows: general formula [ I-016]Is (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ol derivatives with 2,4, 6-triisopropylbenzenesulfonyl chloride in tertiary alkyl amine bases such as Et₃N, DIPEA or NMM with catalytic amounts of DMAP in polar aprotic solvents such as DMA, DMF, NMP [ method B]. Then intermediate 6, 7-substituted-, (2,4, 6-triisopropyl-benzenesulfonic acid) - (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl esters with the general formula [ G-117 ]]In a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature. After work-up of the reaction, usually by liquid-liquid extraction, or purification by acidic ion exchange capture-release, the N-Boc derivative is treated under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄Deprotection is carried out in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product is purified by reverse phase preparative HPLC.

Scheme D3

Synthesis of 5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1209]

3-bromo-5-fluoro-isonicotinic acid tert-butyl ester [ D013]

To a solution of LDA (2M, 72mL, 144mmol) in THF (100mL) at-78 deg.C was added dropwise via catheter a solution of 3-bromo-5-fluoropyridine (21.12g, 120mmol) in THF (50mL) pre-cooled to-78 deg.C. During the addition, the internal temperature did not rise above-65 ℃. The dark red-brown solution was stirred for 1 hour. Di-tert-butyldicarbonate (52.4g, 240mmol) in THF (50mL) was cooled to-10 deg.C in a methanol/ice bath, and the dark red-brown solution was then added dropwise through a catheter. The mixture was stirred for 2 hours, then allowed to warm to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride (100mL) was added slowly followed by water (200mL) and ethyl acetate (200mL) and the mixture stirred vigorously for 45 minutes. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The THF and ethyl acetate layers were combined, dried over magnesium sulfate, filtered and evaporated. The recovered dark red-brown oil was purified by column chromatography (cyclohexane/AcOEt: 1/0 to 97/3). The fractions containing the desired material were concentrated in vacuo (14g, 85%). LCMS method 5, RT 5.44min, MI 277[ M + H ]; NMR (1H,500MHz, CDCl3)8.56(s,1H),8.43(s,1H),1.62(s, 9H).

3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester [ D014]

A solution of 3-bromo-5-fluoro-isonicotinic acid tert-butyl ester [ D013] (5.52g, 20mmol), tripotassium phosphate (12.74g, 60mmol) and cyclopropylboronic acid (2.58g, 30mmol) in dioxane (100mL) was treated with vacuum/argon balloon (three times). Dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloromethane adduct (0.408g, 0.5mmol) was added and the reaction was heated at 96 ℃ overnight under a positive pressure of nitrogen. The mixture was cooled to room temperature, filtered through a pad of 200g silica and washed with ethyl acetate (1L). The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (cyclohexane/AcOEt: 98:2 to 96: 4). The combined fractions were concentrated under reduced pressure to give the title compound [ D014] (3.42g, 72%) as a colorless oil. LCMS method 5, RT5.36min, MI 238[ M + H ]; NMR (1H,500MHz, CDCl3), 8.33(s,1H),8.15(s,1H),2.05-2.00(m,1H),1.62(s,9H),1.04-1.009m,2H),0.82-0.78(m, 2H).

3-cyclopropyl-5-fluoro-isonicotinic acid [ D015]

In a microwave vial, 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester [ D014] (1.186g, 5mmol) was dissolved in methanol and then heated in the microwave at 140 ℃ for 1 hour. The reaction was concentrated in vacuo to give 0.84g (92%) of the title compound [ D015] as a white crystalline solid. LC-MS 1NJM406_1_28Jul 2011; 1.51min, 87%; 182 +; 1LCMS 5.

3-cyclopropyl-5-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -methyl ] -isonicotinamide [ D016]

3-cyclopropyl-5-fluoro-isonicotinic acid [ D015] (0.681g, 3.76mmol), HATU (1.43g, 3.76mmol) and diisopropylethylamine (2.29mL, 13.16mmol) were stirred in DMF (5 mL). After 1H, 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate (0.92g, 3.76mmol) was added. After stirring for 18 hours, the mixture was poured into water (180ml), stirred for 2 hours, and then the white solid was collected by filtration and washed with water to give the title compound [ D016] as a white solid, which was used without further purification. LCMS method 5, RT 3.22min, MI 324[ M + H ].

5-cyclopropyl-2-pyridin-4-yl-pyrido [3,4-D ] pyrimidin-4-ol [ D017]

A mixture of N- [ (2-chloro-pyridin-4-yl) -imino-methyl ] -3-cyclopropyl-5-fluoro-isonicotinamide [ D016] (1.164g, 3.6mmol) and Cs2CO3(1.18g, 3.60mmol) in DMA (12mL) was heated at 90 ℃ overnight. The reaction mixture was poured into water (20ml), and acidified by dropwise addition of acetic acid at 0 ℃. The beige precipitate (0.474g, 43%) was collected by filtration and washed with water to give the title compound [ D017], which was used without further purification. LCMS method 5, RT 4.58min, MI 304[ M + H ]; NMR (1H,500MHz, d6-dmso)12.12(brs,1H),9.09(s,1H),8.54(d,1H),8.37(s,1H),7.90(d,1H),7.83(s,1H),7.36(s,1H),3.56-3.64(m,1H),1.24-1.30(m,2H),1.08-1.14(m, 2H).

4- [ 5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ D018]

To a solution of 5-cyclopropyl-2-pyridin-4-yl-pyrido [3,4-D ] pyrimidin-4-ol [ D017] (0.47g, 1.55mmol) in DMF (25mL) was added DIPEA (0.809mL, 4.65mmol) and DMAP (5 mg). 2,4, 6-triisopropylbenzenesulfonyl chloride (0.563g, 1.86mmol) was then added and the mixture was stirred for 2 hours. N-Boc-piperazine (0.318g, 1.705mmol) was then added and the mixture was stirred overnight. Water (60-70mL) was added and the solution was stirred at room temperature for 15 minutes. The resulting solid was collected and washed twice with water. The solid was dissolved in DCM and purified by column chromatography (eluent: DCM/methanol gradient 0% to 10% methanol) to give the title compound as a dark brown gum (0.6g, 82%) which was used in the next step without further purification. LCMS method 5, RT 5.85min, MI 472[ M + H ].

5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1209]

To a solution of 4- [ 5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ D018] (0.6g, 1.27mmol) in DCM (15mL) was added HCl (4N, dioxane, 2mL) and the resulting bright yellow suspension was stirred at room temperature for 90 minutes. The solution was concentrated under reduced pressure and dissolved in methanol, added to a SCX-2 cartridge (10g) and washed with methanol/DCM (1:1, 40mL) and methanol (20 mL). The SCX-2 cartridge was then washed with ammonia (7N in methanol, 30 mL). The ammonia wash was concentrated in vacuo and the material purified by column chromatography (eluent: DCM/methanol gradient 0-20% methanol/DCM). The fractions were combined and concentrated under reduced pressure to give the title compound [1009 ]: LCMS method 5, RT2.65min, MI 372[ M + H ]; NMR (1H,500MHz, d6-dmso)11.82(brs,1H),9.13(s,1H),8.36(d,1H),8.10(d,1H),7.62(t,1H),7.45(dd,1H),3.50-3.90(m,4H),2.88-2.91(m,4H),2.66-2.69(m,1H),1.22-1.27(m,2H),1.02-1.06

Synthesis of 8-chloro-5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1210]

5-bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester [ D019]

5-bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester was prepared as a colorless oil by the reaction of 5-bromo-2-chloro-3-fluoropyridine, LDA (2M), di-tert-butyl dicarbonate and THF following the procedure described in scheme D31 [ D019 ]. LCMS method 5, RT 6.25min, MI 311[ M + H ].

S2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester [ D020]

Following the procedure described in scheme D3, 5-bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester was reacted with cyclopropylboronic acid to give 2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester [ D020 ]. LCMS method 5, RT 6.19min, MI272[ M + H ].

2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid [ D021]

2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester [ D020] (815mg, 3.00mmol) was suspended in 2-propanol (9mL) and HCl (5mL of a 4M solution in dioxane) was added. The reaction mixture was heated to 50 ℃ overnight. The reaction mixture was concentrated under reduced pressure to give the title compound [ D021] (530mg, 82%) as a white crystalline solid, which was used without purification. LCMS method 5, RT 0.91min, MI 216[ M + H ].

2-chloro-5-cyclopropyl-3-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -methyl ] -isonicotinamide [ D022]

Following the procedure described in scheme D3, 2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid [ D021] was reacted with 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine to give the title compound [ D022 ]. LCMS method 5, RT4.45min, MI 358[ M + H ].

8-chloro-5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-ol [ D023]

Following the procedure described in scheme D3, 2-chloro-5-cyclopropyl-3-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -methyl]-isonicotinamide [ D022]And Cs₂CO₃Reacted to give the title compound [ D023]. LCMS method 5, RT 4.87min, MI 306[ M + H ]]。

4- [ 8-chloro-5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ D024]

Following the procedure described in scheme D3, 8-chloro-5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-ol [ D023] was reacted with 1-Boc-piperazine to give the title compound [ D024 ]. LCMS method 5, RT 6.05min, MI 506[ M + H ].

8-chloro-5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1210]

Following the procedure described in scheme D3, tert-butyl 4- [ 8-chloro-5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylate [ D024] was reacted with 4N HCl in dioxane to give the title compound [1210 ]: LCMS method 5, RT 3.22min, MI 406[ M + H ].

Synthesis of 5-isopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1211]

3-fluoro-5-isopropenyl-isonicotinic acid tert-butyl ester [ D025]

Following the procedure described in scheme D3, 3-bromo-5-fluoro-isonicotinic acid tert-butyl ester [ D013] was reacted with pinacol isopropylborate (containing phenothiazine as stabilizer) with dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloromethane adduct as catalyst to give 3-fluoro-5-isopropenyl-isonicotinic acid tert-butyl ester [ D025 ]. LCMS method 5, RT5.41min, MI 238[ M + H ].

3-fluoro-5-isopropyl-isonicotinic acid tert-butyl ester [ D026]

3-fluoro-5-isopropenyl-isonicotinic acid tert-butyl ester [ D025] in ethanol]Ammonium formate and palladium on charcoal (5% w/w) were added and the mixture was heated at 60 c overnight. More ammonium formate was added and the mixture was stirred at 60 ℃ for an additional 45 minutes, then allowed to cool to room temperature and stirred overnight. The mixture was filtered through a pad of celite, washing with ethyl acetate. Water was added to the filtrate and the layers were separated. The organic phase was washed with MgSO₄Dried and concentrated in vacuo. The crude product is purified by column chromatography (gradient cyclohexane/ethyl acetate: 1:0 to 92: 8). The combined fractions were concentrated under reduced pressure to give the title compound [ D026 as a pale yellow oil](0.34g, 37%). LCMS method 5, RT 5.55min, MI 240[ M + H ]]；NMR:(1H,500MHz,CDCl3)8.42(1H,s),8.35(1H,s),3.09(1H,sept),1.60(9H,s),1.33(6H,d)。

3-fluoro-5-isopropyl-isonicotinic acid [ D027]

To a solution of 3-fluoro-5-isopropyl-isonicotinic acid tert-butyl ester [ D026] (0.335g, 1.4mmol) in isopropanol (5mL) was added HCl solution (4N in dioxane, 1mL) and the solution was warmed to 50 ℃ overnight. LC-MS showed some progress, but not completion. HCl (4N in dioxane, 1mL) was added again and left overnight at 50 ℃. The reaction was not yet complete, so more HCl (4N in dioxane, 1mL) was added and left for a full day (. about.6-7 hours). The solution was concentrated in vacuo to give the title compound [ D027] as an off-white solid, which was used without further purification and analysis.

3-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -methyl ] -5-isopropyl-isonicotinamide [ D028]

Following the procedure described in scheme D3, 3-fluoro-5-isopropyl-isonicotinic acid [ D027] was reacted with 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine to give 3-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -methyl ] -5-isopropyl-isonicotinamide [ D028 ]. LCMS method 5, RT 3.67min, MI 326[ M + H ].

5-isopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-ol [ D029]

Following the procedure described in scheme D3, with Cs₂CO₃Treatment of 3-fluoro-N- [ imino- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -methyl]-5-isopropyl-isonicotinamide [ D028]To obtain 5-isopropyl-2- (1H-pyrrolo [2,3-b ] as a brown solid]Pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-ol [ D029]. LCMS method 5, RT 4.87min, MI 306[ M + H ]]。

4- [ 5-isopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ D030]

Following the procedure described in scheme D3, 5-isopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-ol [ D029] was treated with 1-Boc-piperazine to give the title compound [ D030] as a brown solid. LCMS method 5, RT 5.78min, MI 474[ M + H ].

5-isopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine [1211]

Following the procedure described in scheme D3, 4- [ 5-isopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-D ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid tert-butyl ester [ D030] was treated with 4N HCl to give the title compound [1211] as a brown solid. LCMS method 5, RT 2.82min, MI 374[ M + H ], NMR (1H,500MHz, CDCl3)9.28(1H, s),9.0(1H, br s),8.61(1H, s),8.46(1H, s),8.23(1H, d),7.63(1H, s),7.47(1H, s),4.07(1H, M),3.86(2H, M),3.49(2H, M),3.11(4H, M),1.25(6H, d).

General Synthesis scheme D4 for substituted 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine derivatives of general formula [ I-012]

A substituted 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine derivative of the general formula [ I-012] is prepared by: tert-butyl 2-methylpyridin-2-ylcarbamate derivatives of the general formula [ I-019] are reacted with a polar aprotic solvent such as a strong base in THF, e.g., nBuLi, and substituted Weinreb amide derivatives of the general formula [ I-025] at low temperatures, and then reacted with an inorganic acid such as hydrochloric acid at high temperatures to give 1-H-pyrrolo [2,3-b ] pyridine derivatives of the general formula [ I-020], which are purified by column chromatography after the reaction usually carried out by liquid-liquid extraction. The 1-H-pyrrolo [2,3-b ] pyridine derivative of the general formula [ I-020] is then subjected to pyridine N-oxidation using an oxidizing reagent such as mCPBA in a solvent such as DCM. The intermediate 1-H-pyrrolo [2,3-b ] pyridine-7-oxide derivative of general formula [ I-021] is then reacted with a chlorinating agent such as methanesulfonyl chloride in a polar aprotic solvent such as DMF at elevated temperature, after work-up of the reaction, typically by liquid-liquid extraction, the intermediate is purified by column chromatography. The intermediate 4-chloro-1H-pyrrolo [2,3-b ] pyridine derivative of general formula [ I-022] is then subjected to a palladium catalyzed cross-coupling reaction using a cyanide such as zinc cyanide, a palladium catalyst such as dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloromethane adduct, zinc powder in a polar aprotic solvent such as DMF at elevated temperature, and after work-up of the reaction, typically by liquid-liquid extraction, the intermediate is purified by column chromatography. The intermediate 1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile derivative of the general formula [ I-023] is then reacted with hydroxylamine (50% w/w in water) and a polar protic solvent such as ethanol at elevated temperature. The intermediate N-hydroxy-1H-pyrrolo [2,3-b ] pyridine-4-carboxamide of formula [ I-024] is then subjected to hydrogenolysis using acetic anhydride in a polar protic solvent such as methanol, palladium on a palladium catalyst such as activated carbon under a hydrogen atmosphere to give the substituted 1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine derivative of formula [ I-012], scheme D4.

Scheme D4

Synthesis of 2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D036]

Step 1 2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine [ D031]

To a solution of (3-methyl-pyridin-2-yl) -carbamic acid tert-butyl ester (5g, 24mmol) in THF (50mL) at-30 deg.C was added BuLi (2.5M, 28.5mL, 72mmol) and the reaction mixture was warmed to 0 deg.C and stirred for 90 min. A solution of 2,2, 2-trifluoro-N-methoxy-N-methylacetamide (2.9mL, 24mmol) in THF (10mL) was slowly added and the reaction stirred at 0 deg.C for 3 hours. The reaction mixture was slowly treated with HCl (30mL, 6M) and then heated at 60 ℃ for 18 hours. The reaction mixture was cooled, the layers were separated, the aqueous layer was basified with NaOH (5M), and extracted twice with ethyl acetate. The combined organic layers (plus the organic layer from the first extraction) were washed over MgSO₄Dried on top, concentrated and the residue purified by column chromatography (eluent cyclohexane/ethyl acetate, 1/0 to 8/2) to give the title compound [ D031] as a yellow solid](1.2g, 27%): LCMS method 5, RT 4.44min, MI 187[ M + H],NMR:(1H,500MHz,d6-dmso)14.33(brs,1H),8.49(d,1H),8.09(d,1H),7.27(dd,1H),6.90(s,1H)。

2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine 7-oxide [ D032]

2-trifluoromethyl-1H-pyrrolo [2,3-b ] in DCM (10mL)]Pyridine [ D031]](1.2g, 6.45mmol) of 3-chloroperoxybenzoic acid (1.22g, 7.09mmol) was added to the solution and the mixture was stirred overnight. Adding NaHCO₃The layers were separated. The organic phase was washed with MgSO₄Dried and concentrated under reduced pressure. The title compound [ D032] was obtained as a yellow solid](0.82g, 63%) was used without further purification. LCMS method 5, RT 3.43min, MI 203[ M + H ]],NMR:(1H,500MHz,d6-dmso)8.34(d,1H),7.76(d,1H),7.19(d,1H),7.18(s,1H),

4-chloro-2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine [ D033]

To a solution of 2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine 7-oxide [ D032] (0.82g, 4.05mmol) in DMF (10mL) at 50 ℃ methanesulfonyl chloride (1.57mL, 20.28mmol) was added dropwise. The solution was stirred at 50 ℃ for 3 hours. The reaction was then cooled to room temperature and water (5mL) was added. A solution of 5M NaOH was added and the solid was collected and dried using an azeotrope containing toluene to give the title compound [ D032] which was used without further purification. LCMS:1LCMS55.77min, 221-.

2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D034]

Filling a sealable bottle with 4-chloro-2-trifluoromethyl-1H-pyrrolo [2,3-b ]]Pyridine [ D033](0.6g, 2.72mmol), dichloro [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloromethane adduct (0.222g, 0.27mmol), zinc cyanide (0.958g, 8.16mmol), zinc (powder, 0.036g, 0.54mmol), and DMF (15 mL). The caps were capped and heated at 90 ℃ overnight. The reaction was poured into water and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, the organic phases were combined, washed with water and brine and over MgSO₄Drying to obtain the title compound [ D043]Its use without further purification: LCMS method 5, RT 4.98min, MI 212[ M + H]。

N-hydroxy-2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D035]

A mixture of 2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D034] (0.68g, 3.22mmol) and hydroxylamine (50% w/w in water, 0.205mL, 6.44mmol) and ethanol (5mL) was heated at 80 deg.C overnight. The solvent was then evaporated and the mixture was azeotroped twice with toluene under vacuum. The title compound [ D035] (0.78g, 99%) was obtained as a yellow solid, which was used in the next step without further purification: LCMS method 5, RT 2.22min, MI 245[ M + H ], NMR (1H,500MHz, d6-dmso):13.14(brs,1H),10.40(s,1H),8.70(s,1H),7.70(s,1H),7.56(d,1H),6.27(s, 2H).

2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine; compounding with acetic acid [ D036]

N-hydroxy-2-trifluoromethyl-1H-pyrrolo [2,3-b ] in methanol (10mL) at room temperature]Pyridine-4-carboxamidine [ D035]](0.43g, 1.76mmol) acetic anhydride (0.175mL, 1.85mmol) was added dropwise to the suspension. The suspension was stirred for 15 minutes and palladium on charcoal (5% w/w, 0.1g) was added. The vessel was sealed, hydrogen (balloon) was bubbled through the mixture for 10 minutes, and left to stir at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through celite and concentrated in vacuo to give the title compound [ D036] as a yellow solid](0.51g, 100%) and used without further purification. LCMS method 5, RT4.45min, MI 229[ M + H],NMR:(1H,500MHz,d6-dmso)1.79(s,3H,CH₃CO₂H),8.50(s,1H),7.35(s,1H),7.03(s,1H)。

Synthesis of 2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D042]

2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine [ D037]

Prepared according to the procedure described in scheme D4, step 1, by reaction of (3-methyl-pyridin-2-yl) -carbamic acid tert-butyl ester, thiophene-2-carboxylic acid methoxy-methyl-amide, BuLi and THF to give the title compound as a yellow solid. LCMS method 5, RT 4.79min, MI 201[ M + H ].

2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine 7-oxide [ D038]

Prepared according to the procedure described in scheme D4, step 2, by reaction of 2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine [ D037], m-CPBA and DCM to give the title compound as a yellow solid. LCMS method 5, RT3.38min, MI 217[ M + H ].

4-chloro-2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine [ D039]

Prepared according to the procedure described in scheme D4, step 3, by reaction of 2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine 7-oxide [ D038], methanesulfonyl chloride and DMF to give the title compound as a yellow solid. LCMS method 5, RT 6.05min, MI 235[ M + H ].

2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D040]

Following the procedure described in scheme D4 step 4, by 4-chloro-2-thiophen-2-yl-1H-pyrrolo [2,3-b ]]Pyridine [ D039]]、PdCl₂dppf:CH₂Cl₂The reaction of zinc cyanide, zinc powder and DMA was carried out to give the title compound as a yellow solid. LCMS method 5, RT 5.28min, MI 226[ M + H]。

N-hydroxy-2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D041]

Prepared according to the procedure described in scheme D4, step 5, by reaction of 2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D040], hydroxylamine and ethanol to give the title compound as a yellow solid. LCMS method 5, RT2.38min, MI 259[ M + H ].

2-Thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D042]

Prepared according to the procedure described in scheme D4, step 6, by reaction of N-hydroxy-2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetic anhydride [ D041], Pd/C, hydrogen and methanol to give the title compound as a yellow solid. LCMS method 5, RT4.45min, MI 243[ M + H ].

Synthesis of 2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D045]

2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D043]

Following the procedure described in scheme D4 step 4, by 4-chloro-2-methyl-1H-pyrrolo [2,3-b ]]Pyridine, PdCl₂dppf:CH₂Cl₂The reaction of zinc cyanide, zinc powder and DMA was carried out to give the title compound as a white solid. LCMS method 5, RT 4.17min, MI 158[ M + H]。

N-hydroxy-2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D044]

Prepared according to the procedure described in scheme D4, step 5, by reaction of 2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile [ D043], hydroxylamine and ethanol to give the title compound as a yellow solid. LCMS method 5, RT1.92min, MI 191[ M + H ].

2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D045]

Prepared according to the procedure described in scheme D4, step 6, by reaction of N-hydroxy-2-methyl-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D044], acetic anhydride, Pd/C, hydrogen and methanol to give the title compound as a yellow solid. LCMS method 5, RT 2.44min, MI 175[ M + H ].

Synthesis of, for example, 21H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D047]

N-hydroxy-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D047]

Prepared according to the procedure described in scheme D4, step 5, by reaction of 1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile, hydroxylamine and ethanol to give the title compound as a yellow solid. LCMS method 5, RT 1.24min, MI 162[ M + H ].

2-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine acetate [ D047]

Prepared according to the procedure described in scheme D4, step 6, by reaction of N-hydroxy-1H-pyrrolo [2,3-b ] pyridine-4-carboxamidine [ D047], acetic anhydride, Pd/C, hydrogen and methanol to give the title compound as a yellow solid. LCMS method 5, RT 1.23min, MI 161[ M + H ], NMR (1H,500MHz, d6-dmso)8.38(1H, d),7.71(1H, d),7.30(1H, d),6.58(1H, d),1.80(8H, s)

Following the procedure described in example AZA-9, the following compound was prepared from 3-cyclopropyl-5-fluoro-isonicotinic acid:

the following compounds were synthesized following the general synthesis shown in scheme [ B4 ]:

example 1253.4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole trifluoroacetate

1253a) Azeotropic drying of (xylene) 4-chloro-9H-pyrido [2,3-b ]]A mixture of indole (1.31g, 6.46mmol), zinc cyanide (1.21g, 10.3mmol), zinc (0.145g, 2.22mmol), tris (dibenzylideneacetone) dipalladium (0) (0.479g, 0.523mmol) and 1,1' -bis (diphenylphosphino) ferrocene (0.375g, 0.676mmol) in N, N-dimethylformamide (27mL) was degassed under vacuum and then heated at 100 ℃ under argon overnight. The mixture was cooled and poured with water: in ethyl acetate (2:1, 150 mL). The layers were separated, the aqueous phase was extracted with ethyl acetate (2X50mL), and the combined organic extracts were diluted with hexane (15mL) and brine (100 mL). Removing fine suspended solid particles by filtering the aqueous phase with diatomaceous earth, and filtering with a filterAlcohol and ethyl acetate washes. The organic extracts and the water/organic rinse were combined, separated, and the organic layer was washed with additional brine (100mL), dried over magnesium sulfate, filtered, and concentrated under vacuum on silica gel (12g), followed by purification on silica gel (80g, 5-35% ethyl acetate: hexanes). 9H-pyrido [2,3-b ] isolated as a yellow solid]Indole-4-carbonitrile (0.830g, 66% yield). LCMS (ESI) 194(M + H)⁺；¹H-NMR(DMSO-d₆,400MHz):12.45(s,1H),8.63(d,1H,J＝5.0Hz),8.32(d,1H,J＝8.0Hz),7.68(d,1H,J＝5.0Hz),7.64(m,2H),7.40(m,1H)；¹³C-NMR(DMSO-d₆,100MHz):151.6,146.2,139.7,128.6,121.1,120.5,117.9,116.9,116.7,114.1,112.0,109.8。

1253b) 9H-pyrido [2,3-b ] in tetrahydrofuran (12.0mL, 148mmol) under a nitrogen atmosphere at room temperature]A suspension of indole-4-carbonitrile (0.422g, 2.18mmol) was added to lithium hexamethyldisilylamide (1.0M, 7.0mL, 7.0mmol) in tetrahydrofuran. Additional lithium hexamethyldisilylamide (1.0M, 7mL) in tetrahydrofuran was added over 48 hours to drive the reaction to completion. After stirring for a total of 72 hours, the mixture was diluted with water (50mL), and the resulting solid was collected by filtration, washed with water and dried on a buchner funnel and in vacuo. 9H-pyrido [2,3-b ] isolated as a beige solid]Indole-4-carboxamidine (0.297g, 65% yield) was used without further purification. LCMS (ESI) 211(M + H)⁺。

1253c) Reacting 9H-pyrido [2,3-b ]]Indole-4-carboxamidine (0.295g, 1.40mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (0.806g, 2.12mmol), 3-cyclopropyl-5-fluoro-isonicotinic acid (0.320g, 1.76mmol) and N, N-diisopropylethylamine (0.750mL, 4.30mmol) were combined in N, N-dimethylformamide (8.0mL) and stirred for 90 min. The mixture was poured into ethyl acetate (50mL) and washed with water (2X5 mL). The combined water washes were extracted with ethyl acetate (3X15mL) and combined with the first organic extract, washed with brine (30mL), dried over sodium sulfate, filtered and concentrated in vacuo. Reacting 3-cyclopropyl-5-fluoro-N- [ imino- (9H-pyrido [2,3-b ]]Indol-4-yl) -methyl]Crude isonicotinamide with N, N-dimethylformamideCesium carbonate (0.914g, 2.81mmol) in (14.0mL) was combined and heated at 90 ℃ under nitrogen overnight. The mixture was concentrated in vacuo onto silica gel (4.5g) and then purified (silica gel 40g, 0-10% methanol: DCM) to give 5-cyclopropyl-2- (9H-pyrido [2,3-b ]]Indol-4-yl) -3H-pyrido [3,4-d]Pyrimidin-4-one (0.230 g; yield 46.4%). LCMS (ESI):354(M + H)⁺。

1253d) 5-cyclopropyl-2- (9H-pyrido [2,3-b ] in N, N-dimethylformamide (1.00mL)]Indol-4-yl) -3H-pyrido [3,4-d]Pyrimidin-4-one (18mg, 0.051mmol), 2,4, 6-triisopropylbenzenesulfonyl chloride (17.5mg, 0.0578mmol), 4-dimethylaminopyridine (1.0mg, 0.0082mmol) and triethylamine (35.0 μ L, 0.251mmol) were stirred at room temperature under nitrogen for 1 hour, then a solution of piperazine (74.0mg, 0.859mmol) in N, N-dimethylformamide (1.0mL) was added and stirring was continued for 3 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (0-45% acetonitrile: water, 0.1% trifluoroacetic acid) to give 4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3, 4-d) as a yellow lyophilizate]Pyrimidin-2-yl) -9H-pyrido [2,3-b]Indole trifluoroacetate (10.0 mg; yield: 37%). LCMS (ESI) 422(M + H)⁺；¹H-NMR(DMSO-d₆,400MHz):12.08(s,1H),9.17(s,1H),8.83(br s,1H),8.68(d,1H,J＝8.4Hz),8.59(d,1H,J＝5.1Hz),8.26(s,1H),7.89(d,1H,J＝5.1Hz),7.55(d,1H,J＝7.9Hz),7.49(m,1H),7.18(m,1H),3.68(br s,4H),3.34(br s,4H),2.77(m,1H),1.30(m,2H),1.14(m,2H)。

Example 1254.1- [ 5-cyclopropyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol trifluoroacetate

In analogy to example 1253d, 5-cyclopropyl-2- (9H-pyrido [2, 3-b)]Indol-4-yl) -3H-pyrido [3,4-d]Pyrimidin-4-one (44.0mg, 0.124mmol) was reacted with piperidin-4-ol (34.0mg, 0.336mmol) to give 1- [ 5-cyclopropyl-2- (9H-pyrido [2,3-b ] as a yellow lyophilizate]Indol-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-piperidin-4-ol trifluoroacetate (32 mg; yield ═ 47%). LCMS (ESI) 437(M + H)⁺；¹H-NMR(DMSO-d₆,400MHz):12.12(s,1H),9.07(s,1H),8.60(d,1H,J＝5.0Hz)8.54(d,1H,J＝8.1Hz),8.22(s,1H),7.84(d,1H,J＝5.0Hz),7.56(d,1H,J＝8.0Hz),7.49(m,1H),7.17(m,1H),4.11(m,3H),3.58(br s,2H),2.61(m,1H),1.89(m,2H),1.55(m,2H),1.92(m,2H),1.21(m,2H)。

Example 1255.4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -9H-pyrido [2,3-b ] indole trifluoroacetate

In analogy to example 1253d, 5-cyclopropyl-2- (9H-pyrido [2, 3-b)]Indol-4-yl) -3H-pyrido [3,4-d]Pyrimidin-4-one (52.5mg, 0.148mmol) was reacted with 2, 2-dimethylpiperazine (31.4mg, 0.275mmol) to give 4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] as a yellow lyophilizate]Pyrimidin-2-yl]-9H-pyrido [2,3-b]Indole trifluoroacetate (17.5 mg; yield ═ 21%). LCMS (ESI) 450(M + H)⁺；¹H-NMR(DMSO-d₆,400MHz):12.09(s,1H),9.17(s,1H),9.05(br s,2H),8.67(d,1H,J＝8.1Hz),8.60(d,1H,J＝5.1Hz),8.29(s,1H),7.93(d,1H,J＝5.1Hz)7.55(d,1H,J＝7.9Hz),7.49(m,1H),7.18(m,1H),3.93(m,4H),3.39(m,2H),2.61(m,1H),1.01-1.48(m,10H)。

Following the general synthesis shown in any of the schemes provided above, the following compounds were synthesized using similar procedures, starting materials and intermediates.

General Synthesis scheme D5 for 2-substituted-azaindole derivatives of general formula [ I-034]

General formula [ I-034]The 2-substituted azaindole derivatives of (a) are prepared by the following reaction: using palladium catalysts such as PdCl₂dppf∶CH₂Cl₂Cyanide reagents such as Zn (CN)₂Zinc powder in a polar aprotic solvent such as DMF at elevated temperature obtained by heating or using a microwave reactor]1-benzenesulfonyl-4-bromo-1H-pyrrolo [2,3-b ] of]The pyridine derivative is subjected to palladium-catalyzed cross-coupling reaction. The crude product was purified by column chromatography. Then the general formula [ I-031 ]]1-benzenesulfonyl-1H-pyrrolo [2,3-b ] of]Pyridine-4-carbonitrile derivatives with strong bases such as LDA in polar aprotic solvents such as THF at low reaction temperatures such as-78 deg.C, with electrophiles such as ketones, general formula [ I-035 ]]To a disulfide or halogenating agent such as NIS or NCS to give the general formula [ I-032]2-substituted 1-benzenesulfonyl-1H-pyrrolo [2,3-b ] of]Pyridine-4-carbonitrile derivatives, after work-up by reaction, usually by liquid-liquid extraction, are purified by column chromatography. General formula [ I-032]Is deprotected by reaction with a fluoride reagent such as TBAF in a polar aprotic solvent such as THF to give the general formula [ I-033]A reaction intermediate of (1). Then the general formula [ I-033]With hydroxylamine (50% w/w in water) and a polar protic solvent such as ethanol at elevated temperature. Then the intermediate N-hydroxy-1H-pyrazolo [3,4-b]Pyridine-4-formamidine

Biology, VI

₅₀Iota IC assay of PKC

The assay is based on the ability of PKC iota to phosphorylate commercially available peptide substrates in vitro. The peptide substrate is a FAM-PKC pseudopeptide-derived peptide and comprises the amino acid sequence 5FAM-ERMRPRKRQGSVRRRV-NH₂. Recombinant full length human PKC iota expressed in Sf21 insect cells is also commercially available. Internally expressing and purifying the recombinant, kinase-domain human PKC iota.

The following procedure explains how to obtain a dose response curve for the inhibitor of PKC iota. The screen described is for the 384-well format, but the assay can be changed to 1536 or other formats as needed.

Test compounds were dissolved in 100% DMSO. Compounds were diluted as needed to give a final concentration of 4% DMSO (volume/volume) in the assay. Mu.l of the plate was plated in 384-well black, low-binding flat-bottom assay plates and used immediately. Using MatrixAnd MatrixPlus liquid handling system to dilute and add compounds to assay plates.

On the day of screening, PKC iota/substrate working solutions and ATP working solutions were prepared in a buffer containing 20mM tris-HCl, pH 7.5, 10mM MgCl2, 0.01% Triton X100, 250. mu.M EGTA and 1mM DTT. The final concentration of PKC iota used varied from protein batch to protein batch, but was typically 15 pM. The final concentration of peptide substrate in the assay was 100 nM. The final concentrations of ATP used in the assays containing the full-length or kinase-domain PKC iota were 150 μ M or 25 μ M, respectively, which correspond to the K of ATP for each enzyme, respectively_M ^APP5 times or equivalent to said K_M ^APP. The final buffer concentration in the assay was 18mM tris-HCl, pH 7.5, 9mM MgCl₂0.009% Triton X100, 225. mu.M EGTA and 0.9mMAnd (4) DTT. Relevant controls, i.e., no compound and no enzyme controls, were included. Using a 16-channel matrix pipette, 5. mu.l of 30pM and 200nM of the PKC iota/substrate working solution, respectively, were added to the wells followed by 4. mu.l of the ATP working solution at 375. mu.M or 62.5. mu.M for the full-length or kinase-domain PKC iota, respectively. The reaction was incubated at room temperature for 60 minutes and then incubated by adding 20. mu.l of IMAP^TMThe developer (Molecular Devices) terminates the reaction and develops. The IMAP imaging agent consists of 0.25% (v/v) IMAP step binding reagent, 17% (v/v) IMAP step binding buffer a and 3% (v/v) IMAP step binding buffer B. The plates are then incubated for 2 hours at room temperature, followed by reading using a suitable plate reader, such as Molecular Devices HT analysis or BMG Pheastar. The plate readings were performed using a fluorescence polarization protocol, excitation at 485nm, emission at 530nm, and dichroic mirror at 505 nm.

Percent inhibition values were calculated from fluorescence polarization values using no compound and no enzyme control values as 0% and 100% inhibition, respectively. IC Using excelFit software (IDBS), Using Curve fitting 205₅₀And (4) measuring. The Z' factor was determined for each plate tested and was higher than 0.5.

Alternatively, immobilized metal ion affinity particles are usedThe inhibitory ability of the compounds against baculovirus-expressed recombinant human PKC iota was determined by a fluorescence polarization detection system (Molecular Devices, Sunnyvale, CA). Preparation in 1 XT containing 1mM DTT 1 IMAP assay buffer (Molecular Devices)Substrate mixture (2X) to final assay concentrations of 15pM PKC iota (EMD Millipore, Billerica, MA) and 100nM 5-fluorescein-amidite (FAM) -PKC € -pseudo-substrate (5-FAM-ERMRPRKRQGSVRRRV-NH2) (molecular devices) to 384-well black, no binding flat-bottomed assay plates (Corning, Corning, NY) at 5. mu.L/well 2X working solution was added, and the combination was performed in 100% DMSOThe contents were serially diluted and then 100nL were transferred to assay plates containing 5. mu.L of 2 Xenzyme/substrate solution using a BioMek NX needle tool (Beckmann Coulter, Indianapolis, Ind.). The enzyme reaction was started by adding 5. mu.L of 2X ATP so that the final assay concentration was 150. mu.M. The assay plate was incubated for 1 hour at 25 ℃ in an incubator and then 20. mu.L was addedAnd (3) detecting the reagent. The detection reagent is diluted by 85% of 1 Xbuffer solution A, 15% of 1 Xbuffer solution B and 1:400And (3) a binding agent. The assay plates were then incubated in a 25 ℃ incubator for 2 hours. After incubation, Perkinelmer Envision was used^TMA2102 plate reader (PerkinElmer, Waltham, Mass.) measures fluorescence polarization at 480nm excitation wavelength and 535nm emission wavelength.

Results

Biological data for the example compounds are given in the table below. The activity is shown below:

IC against full-Length PKCi in IMAP assay at 150. mu.M ATP₅₀：

++++ ＝<100nM

100nM to 1,000nM +++, 2

1,000nM to 10,000nM

10,000nM to 40,000nM

Preferably, the compounds of the invention (i.e. the compound of formula (I) or a salt thereof) have an IC for the full length PKC iota at 150 μ M ATP in an IMAP assay₅₀Is composed of<40 μ M. In one embodiment, the compound of the invention has an IC for the full length PKC iota at 150 μ MATP in an IMAP assay₅₀The concentration is 40-10. mu.M. More preferably, the compounds of the present invention have IC against full length PKC iota at 150 μ MATP in IMAP assay₅₀Is 10 μ M to 1 μ M. In one embodiment, the compounds of the invention target the IC of full length PKC iota at 150 μ M ATP in an IMAP assay₅₀Is 1 μ M to 0.1 μ M. More preferably, the compounds of the invention target the IC of full length PKC iota at 150 μ M ATP in an IMAP assay₅₀Is composed of<0.1μM。

Preferably, a compound of the invention (i.e. a compound of formula (I) or a salt thereof) has an IC for the kinase domain PKC iota at 25 μ M ATP in an IMAP assay₅₀Is composed of<40 μ M. In one embodiment, a compound of the invention has an IC for the kinase domain PKC iota at 25 μ M ATP in an IMAP assay₅₀The concentration is 40-10. mu.M. More preferably, the compounds of the invention target the IC of the kinase domain PKC iota at 25 μ M ATP in an IMAP assay₅₀Is 10 μ M to 1 μ M. In one embodiment, a compound of the invention has an IC for the kinase domain PKC iota at 25 μ M ATP in an IMAP assay₅₀Is 1 μ M to 0.1 μ M. More preferably, the compounds of the invention target the IC of the kinase domain PKC iota at 25 μ M ATP in an IMAP assay₅₀Is composed of<0.1μM。

As will be appreciated by those skilled in the art, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein, and that the scope of the invention is intended to encompass all such variations.

Each of the publications referred to herein is incorporated by reference in its entirety for all purposes.

Claims (65)

1. A compound of formula (I)Or a salt form thereof, or a pharmaceutically acceptable salt form thereof,

wherein

G is formulaA group of (a);

x is selected from the group consisting of optionally substituted 1-6R¹⁹Substituted 5-6 membered heterocycloalkyl and-NR²⁴R²⁸；

R⁷Selected from H, C_3-6Cycloalkyl and-OR²⁰；

R⁸Is H; and R⁹Is H;

R¹²、R¹³、R¹⁴、R¹⁵independently selected from H, optionally substituted with 1-13R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-C(＝O)C(＝O)R²⁰、-C(＝NR²⁵)R²⁰、-C(＝NR²⁵)NR²²R²³、-C(＝NOH)NR²²R²³、-C(＝NOR²⁶)R²⁰、-C(＝NNR²²R²³)R²⁰、-C(＝NNR²⁴C(＝O)R²¹)R²⁰、-C(＝NNR²⁴C(＝O)OR²¹)R²⁰、-C(＝S)NR²²R²³、-NC、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-N＝NR²⁴、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴C(＝O)NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)NR²⁴C(＝O)OR²⁰、-NR²⁴C(＝NR²⁵)NR²²R²³、-NR²⁴C(＝O)C(＝O)NR²²R²³、-NR²⁴C(＝S)R²⁰、-NR²⁴C(＝S)OR²⁰、-NR²⁴C(＝S)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-NR²⁴P(＝O)R⁷⁸R⁷⁸、-NR²⁴P(＝O)(NR²²R²³)(NR²²R²³)、-NR²⁴P(＝O)(OR²⁰)(OR²⁰)、-NR²⁴P(＝O)(SR²⁰)(SR²⁰)、-OR²⁰、-OCN、-OC(＝O)R²⁰、-OC(＝O)NR²²R²³、-OC(＝O)OR²⁰、-OC(＝NR²⁵)NR²²R²³、-OS(＝O)R²⁰、-OS(＝O)₂R²⁰、-OS(＝O)₂OR²⁰、-OS(＝O)₂NR²²R²³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR²²R²³)(NR²²R²³)、-OP(＝O)(OR²⁰)(OR²⁰)、-OP(＝O)(SR²⁰)(SR²⁰)、-Si(R²⁴)₃、-SCN、-S(＝O)_nR²⁰、-S(＝O)₂OR²⁰、-SO₃R²⁷、-S(＝O)₂NR²²R²³、-S(＝O)NR²²R²³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR²²R²³)(NR²²R²³)、-SP(＝O)(OR²⁰)(OR²⁰)、-SP(＝O)(SR²⁰)(SR²⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR²²R²³)(NR²²R²³)、-P(＝O)(OR²⁰)(OR²⁰) and-P (═ O) (SR)²⁰)(SR²⁰)；

Or R¹²And R¹³、R¹⁴And R¹⁵May form, together with the atoms to which they are attached, an optionally substituted 1-11R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl;

R¹⁹independently at each occurrence is selected from the group consisting of optionally substituted 1-13R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R³⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R³⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-C(＝O)C(＝O)R³⁰、-C(＝NR³⁵)R³⁰、-C(＝NR³⁵)NR³²R³³、-C(＝NOH)NR³²R³³、-C(＝NOR³⁶)R³⁰、-C(＝NNR³²R³³)R³⁰、-C(＝NNR³⁴C(＝O)R³¹)R³⁰、-C(＝NNR³⁴C(＝O)OR³¹)R³⁰、-C(＝S)NR³²R³³、-NC、-NO₂、-NR³²R³³、-NR³⁴NR³²R³³、-N＝NR³⁴、＝NR³⁰、＝NOR³⁰、-NR³⁴OR³⁶、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)C(＝O)R³⁰、-NR³⁴C(＝O)OR³¹、-NR³⁴C(＝O)C(＝O)OR³¹、-NR³⁴C(＝O)NR³²R³³、-NR³⁴C(＝O)NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³⁴C(＝O)OR³⁰、-NR³⁴C(＝NR³⁵)NR³²R³³、-NR³⁴C(＝O)C(＝O)NR³²R³³、-NR³⁴C(＝S)R³⁰、-NR³⁴C(＝S)OR³⁰、-NR³⁴C(＝S)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-NR³⁴P(＝O)R⁷⁸R⁷⁸、-NR³⁴P(＝O)(NR³²R³³)(NR³²R³³)、-NR³⁴P(＝O)(OR³⁰)(OR³⁰)、-NR³⁴P(＝O)(SR³⁰)(SR³⁰)、-OR³⁰、＝O、-OCN、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-OC(＝O)OR³⁰、-OC(＝NR³⁵)NR³²R³³、-OS(＝O)R³⁰、-OS(＝O)₂R³⁰、-OS(＝O)₂OR³⁰、-OS(＝O)₂NR³²R³³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR³²R³³)(NR³²R³³)、-OP(＝O)(OR³⁰)(OR³⁰)、-OP(＝O)(SR³⁰)(SR³⁰)、-Si(R³⁴)₃、-SCN、＝S、–S(＝O)_nR³⁰、-S(＝O)₂OR³⁰、-SO₃R³⁷、-S(＝O)₂NR³²R³³、-S(＝O)NR³²R³³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR³²R³³)(NR³²R³³)、-SP(＝O)(OR³⁰)(OR³⁰)、-SP(＝O)(SR³⁰)(SR³⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR³²R³³)(NR³²R³³)、-P(＝O)(OR³⁰)(OR³⁰) and-P (═ O) (SR)³⁰)(SR³⁰)；

R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-13R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁴⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁴⁹Substituted 6-21 membered heteroarylalkyl;

R²⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁴⁹Substituted C_1-10Alkyl, optionally substituted with 1-11R⁴⁹Substituted C_2-10Alkenyl, optionally substituted by 1-9R⁴⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁴⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁴⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁴⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁴⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁴⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁴⁹Substituted 6-21 membered heteroarylalkyl;

R²²、R²³、R³²and R³³Independently at each occurrence selected from H, optionally substituted with 1-13R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁵⁹Substituted C_6-11Aryl radicalsOptionally substituted with 1-19R⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁵⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁵⁹Substituted 6-21 membered heteroarylalkyl;

or any R²²And R²³And/or R³²And R³³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R⁶⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R⁶⁹Substituted 5-15 membered heteroaryl;

R³⁹、R⁴⁹、R⁵⁹and R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁷⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R⁷⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R⁷⁰、-C(＝O)OR⁷⁰、-C(＝O)NR⁷²R⁷³、-C(＝O)C(＝O)R⁷⁰、-C(＝NR⁷⁵)R⁷⁰、-C(＝NR⁷⁵)NR⁷²R⁷³、-C(＝NOH)NR⁷²R⁷³、-C(＝NOR⁷⁶)R⁷⁰、-C(＝NNR⁷²R⁷³)R⁷⁰、-C(＝NNR⁷⁴C(＝O)R⁷¹)R⁷⁰、-C(＝NNR⁷⁴C(＝O)OR⁷¹)R⁷⁰、-C(＝S)NR⁷²R⁷³、-NC、-NO₂、-NR⁷²R⁷³、-NR⁷⁴NR⁷²R⁷³、-N＝NR⁷⁴、＝NR⁷⁰、＝NOR⁷⁰、-NR⁷⁴OR⁷⁶、-NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)C(＝O)R⁷⁰、-NR⁷⁴C(＝O)OR⁷¹、-NR⁷⁴C(＝O)C(＝O)OR⁷¹、-NR⁷⁴C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)R⁷⁰、-NR⁷⁴C(＝O)NR⁷⁴C(＝O)OR⁷⁰、-NR⁷⁴C(＝NR⁷⁵)NR⁷²R⁷³、-NR⁷⁴C(＝O)C(＝O)NR⁷²R⁷³、-NR⁷⁴C(＝S)R⁷⁰、-NR⁷⁴C(＝S)OR⁷⁰、-NR⁷⁴C(＝S)NR⁷²R⁷³、-NR⁷⁴S(＝O)₂R⁷¹、-NR⁷⁴S(＝O)₂NR⁷²R⁷³、-NR⁷⁴P(＝O)R⁷⁸R⁷⁸、-NR⁷⁴P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-NR⁷⁴P(＝O)(OR⁷⁰)(OR⁷⁰)、-NR⁷⁴P(＝O)(SR⁷⁰)(SR⁷⁰)、-OR⁷⁰、＝O、-OCN、-OC(＝O)R⁷⁰、-OC(＝O)NR⁷²R⁷³、-OC(＝O)OR⁷⁰、-OC(＝NR⁷⁵)NR⁷²R⁷³、-OS(＝O)R⁷⁰、-OS(＝O)₂R⁷⁰、-OS(＝O)₂OR⁷⁰、-OS(＝O)₂NR⁷²R⁷³、-OP(＝O)R⁷⁸R⁷⁸、-OP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-OP(＝O)(OR⁷⁰)(OR⁷⁰)、-OP(＝O)(SR⁷⁰)(SR⁷⁰)、-Si(R⁷⁴)₃、-SCN、＝S、–S(＝O)_nR⁷⁰、-S(＝O)₂OR⁷⁰、-SO₃R⁷⁷、-S(＝O)₂NR⁷²R⁷³、-S(＝O)NR⁷²R⁷³、-SP(＝O)R⁷⁸R⁷⁸、-SP(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-SP(＝O)(OR⁷⁰)(OR⁷⁰)、-SP(＝O)(SR⁷⁰)(SR⁷⁰)、-P(＝O)R⁷⁸R⁷⁸、-P(＝O)(NR⁷²R⁷³)(NR⁷²R⁷³)、-P(＝O)(OR⁷⁰)(OR⁷⁰) and-P (═ O) (SR)⁷⁰)(SR⁷⁰)；

R⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence selected from H, optionally substituted with 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl;

R⁷²and R⁷³Independently at each occurrence selected from H, optionally substituted with 1-13R⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁹⁹Substituted 6-21 membered heteroarylalkyl;

or any R⁷²And R⁷³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁰⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁰⁹Substituted 5-15 membered heteroaryl;

R⁷⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R⁸⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R⁸⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R⁸⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R⁸⁹Substituted C_6-11Aryl, optionally substituted with 1-19R⁸⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R⁸⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R⁸⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R⁸⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁸⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R⁸⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R⁸⁹Substituted 6-21 membered heteroarylalkyl;

or any two R attached to the same phosphorus atom⁷⁸May form optionally substituted 1-6R together with the phosphorus atom to which they are attached⁸⁹Substituted 3-10 membered heterocycloalkyl;

R⁷⁹、R⁸⁹、R⁹⁹and R¹⁰⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹¹⁹C substituted by one_7-16Arylalkyl, optionally substituted with 1-21R¹¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹¹⁹Substituted 4-21Membered heterocycloalkylalkyl, optionally substituted with 1-15R¹¹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹¹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹¹⁰、-C(＝O)OR¹¹⁰、-C(＝O)NR¹¹²R¹¹³、-C(＝O)C(＝O)R¹¹⁰、-C(＝NR¹¹⁵)R¹¹⁰、-C(＝NR¹¹⁵)NR¹¹²R¹¹³、-C(＝NOH)NR¹¹²R¹¹³、-C(＝NOR¹¹⁶)R¹¹⁰、-C(＝NNR¹¹²R¹¹³)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)R¹¹¹)R¹¹⁰、-C(＝NNR¹¹⁴C(＝O)OR¹¹¹)R¹¹⁰、-C(＝S)NR¹¹²R¹¹³、-NC、-NO₂、-NR¹¹²R¹¹³、-NR¹¹⁴NR¹¹²R¹¹³、-N＝NR¹¹⁴、＝NR¹¹⁰、＝NOR¹¹⁰、-NR¹¹⁴OR¹¹⁶、-NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)C(＝O)OR¹¹¹、-NR¹¹⁴C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)R¹¹⁰、-NR¹¹⁴C(＝O)NR¹¹⁴C(＝O)OR¹¹⁰、-NR¹¹⁴C(＝NR¹¹⁵)NR¹¹²R¹¹³、-NR¹¹⁴C(＝O)C(＝O)NR¹¹²R¹¹³、-NR¹¹⁴C(＝S)R¹¹⁰、-NR¹¹⁴C(＝S)OR¹¹⁰、-NR¹¹⁴C(＝S)NR¹¹²R¹¹³、-NR¹¹⁴S(＝O)₂R¹¹¹、-NR¹¹⁴S(＝O)₂NR¹¹²R¹¹³、-NR¹¹⁴P(＝O)R¹¹⁸R¹¹⁸、-NR¹¹⁴P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-NR¹¹⁴P(＝O)(OR¹¹⁰)(OR¹¹⁰)、-NR¹¹⁴P(＝O)(SR¹¹⁰)(SR¹¹⁰)、-OR¹¹⁰、＝O、-OCN、-OC(＝O)R¹¹⁰、-OC(＝O)NR¹¹²R¹¹³、-OC(＝O)OR¹¹⁰、-OC(＝NR¹¹⁵)NR¹¹²R¹¹³、-OS(＝O)R¹¹⁰、-OS(＝O)₂R¹¹⁰、-OS(＝O)₂OR¹¹⁰、-OS(＝O)₂NR¹¹²R¹¹³、-OP(＝O)R¹¹⁸R¹¹⁸、-OP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-OP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-OP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-Si(R¹¹⁴)₃、-SCN、＝S、–S(＝O)_nR¹¹⁰、-S(＝O)₂OR¹¹⁰、-S(＝O)₂NR¹¹²R¹¹³、-S(＝O)NR¹¹²R¹¹³、-SP(＝O)R¹¹⁸R¹¹⁸、-SP(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-SP(＝O)(OR¹¹⁰)(OR¹¹⁰)、-SP(＝O)(SR¹¹⁰)(SR¹¹⁰)、-P(＝O)R¹¹⁸R¹¹⁸、-P(＝O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³)、-P(＝O)(OR¹¹⁰)(OR¹¹⁰) and-P (═ O) (SR)¹¹⁰)(SR¹¹⁰)；

R¹¹⁰、R¹¹¹、R¹¹⁴、R¹¹⁵And R¹¹⁶Independently at each occurrence selected from H, optionally substituted with 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl;

R¹¹²and R¹¹³Independently at each occurrence selected from H, optionally substituted with 1-13R¹³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹³⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹³⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹³⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹³⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹¹²And R¹¹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁴⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁴⁹Substituted 5-15 membered heteroaryl;

R¹¹⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹²⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹²⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹²⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹²⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹²⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹²⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹²⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹²⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹²⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹²⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹²⁹Substituted 6-21 membered heteroarylalkyl;

R¹¹⁹、R¹²⁹、R¹³⁹and R¹⁴⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁵⁹Substituted byC_1-6Alkyl, optionally substituted with 1-11R¹⁵⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁵⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁵⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁵⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁵⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁵⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁵⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁵⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁵⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁵⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁵⁰、-C(＝O)OR¹⁵⁰、-C(＝O)NR¹⁵²R¹⁵³、-C(＝O)C(＝O)R¹⁵⁰、-C(＝NR¹⁵⁵)R¹⁵⁰、-C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-C(＝NOH)NR¹⁵²R¹⁵³、-C(＝NOR¹⁵⁶)R¹⁵⁰、-C(＝NNR¹⁵²R¹⁵³)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)R¹⁵¹)R¹⁵⁰、-C(＝NNR¹⁵⁴C(＝O)OR¹⁵¹)R¹⁵⁰、-C(＝S)NR¹⁵²R¹⁵³、-NC、-NO₂、-NR¹⁵²R¹⁵³、-NR¹⁵⁴NR¹⁵²R¹⁵³、-N＝NR¹⁵⁴、＝NR¹⁵⁰、＝NOR¹⁵⁰、-NR¹⁵⁴OR¹⁵⁶、-NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)C(＝O)OR¹⁵¹、-NR¹⁵⁴C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)R¹⁵⁰、-NR¹⁵⁴C(＝O)NR¹⁵⁴C(＝O)OR¹⁵⁰、-NR¹⁵⁴C(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝O)C(＝O)NR¹⁵²R¹⁵³、-NR¹⁵⁴C(＝S)R¹⁵⁰、-NR¹⁵⁴C(＝S)OR¹⁵⁰、-NR¹⁵⁴C(＝S)NR¹⁵²R¹⁵³、-NR¹⁵⁴S(＝O)₂R¹⁵¹、-NR¹⁵⁴S(＝O)₂NR¹⁵²R¹⁵³、-NR¹⁵⁴P(＝O)R¹⁵⁸R¹⁵⁸、-NR¹⁵⁴P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-NR¹⁵⁴P(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-NR¹⁵⁴P(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-OR¹⁵⁰、＝O、-OCN、-OC(＝O)R¹⁵⁰、-OC(＝O)NR¹⁵²R¹⁵³、-OC(＝O)OR¹⁵⁰、-OC(＝NR¹⁵⁵)NR¹⁵²R¹⁵³、-OS(＝O)R¹⁵⁰、-OS(＝O)₂R¹⁵⁰、-OS(＝O)₂OR¹⁵⁰、-OS(＝O)₂NR¹⁵²R¹⁵³、-OP(＝O)R¹⁵⁸R¹⁵⁸、-OP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-OP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-OP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-Si(R¹⁵⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁵⁰、-S(＝O)₂OR¹⁵⁰、-S(＝O)₂NR¹⁵²R¹⁵³、-S(＝O)NR¹⁵²R¹⁵³、-SP(＝O)R¹⁵⁸R¹⁵⁸、-SP(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-SP(＝O)(OR¹⁵⁰)(OR¹⁵⁰)、-SP(＝O)(SR¹⁵⁰)(SR¹⁵⁰)、-P(＝O)R¹⁵⁸R¹⁵⁸、-P(＝O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³)、-P(＝O)(OR¹⁵⁰)(OR¹⁵⁰) and-P (═ O) (SR)¹⁵⁰)(SR¹⁵⁰)；

R¹⁵⁰、R¹⁵¹、R¹⁵⁴、R¹⁵⁵And R¹⁵⁶Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R is¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁵²and R¹⁵³Independently at each occurrence selected from H, optionally substituted with 1-13R¹⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁷⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁷⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁷⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁷⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁷⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁷⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁷⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁷⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁷⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁷⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹⁵²And R¹⁵³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R¹⁸⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁸⁹Substituted 5-15 membered heteroaryl;

R¹⁵⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁶⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁶⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁶⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁶⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁶⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁶⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁶⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁶⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁶⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁶⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R¹⁶⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁵⁹、R¹⁶⁹、R¹⁷⁹and R¹⁸⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R¹⁹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R¹⁹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R¹⁹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R¹⁹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R¹⁹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R¹⁹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R¹⁹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R¹⁹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R¹⁹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R¹⁹⁹Substituted 5-15 membered heteroaryl, optionally substituted with 1-27R¹⁹⁹Substituted 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R¹⁹⁰、-C(＝O)OR¹⁹⁰、-C(＝O)NR¹⁹²R¹⁹³、-C(＝O)C(＝O)R¹⁹⁰、-C(＝NR¹⁹⁵)R¹⁹⁰、-C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-C(＝NOH)NR¹⁹²R¹⁹³、-C(＝NOR¹⁹⁶)R¹⁹⁰、-C(＝NNR¹⁹²R¹⁹³)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)R¹⁹¹)R¹⁹⁰、-C(＝NNR¹⁹⁴C(＝O)OR¹⁹¹)R¹⁹⁰、-C(＝S)NR¹⁹²R¹⁹³、-NC、-NO₂、-NR¹⁹²R¹⁹³、-NR¹⁹⁴NR¹⁹²R¹⁹³、-N＝NR¹⁹⁴、＝NR¹⁹⁰、＝NOR¹⁹⁰、-NR¹⁹⁴OR¹⁹⁶、-NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)C(＝O)OR¹⁹¹、-NR¹⁹⁴C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)R¹⁹⁰、-NR¹⁹⁴C(＝O)NR¹⁹⁴C(＝O)OR¹⁹⁰、-NR¹⁹⁴C(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝O)C(＝O)NR¹⁹²R¹⁹³、-NR¹⁹⁴C(＝S)R¹⁹⁰、-NR¹⁹⁴C(＝S)OR¹⁹⁰、-NR¹⁹⁴C(＝S)NR¹⁹²R¹⁹³、-NR¹⁹⁴S(＝O)₂R¹⁹¹、-NR¹⁹⁴S(＝O)₂NR¹⁹²R¹⁹³、-NR¹⁹⁴P(＝O)R¹⁹⁸R¹⁹⁸、-NR¹⁹⁴P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-NR¹⁹⁴P(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-NR¹⁹⁴P(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-OR¹⁹⁰、＝O、-OCN、-OC(＝O)R¹⁹⁰、-OC(＝O)NR¹⁹²R¹⁹³、-OC(＝O)OR¹⁹⁰、-OC(＝NR¹⁹⁵)NR¹⁹²R¹⁹³、-OS(＝O)R¹⁹⁰、-OS(＝O)₂R¹⁹⁰、-OS(＝O)₂OR¹⁹⁰、-OS(＝O)₂NR¹⁹²R¹⁹³、-OP(＝O)R¹⁹⁸R¹⁹⁸、-OP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-OP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-OP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-Si(R¹⁹⁴)₃、-SCN、＝S、–S(＝O)_nR¹⁹⁰、-S(＝O)₂OR¹⁹⁰、-S(＝O)₂NR¹⁹²R¹⁹³、-S(＝O)NR¹⁹²R¹⁹³、-SP(＝O)R¹⁹⁸R¹⁹⁸、-SP(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-SP(＝O)(OR¹⁹⁰)(OR¹⁹⁰)、-SP(＝O)(SR¹⁹⁰)(SR¹⁹⁰)、-P(＝O)R¹⁹⁸R¹⁹⁸、-P(＝O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)、-P(＝O)(OR¹⁹⁰)(OR¹⁹⁰) and-P (═ O) (SR)¹⁹⁰)(SR¹⁹⁰)；

R¹⁹⁰、R¹⁹¹、R¹⁹⁴、R¹⁹⁵And R¹⁹⁶Independently at each occurrence selected from H, optionally substituted with 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁹²and R¹⁹³Independently at each occurrence selected from H, optionally substituted with 1-13R²¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²¹⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²¹⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²¹⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²¹⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²¹⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²¹⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²¹⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²¹⁹Substituted 6-21 membered heteroarylalkyl;

or any R¹⁹²And R¹⁹³May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-28R²²⁹Substituted by3-15 membered heterocycloalkyl or optionally substituted with 1-15R²²⁹Substituted 5-15 membered heteroaryl;

R¹⁹⁸independently at each occurrence is selected from the group consisting of optionally substituted 1-13R²⁰⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R²⁰⁹Substituted C_2-6Alkenyl, optionally substituted by 1-9R²⁰⁹Substituted C_2-6Alkynyl, optionally substituted by 1-11R²⁰⁹Substituted C_6-11Aryl, optionally substituted with 1-19R²⁰⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R²⁰⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-32R²⁰⁹Substituted C_4-17Cycloalkylalkyl, optionally substituted with 1-28R²⁰⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R²⁰⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R²⁰⁹Substituted 5-15 membered heteroaryl, and optionally substituted with 1-27R²⁰⁹Substituted 6-21 membered heteroarylalkyl;

R¹⁹⁹、R²⁰⁹、R²¹⁹and R²²⁹Independently at each occurrence, is selected from C optionally substituted with 1-13 halogens_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-11Aryl radical, C_7-16Arylalkyl radical, C_3-11Cycloalkyl radical, C_4-17Cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, halo, -CN, -C (═ O) R²³⁰、-C(＝O)OR²³⁰、-C(＝O)NR²³⁰R²³⁰、-C(＝O)C(＝O)R²³⁰、-C(＝NR²³⁰)R²³⁰、-C(＝NR²³⁰)NR²³⁰R²³⁰、-C(＝NOH)NR²³⁰R²³⁰、-C(＝NOR²³⁰)R²³⁰、-C(＝NNR²³⁰R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)R²³⁰)R²³⁰、-C(＝NNR²³⁰C(＝O)OR²³⁰)R²³⁰、-C(＝S)NR²³⁰R²³⁰、-NC、-NO₂、-NR²³⁰R²³⁰、-NR²³⁰NR²³⁰R²³⁰、-N＝NR²³⁰、＝NR²³⁰、＝NOR²³⁰、-NR²³⁰OR²³⁰、-NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)C(＝O)R²³⁰、-NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝O)C(＝O)OR²³⁰、-NR²³⁰C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)R²³⁰、-NR²³⁰C(＝O)NR²³⁰C(＝O)OR²³⁰、-NR²³⁰C(＝NR²³⁰)NR²³⁰R²³⁰、-NR²³⁰C(＝O)C(＝O)NR²³⁰R²³⁰、-NR²³⁰C(＝S)R²³⁰、-NR²³⁰C(＝S)OR²³⁰、-NR²³⁰C(＝S)NR²³⁰R²³⁰、-NR²³⁰S(＝O)₂R²³⁰、-NR²³⁰S(＝O)₂NR²³⁰R²³⁰、-NR²³⁰P(＝O)R²³¹R²³¹、-NR²³⁰P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-NR²³⁰P(＝O)(OR²³⁰)(OR²³⁰)、-NR²³⁰P(＝O)(SR²³⁰)(SR²³⁰)、-OR²³⁰、＝O、-OCN、-OC(＝O)R²³⁰、-OC(＝O)NR²³⁰R²³⁰、-OC(＝O)OR²³⁰、-OC(＝NR²³⁰)NR²³⁰R²³⁰、-OS(＝O)R²³⁰、-OS(＝O)₂R²³⁰、-OS(＝O)₂OR²³⁰、-OS(＝O)₂NR²³⁰R²³⁰、-OP(＝O)R²³¹R²³¹、-OP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-OP(＝O)(OR²³⁰)(OR²³⁰)、-OP(＝O)(SR²³⁰)(SR²³⁰)、-Si(R²³⁰)₃、-SCN、＝S、–S(＝O)_nR²³⁰、-S(＝O)₂OR²³⁰、-SO₃R²³⁰、-S(＝O)₂NR²³⁰R²³⁰、-S(＝O)NR²³⁰R²³⁰、-SP(＝O)R²³¹R²³¹、-SP(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-SP(＝O)(OR²³⁰)(OR²³⁰)、-SP(＝O)(SR²³⁰)(SR²³⁰)、-P(＝O)R²³¹R²³¹、-P(＝O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰)、-P(＝O)(OR²³⁰)(OR²³⁰) and-P (═ O) (SR)²³⁰)(SR²³⁰)；

R²³⁰Independently at each occurrence selected from H, C_1-6Alkyl and C_1-6-a haloalkyl group;

R²³¹is independently selected at each occurrence from C_1-6Alkyl and C_1-6-a haloalkyl group; and is

n is independently selected at each occurrence from 0, 1, and 2;

with the proviso that said compound is not

Wherein D is H orOr a salt form thereof.

2. A compound as defined in claim 1, wherein X is selected from the group consisting of optionally substituted with 1-6R¹⁹Substituted piperidinyl, optionally substituted with 1-6R¹⁹Substituted piperazinyl, and-NR²⁴R²⁸。

3. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹²、R¹³、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴S(＝O)₂R²¹、-OR²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³And/or R¹⁴And R¹⁵Either or both groups may form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl.

4. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹²、R¹⁴And R¹⁵Independently selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, and halogen; r¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted C_3-7Cycloalkyl optionally substituted by 1-3R¹⁹Substituted 3-7 membered heterocycloalkyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

5. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹²And R¹⁴Is H; r¹⁵Selected from H and halogen;

R¹³selected from H, optionally substituted with 1-3R¹⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R²⁰、-C(＝O)OR²⁰、-C(＝O)NR²²R²³、-NO₂、-NR²²R²³、-NR²⁴NR²²R²³、-NR²⁴OR²⁶、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹、-NR²⁴S(＝O)₂NR²²R²³、-OR²⁰、-OC(＝O)R²⁰、-S(＝O)_nR²⁰and-S (═ O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

6. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³、-NR²⁴C(＝O)R²⁰、-NR²⁴C(＝O)OR²¹、-NR²⁴C(＝O)NR²²R²³、-NR²⁴S(＝O)₂R²¹and-NR²⁴S(＝O)₂NR²²R²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-6R¹⁹Substituted 5-6 membered heteroaryl.

7. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹⁴And R¹⁵Is H; r¹²Selected from H and halogen;

R¹³selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-2R¹⁹A substituted 5-membered heteroaryl.

8. A compound as defined in any of claims 1-2, wherein G is of formula (la)And R is¹⁴Is H; r¹²And R¹⁵Independently selected from H and halogen; r¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atom to which they are attached, an optionally substituted 1R¹⁹A substituted pyrrolyl ring.

9. Such asA compound as defined in any one of claims 1-2, wherein G is of formula (la)And R is¹²、R¹³、R¹⁴And R¹⁵Is H; or R¹²And R¹³Together with the atoms to which they are attached form an azolyl ring.

10. A compound as defined in any of claims 1-2, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted C_2-6Alkenyl, optionally substituted by 1-3R³⁹Substituted C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_6-10Aryl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, optionally substituted with 1-3R³⁹Substituted 5-6 membered heteroaryl, halogen, -CN, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NO₂、-NR³²R³³、-NR³⁴C(＝O)R³⁰、-NR³⁴C(＝O)NR³²R³³、-NR³⁴S(＝O)₂R³¹、-NR³⁴S(＝O)₂NR³²R³³、-OR³⁰、＝O、-OC(＝O)R³⁰、-OC(＝O)NR³²R³³、-Si(R³⁴)₃、＝S、–S(＝O)_nR³⁰and-S (═ O)₂NR³²R³³。

11. A compound as defined in any of claims 1-2, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl radical, C_6-10Aryl radical, C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycleAlkyl, 5-6 membered heteroaryl, halo, -C (═ O) R³⁰、-C(＝O)OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³and-OR³⁰。

12. A compound as defined in any of claims 1-2, wherein R¹⁹Is independently selected at each occurrence from C_1-6Alkyl, optionally substituted with 1-3R³⁹Substituted phenyl, C_3-6Cycloalkyl optionally substituted by 1-3R³⁹Substituted 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -C (═ O) OR³⁰、–NR³²R³³and-OR³⁰。

13. A compound as defined in any of claims 1-2, wherein R¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, optionally substituted with 1-3R³⁹Substituted C_7-11Arylalkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴S(＝O)₂R³¹、-OR³⁰And ═ O.

14. A compound as defined in any of claims 1-2, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, and optionally substituted with 1-3R⁴⁹Substituted C_3-6A cycloalkyl group.

15. A compound as defined in any of claims 1-2, wherein R²⁰Independently at each occurrence selected from H, optionally substituted with 1-3R⁴⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁴⁹Substituted phenyl, optionally substituted with 1-3R⁴⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; r²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷At each occurrence is H.

16. A compound as defined in any of claims 1-2, wherein R²⁰、R²¹、R²⁴、R²⁵、R²⁶、R²⁷、R³⁰、R³¹、R³⁴、R³⁵、R³⁶And R³⁷Independently at each occurrence selected from H and C_1-6An alkyl group.

17. A compound as defined in any of claims 1-2, wherein R²²、R²³、R³²And R³³Independently at each occurrence selected from H, optionally substituted with 1-3R⁵⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 5-6 membered heteroaryl.

18. A compound as defined in any of claims 1-2, wherein R²²Independently at each occurrence selected from H, C_1-6Alkyl, optionally substituted with 1-3R⁵⁹Substituted phenyl, and optionally substituted with 1-3R⁵⁹Substituted 5-6 membered heteroaryl; r²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

19. A compound as defined in any one of claims 1 to 2In which R is²²、R²³、R³²And R³³Independently at each occurrence selected from H and C_1-6An alkyl group.

20. A compound as defined in any of claims 1-2, wherein R³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6Alkyl, optionally substituted with 1-3R⁷⁹Substituted phenyl, optionally substituted with 1-3R⁷⁹Substituted benzyl, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, -CN, -C (═ O) NR⁷²R⁷³、-NR⁷²R⁷³、-OR⁷⁰and-S (═ O)_nR⁷⁰。

21. A compound as defined in any of claims 1-2, wherein R³⁹、R⁴⁹、R⁵⁹And R⁶⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-3R⁷⁹Substituted C_1-6An alkyl group.

22. A compound as defined in any of claims 1-2, wherein R⁷⁰、R⁷¹、R⁷⁴、R⁷⁵、R⁷⁶And R⁷⁷Independently at each occurrence, selected from H and optionally substituted with 1-3R⁸⁹Substituted C_1-6An alkyl group.

23. A compound as defined in any of claims 1-2, wherein R⁷²And R⁷³Independently at each occurrence selected from H and C_1-6An alkyl group.

24. A compound as defined in any of claims 1-2, wherein R⁷⁹And R⁸⁹、R⁹⁹And R¹⁰⁹Is independently selected at each occurrence from C_1-6Alkyl and benzeneAnd (4) a base.

25. A compound as defined in any of claims 1-2, wherein R⁷⁹、R⁸⁹、R⁹⁹And R¹⁰⁹Independently at each occurrence is C_1-6An alkyl group.

26. A compound as defined in claim 1, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

27. A compound as defined in claim 1, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

28. A compound as defined in claim 1, wherein X is selected from-NHR²⁸And a 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, and-OH.

29. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-6R)⁴⁹Substituted C_7-11Arylalkyl), -NH (optionally substituted with 1-6R)⁴⁹Substituted 3-10 membered heterocycloalkyl), and-NH (optionally substituted with 1-6R)⁴⁹Substituted 4-11 membered heterocycloalkyl).

30. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), and-NH (6-10 membered heterocycloalkyl alkyl).

31. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1-6R¹⁹And (4) substitution.

32. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), and-NH (6-10 membered heterocycloalkyl alkyl).

33. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (optionally substituted by 1-3R)⁴⁹Substituted C_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

34. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (5-6 membered heterocycloalkyl), -NH (6-10 membered heterocycloalkyl alkyl), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

35. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (C)_7-11Arylalkyl), -NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), -NH (6-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: optionally substituted by 1-3R³⁹Substituted C_1-6Alkyl radical, C_2-6Alkynyl, C_6-11Aryl, optionally substituted with 1-3R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R³⁹Substituted C_3-11Cycloalkyl, 5-10 membered heterocycloalkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

36. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl), -NH (a 5-to 6-membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atomsGroup), -NH (6-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms, wherein said heterocycloalkyl is optionally substituted with 1 or 2 members selected from the group consisting of: c optionally substituted by 1-6 halogen_1-6Alkyl, halogen, -CN, -C (═ O) OR³⁰、-C(＝O)NR³²R³³、-NR³²R³³、-NR³⁴C(＝O)R³⁰and-OR³⁰。

37. A compound as defined in claim 1, wherein X is selected from-NH (optionally substituted by 1-6R)⁴⁹Substituted C_1-6Alkyl) and-NH (5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms).

38. A compound as defined in claim 1, wherein R is⁷Selected from H, C_3-6Cycloalkyl, and-O (C)_1-6Alkyl groups).

39. A compound as defined in claim 1, wherein R is⁷Selected from H, cyclopropyl, and-O (C)_1-6Alkyl groups).

40. A compound as defined in claim 1, wherein R is⁷Selected from H, cyclopropyl, and-O (CH)₃)。

41. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, optionally substituted with 1-6R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³Can be connected with itThe atoms together forming an optionally substituted 1-6R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-6R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-6R¹⁹Substituted 5-10 membered heteroaryl.

42. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, optionally substituted with 1-3R¹⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

43. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

44. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

45. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, halogen, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon and 1 nitrogen, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

46. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

47. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NR²²R²³and-NR²⁴C(＝O)R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon and 1 nitrogen, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 nitrogen atom.

48. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted C_6-11Aryl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, or optionally substituted with 1-3R¹⁹Substituted 5-10 membered heteroaryl.

49. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³Can be connected withThe atoms together forming an optionally substituted 1-3R¹⁹Substituted phenyl, optionally substituted with 1-3R¹⁹Substituted 5-10 membered heterocycloalkyl, wherein said heterocycloalkyl comprises carbon atoms and 1 or 2 nitrogen atoms, or is optionally substituted with 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

50. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl.

51. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

52. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H, -NHR²³and-NHC (═ O) R²⁰(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbonAtoms and 1 nitrogen atom.

53. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H and-NHR²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹Substituted 5-10 membered heteroaryl.

54. A compound as defined in any one of claims 1 or 26 to 40, wherein R¹²、R¹⁴And R¹⁵Is H, and R¹³Selected from H and-NHR²³(ii) a Or R¹²And R¹³May form, together with the atoms to which they are attached, an optionally substituted 1-3R¹⁹A substituted 5-10 membered heteroaryl, wherein the heteroaryl comprises carbon atoms and 1 or 2 nitrogen atoms.

55. A compound selected from:

1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine;

n- (2-aminoethyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2R) -2-aminopropyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-aminopropyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

(3R) -N- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-amine;

(3R) -N- [2- (3-fluoropyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -2- (3-fluoropyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -6-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

1- [ 6-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(3S) -3-benzyl-1- [ 6-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-ol;

(3S) -3-benzyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(3R) -3-benzyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1-methyl-4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1-methyl-4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -1, 4-diazepane;

(2S) -2, 4-dibenzyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] morpholine;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -1, 4-diazepan-1-carboxylic acid tert-butyl ester;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] thiomorpholine;

n, N-dimethyl [ (2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl ] amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -N-methyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-2-one;

n- [ (2S) -1-amino-3-phenylprop-2-yl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

(2R) -2-benzyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(3S) -3-benzyl-1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [ 8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -1, 4-diazepane;

2- {4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-1-yl } ethan-1-ol;

(3S) -1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-ol;

(3R) -1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-ol;

(3R) -3-benzyl-1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(2S) -2-benzyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

methyl (2S,4S) -4- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } pyrrolidine-2-carboxylate;

(2S,4S) -4- [ (2S,4S) -4- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } pyrrolidine-2-amido ] pyrrolidine-2-carboxylic acid methyl ester;

[ (2S) -1- { [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } -3-phenylprop-2-yl ] (methyl) amine;

n- [ (3R) -Oxetapen-3-yl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3- (trifluoromethyl) piperazine;

(3S) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3-methylpiperazine;

(3R) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-amine;

[ (2R) -4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-2-yl ] methanol;

n- [ (2R,3R) -2-amino-3-fluoro-3-phenylpropyl ] -5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

2- [ (2S) -2-benzyl-4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-1-yl ] acetamide;

[ (2S) -1- { [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } -3-phenylprop-2-yl ] dimethylamine;

(3S) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-ol;

1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3, 5-cis-dimethylpiperazine;

(3R) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3-methylpiperazine;

(3S) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] pyrrolidin-3-amine;

3- (fluoromethyl) -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

n- (prop-2-yl) -1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperidine-4-carboxamide;

4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine-1-carboxamide;

n-cyclohexyl-4- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine-1-carboxamide;

2- {4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-2-yl } acetonitrile;

1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3- (trifluoromethyl) piperazine;

1- [ 8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3- (trifluoromethyl) piperazine;

(3S) -3-ethyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(3S) -3- (propan-2-yl) -1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [2- (3-fluoropyridin-4-yl) -5-methoxypyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

4- {4- [ (8aR) -octahydropyrrolo [1,2-a ] piperazin-2-yl ] pyrido [3,4-d ] pyrimidin-2-yl } pyridine;

1- [2- (3-fluoropyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [2- (3-fluoropyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -3- (trifluoromethyl) piperazine;

4- {4- [ (3aS) -octahydro-1H-pyrrolo [3,2-c ] pyridin-5-yl ] pyrido [3,4-d ] pyrimidin-2-yl } pyridine;

(3S) -3-benzyl-1- [ 8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

3-phenyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] morpholine;

3-ethynyl-1- [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

2-benzyl-4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] morpholine;

{1- [ 8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] azetidin-3-yl } methanol;

(3R) -3- [ fluoro (phenyl) methyl ] -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [ 8-chloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperidin-4-ol;

(3R) -3- [ fluoro (phenyl) methyl ] -1- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

(4-fluorophenyl) [ (2R) -4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-2-yl ] methanol;

n- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -carboxamide;

n- [ (S) -1-benzyl-2- (2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-ylamino) -ethyl ] -acetamide;

methyl [ (2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl ] amine;

(2S) -2-benzyl-4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] -1-methylpiperazine;

2- { [ (2S) -1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } prop-2-yl ] amino } acetamide;

n- (1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) methanesulfonamide;

(1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) urea;

3-ethyl-1- (1-phenyl-3- { [2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] amino } propan-2-yl) urea;

(3aR) -5- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-1H- [1,3]Azolo [3,4-a ] s]Piperazin-1-one;

2- {4- [ 5-methoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazin-1-yl } acetonitrile;

n- {3- [4- ((S) -2-amino-3-phenyl-propylamino) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-8-yl ] -phenyl } -methanesulfonamide;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1H-pyrazol-5-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8-phenyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

4- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) phenol;

3- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) phenol;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (2-methoxyphenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (3-methoxyphenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (4-methoxyphenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (2-chlorophenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1-benzofuran-5-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1-methyl-1H-pyrazol-4-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (pyridin-3-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -2, 8-bis (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- [1- (2-methylpropyl) -1H-pyrazol-4-yl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (3-chlorophenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (4-chlorophenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1-methyl-1H-pyrazol-5-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

2- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) phenol;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- [3- (3-chlorophenyl) phenyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- [4- (4-chlorophenyl) phenyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -2- (pyridin-4-yl) -8- (pyrimidin-5-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (3-aminophenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1-benzofuran-7-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (5-methylthiophen in-2-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl group]-8- (dimethyl-1, 2-)Azol-4-yl) -2- (pyridin-4-yl) pyrido [3,4-d]Pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (furan-3-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -2- (pyridin-4-yl) -8- (thiophen-3-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (furan-2-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (1H-1, 3-benzodiazol-5-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (3-ethoxyphenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (2-tolyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (3-tolyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ]8- [3- (1H-pyrazol-5-yl) phenyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- [5- (aminomethyl) -furan-2-yl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

(R) -3-phenyl-N¹- (2-pyridin-4-yl-8-pyridin-2-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine;

N⁴- ((R) -2-amino-3-phenyl-propyl) -N⁸-phenyl-2-pyridin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamine;

4-N- [ (2S) -2-amino-3-phenylpropyl ] -2- (pyridin-4-yl) -8-N- (pyrimidin-2-yl) pyrido [3,4-d ] pyrimidine-4, 8-diamine;

4-N- [ (2S) -2-amino-3-phenylpropyl ] -8-N- (3-chlorophenyl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidine-4, 8-diamine;

4-N- [ (2S) -2-amino-3-phenylpropyl ] -2- (pyridin-4-yl) -8-N- (1H-1,2, 4-triazol-3-yl) pyrido [3,4-d ] pyrimidine-4, 8-diamine;

(R)-N¹- [8- (4-methyl-piperazin-1-yl) -2-pyridin-4-yl-pyrido [3,4-d]Pyrimidin-4-yl]-3-phenyl-propane-1, 2-diamine;

(R) -3-phenyl-N¹- (8-phenylthio-2-pyridin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -propane-1, 2-diamine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8-phenoxy-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

n- [ (2S) -2-amino-3-phenylpropyl ] -8- (methylthio) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

4- (4- { [ (2S) -2-amino-3-phenylpropyl ] -amino } -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) -2-methylbut-3-yn-2-ol;

5-chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

1- [ 5-bromo-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [5, 8-dichloro-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

5-butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

1- [ 5-ethyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

n- [ (2S) -2-amino-3-phenylpropyl ] -5-ethyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-amine;

1- [ 5-methyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- [ 5-cyclopropyl-2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl ] piperazine;

1- {5- [ (benzyloxy) methyl ] -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-4-yl } piperazine;

5-chloro-4-piperazin-1-yl-8- (1H-pyrazol-3-yl) -2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

5-chloro-N, N-dimethyl-4- (piperazin-1-yl) -2- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-8-amine;

5-isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

5-methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

3-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidine-3-carboxylic acid amide;

3-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidine-3-carboxylic acid benzamide;

4-amino-1- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-4-carboxylic acid; [ (S) -1- (4-chloro-phenyl) -3-hydroxy-propyl ] -amide;

4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid methyl ester;

4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid benzamide;

4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid benzamide;

4- (5-methoxy-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-2-carboxylic acid phenethyl-amide;

4-piperazin-1-yl-8-propyl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

8-methyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazin-2-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4-trifluoromethyl-Oxazol-2-yl) -amine;

(4, 5-dimethyl-Azol-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]-an amine;

(4-cyclopropyl-thiazol-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

3- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile;

(2-fluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-phenyl) -amine;

4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamine;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-morpholin-4-yl-acetamide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-piperidin-1-yl-acetamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-4-yl-amine;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -benzamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -methyl-amine;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

n- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

cyclopropanecarboxylic acid [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2, 2-dimethyl-propionamide;

tetrahydro-pyran-4-carboxylic acid [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -thiazol-2-yl-amine;

[4- (5-methyl)Oxy-4-piperazin-1-yl-pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]-Oxazol-2-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4-methyl-Oxazol-2-yl) -amine;

{ (S) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -methanol;

1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -4-methyl-piperidin-4-ol;

{4- [4- ((S) -3-isopropyl-piperazin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

2- { (S) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -ethanol;

n- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -N ', N' -dimethyl-benzene-1, 4-diamine;

{ 5-methoxy-2- [2- (3-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (2-fluoro-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{ 5-methoxy-2- [2- (4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (4-fluoro-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{4- [ 5-methoxy-4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{ (S) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -acetonitrile;

{4- [4- ((R) -3-fluoromethyl-piperazin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

cyclopropanecarboxylic acid {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amide;

{4- [4- ((S) -3-fluoromethyl-piperazin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [4- ((S) -3-cyclopropyl-piperazin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [4- ((R) -3-fluoromethyl-piperazin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2,3, 6-trifluoro-phenyl) -amine;

[ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine;

{ 5-methoxy-2- [2- (pyrazin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

thiophene-2-carboxylic acid {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amide;

cyclopentyl- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

cyclohexyl- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{2- [2- (pyrazin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-yl } -methanol;

2- {3- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -R-pyrrolidin-1-yl } -acetamide;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine;

(2-fluoro-phenyl) - {2- [2- (2-fluoro-phenylamino) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-5-yl } -amine;

4- {5- (4-cyano-pyridin-2-ylamino) -2- [2- (4-cyano-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperazine;

{4- [ 5-chloro-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

n- [4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-difluoro-phenyl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridin-2-yl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 4-difluoro-phenyl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-2-yl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 6-trifluoro-phenyl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-fluoro-pyridin-2-yl) -amine;

[4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

5- [4- (5-chloro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -pyridine-2-carbonitrile;

{ 4-piperazin-1-yl-2- [2- (2,3, 6-trifluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-5-yl } - (2,3, 6-trifluoro-phenyl) -amine;

(2, 6-difluoro-phenyl) - {2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-5-yl } -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 6-trifluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (6-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (4, 5-dimethyl-)Oxazol-2-yl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-cyclopropyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

1- { 5-cyclopropyl-2- [2- (2-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

{4- [ 5-cyclopropyl-4- ((S) -3-isopropyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [ 5-cyclopropyl-4- ((S) -3-cyclopropyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2-fluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-cyclopropyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (6-fluoro-pyridin-2-yl) -amine;

(4- { 5-cyclopropyl-4- [3- (1, 1-difluoro-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -phenyl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

{ (S) -4- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -acetonitrile;

cyclopentyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

cyclohexyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (tetrahydro-pyran-4-yl) -amine;

cyclopentyl- {4- [ 5-cyclopropyl-4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amine;

adamantan-1-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

2-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide;

4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -benzamide;

4-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide;

{4- [ (1S,4S) -4- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

pyrazine-2-carboxylic acid {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amide;

3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -benzamide;

3-amino-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzamide;

2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide;

2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide;

2- (4- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide;

2- (4-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (3- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide;

2- (3-amino-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

{2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

(2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine;

2- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

{2- [2- (4-imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenoxy) -acetamide;

2- (3- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide;

2- (3-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (4- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -acetamide;

2- (4-amino-phenyl) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

1- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -1H-pyrrolo [2,3-b ] pyridine-4-carbonitrile;

{ 5-methoxy-2- [2- (5-phenyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{ 5-methoxy-2- [2- (6-morpholin-4-yl-pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

(5-methoxy-2- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-ylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine;

2- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

{2- [2- (4-imidazol-1-ylmethyl-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

2-phenyl-N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (4-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (2-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (3-methoxy-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

{2- [2- (4-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (4-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

6- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -nicotinonitrile;

2- [4- (4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile;

{2- [2- (4-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

6- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -nicotinonitrile;

{2- [2- (5-methyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (5-chloro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

2- [2- (pyrimidin-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

2- (3-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (4-cyano-phenyl) -N- {4- [4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

(R) -pyrrolidin-3-yl- {2- [2- (4-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

(R) -pyrrolidin-3-yl- {2- [2- (5-trifluoromethyl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile;

6- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -nicotinonitrile;

{4- [ 5-methoxy-4- (4-morpholin-4-yl-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

2- (4-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

2- (3-cyano-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

{2- [2- (5-morpholin-4-yl-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

(2-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{ 5-methoxy-2- [2- (2-methoxy-4-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

(5-methoxy-2- {2- [4- (tetrahydro-pyran-4-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [4- (tetrahydro-pyran-4-yl) -phenyl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-2-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methyl-pyridin-2-yl) -amine;

(4-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(5-chloro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine;

2- (4-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

2- (3-chloro-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-acetamide;

2- (3-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2- (3-trifluoromethyl-phenyl) -acetamide;

2- (4-methoxy-phenyl) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-morpholin-4-yl-pyridin-3-yl) -amine;

{2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{ 5-methoxy-2- [2- (pyridin-3-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-3-yl-amine;

2- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinamide;

6- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -nicotinamide;

(3-methoxy-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-4-morpholin-4-yl-phenyl) -amine;

5- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -pyridine-2-carbonitrile;

{ 5-methoxy-2- [2- (pyrimidin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-5-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-5-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-2-yl-amine;

2- [4- (5-methoxy-4-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -isonicotinonitrile;

2- (3-cyano-phenyl) -N- [4- (5-methoxy-4-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,4, 5-trimethoxy-phenyl) -amine;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2- (4-trifluoromethyl-phenyl) -acetamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-phenyl-pyridin-3-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methyl-pyridin-3-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-3-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-3-yl) -amine;

n- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-pyridin-3-yl-acetamide;

2- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

2- (3-chloro-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-pyridin-3-yl-acetamide;

n- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-pyridin-4-yl-acetamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methoxy-pyridin-2-yl) -amine;

2- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

2- (3-cyano-phenyl) -N- {4- [4- (4-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (3-cyano-phenyl) -N- {4- [ 5-methoxy-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

(6-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(R) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-phenyl-propionamide;

(S) -N- {4- [ 5-methoxy-4- ((R) -pyrrolidin-3-ylamino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -2-phenyl-propionamide;

(R) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-propionamide;

(S) -N- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-propionamide;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methyl-pyridin-2-yl) -amine;

(3-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-piperazin-1-ylpyridin-3-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ 2-methyl-4- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-piperidin-4-yl-1H-pyrazol-4-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methyl-pyridin-2-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methyl-pyridin-3-yl) -amine;

(5-chloro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-fluoro-4-morpholin-4-yl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

3-fluoro-4- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile;

4-fluoro-3- [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile;

(2, 6-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-fluoro-6-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrimidin-2-yl-amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methoxy-pyridin-3-yl) -amine;

(S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ol;

2- {4- [4- ((S) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol;

(R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ol;

2- {4- [4- ((R) -3-hydroxy-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

[ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (S) -1-pyrrolidin-2-ylmethyl-amine;

[ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -1-pyrrolidin-2-ylmethyl-amine;

2- {4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-1-yl } -ethanol;

{1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -azetidin-3-yl } -methanol;

{ (R) -4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -methanol;

(R) -7- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-Azolo [3,4-a ] s]Pyrazin-3-one;

(±) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(±) -trans-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

4- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-one;

(2, 3-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2, 5-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,4, 6-trifluoro-phenyl) -amine;

((R) -4- {2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -piperazin-2-yl) -methanol;

3-hydroxymethyl-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 6-trifluoro-phenyl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-trifluoromethyl-phenyl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-trifluoromethyl-phenyl) -amine;

(6-fluoro-pyridin-2-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-2-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-2-yl) -amine;

(2-fluoro-pyridin-3-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-fluoro-3-methyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-fluoro-3-trifluoromethyl-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2, 4-difluoro-phenyl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 4-trifluoro-phenyl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,4, 5-trifluoro-phenyl) -amine;

(3S,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(3R,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

3- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -propionamide;

[4- (5-methoxy-4-piperidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

{4- [4- (4, 4-difluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-4-carbonitrile;

{4- [4- (4-fluoro-piperidin-1-yl) -5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

(3R,4S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(3S,4R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

{ (R) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -pyrrolidin-3-yl } -methanol;

{ (S) -1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -pyrrolidin-3-yl } -methanol;

(meso) -cis-1- [ 5-methoxy-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -azepane-4, 5-diol;

1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

((S) -1- {2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-methoxy-pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol;

((S) -1- { 5-methoxy-2- [2- (6-methoxy-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl) -methanol;

2- (4-cyano-phenyl) -N- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-4-morpholin-4-yl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-morpholin-4-yl-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridin-3-yl-amine;

(2-chloro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-methyl-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

2- {4- [ 5-cyclopropyl-4- (4-hydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-phenyl) -amine;

(±) -2- {4- [ 5-cyclopropyl-4-cis-3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -o-tolyl-amine;

2- {4- [ 5-cyclopropyl-4- ((3R,4S) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

2- {4- [ 5-cyclopropyl-4- ((3S,4R) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -N- (1-phenylpyrazol-4-yl) pyridin-2-amine:

(2, 3-dimethyl-2H-indazol-6-yl) - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[1- (2-fluoro-phenyl) -1H-pyrazol-4-yl ] - [4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-phenyl-1H-pyrazol-4-yl) -amine

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dimethyl-2H-indazol-6-yl) -amine;

phenyl- [4- (4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-pyridin-3-yl) -amine;

[4- (5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (5-methyl-iso)Oxazol-3-yl) -amine;

2[2 (3-piperazin-1-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol;

2- [2- (3-piperazin-1-ylmethyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol;

2- [2- (1-piperidin-4-ylmethyl-1H-pyrazol-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ol;

{ 5-methoxy-2- [2- (3-piperazin-1-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine;

(5-methoxy-2- {2- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -methyl-amine;

{ 5-methoxy-2- [2- (3-piperidin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine;

[4- (5-methoxy-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-piperazin-1-yl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 5-dimethyl-phenyl) -amine;

5- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -pyridine-2-carbonitrile;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazin-2-yl-amine;

cyclopropyl- {4- [ 5-cyclopropyl-4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (R) -tetrahydro-furan-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4, 4-difluoro-cyclohexyl) -amine;

{4- [ 5-cyclopropyl-4- ((R) -3-fluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- ((R) -3-fluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (6-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methoxy-pyridin-3-yl) -amine;

(6-chloro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-trifluoromethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methoxymethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (S) -tetrahydro-furan-3-yl-amine;

2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile;

tert-butyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 5-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-trifluoromethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-fluoro-2-methyl-phenyl) -amine;

3- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -4-methyl-benzonitrile;

7- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d]Pyrimidin-4-yl]-hexahydro-Azolo [3,4-a ] s]Pyrazin-3-one;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-fluoro-pyridin-2-yl) -amine;

(2-chloro-6-methyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

3- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -4-fluoro-benzonitrile;

(4-tert-butyl-2-chloro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

2- {4- [ 5-cyclopropyl-4- ((R) -3-fluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

{4- [ 5-cyclopropyl-4- ((R) -3-fluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2-fluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,2, 2-trifluoro-ethyl) -amine;

2- {4- [ 5-cyclopropyl-4- (3-oxo-tetrahydro-Azolo [3,4-a ] s]Pyrazin-7-yl) -pyrido [3,4-d]Pyrimidin-2-yl]-pyridin-2-ylamino } -isonicotinonitrile;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-trifluoromethyl-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-fluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-trifluoromethyl-pyridin-3-yl) -amine;

{4- [ 5-cyclopropyl-4- (2, 5-diaza-bicyclo [4.1.0] hept-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [ 5-cyclopropyl-4- (2, 5-diaza-bicyclo [4.1.0] hept-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-dichloro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dimethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-dimethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dichloro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 3-dichloro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyridazin-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methyl-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 6-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [4- (dimethyl-phosphono) -phenyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [4- (diethyl-phosphono) -phenyl ] -amine;

n5- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -N2, N2-dimethyl-pyridine-2, 5-diamine;

{4- [ 5-cyclopropyl-4- ((R) -3-fluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-methoxy-2-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-5-trifluoromethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-trifluoromethoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-methanesulfonyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-3-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-isopropyl-2-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -penta-deuterium-phenyl-amine;

1- {2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -phenyl } -ethanol;

(1R,2S) -2-amino-cyclopentanecarboxylic acid [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amide;

1- {4- [2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -cyclopropanol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazolo [1,5-a ] pyridin-6-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazolo [1,5-a ] pyridin-5-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-trifluoromethyl-pyridazin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-3-methoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-ethoxy-2, 6-difluoro-phenyl) -amine;

(2-chloro-3-methyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

(2-chloro-4-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methoxy-phenyl) -amine;

(2-chloro-4-methyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 4-dimethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-3-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-4-methyl-phenyl) -amine;

(2-chloro-5-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-chloro-5-methyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-chloro-3-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

5-cyclopropyl-2- (6, 7-dimethoxy-quinolin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-methoxy-phenyl) -amine;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -acetamide;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamine;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -isobutyramide;

cyclopropanecarboxylic acid [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 3-difluoro-cyclobutyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-phenyl-ethyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((S) -1-phenyl-ethyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-methoxy-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-3-methoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-4-methoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methoxy-2-methyl-phenyl) -amine;

(2-chloro-5-methoxy-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-phenyl) -amine;

(2-chloro-5-trifluoromethyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 4-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methyl-1H-pyrazol-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-cyclohexyl) -amine;

(+/-) - (cis) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

(4-cyclopropyl-2, 6-difluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-4-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methyl-1H-imidazol-4-yl) -amine;

2- {4- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-1-yl } -ethanol;

(S) -3- {4- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-1-yl } -propane-1, 2-diol;

(R) -3- {4- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-1-yl } -propane-1, 2-diol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methoxy-4-methyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 4-dimethoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,4, 5-trimethoxy-phenyl) -amine;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2-phenyl-acetamide;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -3,3,3, -trifluoro-propionamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- [4- (1-methyl-4-oxo-4. lambda.)⁵-[1,4]Azaphosphapan-4-yl) -phenyl]-an amine;

2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-4- [3- (2,2, 2-trifluoro-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidine;

(2-chloro-6-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(6-chloro-2-fluoro-3-methyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(3-chloro-2, 6-difluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 3-difluoro-cyclopentyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-isopropyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-ethyl-phenyl) -amine;

2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- [4- (1-ethyl-4-oxo-4. lambda.)⁵-[1,4]Azaphosphapan-4-yl) -2-methoxy-phenyl]-an amine;

n- (4- { 5-cyclopropyl-4- [3- (2,2, 2-trifluoro-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -acetamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-3-methoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 4-difluoro-5-methoxy-phenyl) -amine;

cyclopropylmethyl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -methyl-amine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -2-fluoro-benzonitrile;

[4- (5-cyclopropyl-4- [1,4] diazepan-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenyl-amine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -cyclohexanol;

(2-chloro-6-fluoro-3-methoxy-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(2-chloro-3, 6-difluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{4- [ 5-cyclopropyl-4- (2,2,3,3,5,5,6, 6-octadeuterium-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

(4-cyclopropyl-3-methoxy-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

4- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid amide;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2- (2, 6-difluoro-phenyl) -acetamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-propyl-phenyl) -amine;

(4-cyclopropyl-2-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(4- { 5-cyclopropyl-4- [3- (2,2, 2-trifluoro-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) - (2, 6-difluoro-phenyl) -amine;

(4- { 5-cyclopropyl-4- [3- (2,2, 2-trifluoro-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -phenyl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (3-fluoro-phenyl) -ethyl ] -amine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzonitrile;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-trifluoromethyl-phenyl) -amine;

(3-chloro-2, 6-difluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,4, 6-trifluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 4-difluoro-phenyl) -amine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (4-fluoro-phenyl) -ethyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (2, 6-difluoro-phenyl) -ethyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5-fluoro-pyridin-2-yl ] -phenyl-amine;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid isopropylamide;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid amide;

n- (1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl) -acetamide;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-fluoro-ethyl) -amide;

n- {4- [ 5-cyclopropyl-4- ((S) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-4- ((R) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

(4- { 5-cyclopropyl-4- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -phenyl-amine;

(4- { 5-cyclopropyl-4- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) - (4-fluoro-phenyl) -amine;

(4- { 5-cyclopropyl-4- [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -phenyl-amine;

(4- { 5-cyclopropyl-4- [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) - (4-fluoro-phenyl) -amine;

cyclopropanecarboxylic acid (4- { 5-cyclopropyl-4- [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -amide;

cyclopropanecarboxylic acid (4- { 5-cyclopropyl-4- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) -amide;

(5-cyclopropyl-2-fluoro-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl) -amide;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid methylamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 4-difluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 3-difluoro-cyclohexyl) -amine;

1- [2- (2-cyclohexylamino-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-4-carboxylic acid isopropylamide;

(+/-) - (cis) -1- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(+/-) - (trans) -1- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(+/-) -2- {4- [ 5-cyclopropyl-4- ((trans) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -isonicotinonitrile;

(+/-) - (trans) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

1- [2- (2-cyclopentylamino-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-4-carboxylic acid isopropylamide;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,3, 6-trifluoro-pyridin-4-yl) -amine;

biphenyl-4-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzoic acid;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-hydroxy-ethyl) -amide;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid dimethylamide;

4- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperazine-1-carboxylic acid amide;

1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidin-4-ol;

5-cyclopropyl-2- (2-fluoro-pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{4- [4- (4-amino-piperidin-1-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2-fluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (4-fluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 6-difluoro-pyridin-2-yl) -amine;

(+/-) - (1RS,2RS,4SR) -bicyclo [2.2.1] hept-2-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{4- [4- (4-aminomethyl-piperidin-1-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

[ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (S) -1-pyrrolidin-2-ylmethyl-amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (S) -1-pyrrolidin-2-ylmethyl-amine;

[4- (5-cyclopropyl-4- [1,4] diazepan-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-phenyl) -amine;

bicyclo [1.1.1] pent-1-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -3-fluoro-pyridin-2-yl ] -phenyl-amine;

[4- (5-cyclopropyl-4- [1,4] diazepan-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

(+/-) cis- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-fluoro-cyclobutyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 5-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 5-difluoro-pyridin-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2,2, 2-trifluoro-1-phenyl-ethyl) -amine;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-3-carboxylic acid methylamide;

{4- [4- (3-amino-pyrrolidin-1-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -phenyl } -acetic acid;

[4- (5-cyclopropyl-4-piperidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

3- {4- [ 5-cyclopropyl-4- ((3R,4S) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -benzonitrile;

chroman-4-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

n- (1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl) -acetamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-4-isopropyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-ethyl-2-fluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-5-isopropyl-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-ethyl-2-fluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (4-fluoro-phenyl) -amine;

(R) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidin-3-ol;

[ (R) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-yl ] -methanol;

[ (S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-yl ] -methanol;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid acetamide

(6-cyclopropyl-2, 4-difluoro-pyridin-3-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(6-cyclopropyl-2-fluoro-pyridin-3-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidine-3-carboxylic acid methylamide;

(S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-ol;

1- (3- {4- [ 5-cyclopropyl-4- (4-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -phenyl) -piperidin-4-ol;

1- { 5-cyclopropyl-2- [2- (3-piperazin-1-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (1-methyl-1H-pyrazol-4-yl) -ethyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-6-morpholin-4-yl-pyridin-3-yl) -amine;

1- { 5-cyclopropyl-2- [2- (1-piperidin-4-ylmethyl-1H-pyrazol-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

4((R) -3-benzyloxymethyl-piperazin-1-yl) -2- (2-chloro-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidine;

(3-cyclopropyl-phenyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl) - (4-methyl-piperazin-1-yl) -methanone;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-dimethylamino-ethyl) -amide;

(S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidin-3-ol;

(R) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidin-3-ol;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-methoxy-ethyl) -amide;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -3, 5-difluoro-benzonitrile;

(1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl) -piperazin-1-yl-methanone;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -benzamide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine;

1- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-4-carboxylic acid (2-methylaminoethyl) -amide;

6- {4- [ 5-cyclopropyl-4- ((cis) -3, 4-dihydroxy-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-ylamino } -pyridine-2-carbonitrile;

6- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -pyridine-2-carbonitrile;

1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -3, 3-difluoro-piperidine-4, 4-diol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4, 6-difluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 5-difluoro-pyridin-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(3R,4S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

(3R,4S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

(3S,4S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

(3S,4S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -piperidine-3, 4-diol;

{4- [ 5-cyclopropyl-4- (2-methylamino-ethoxy) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (piperidin-4-yloxy) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methyl-1H-pyrazol-4-ylmethyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -phenethyl-amine;

[4- (5-cyclopropyl-4-pyrrolidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

[4- (4-azetidin-1-yl-5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-fluoro-6-methoxy-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 6-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5-fluoro-pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5-fluoro-pyridin-2-yl ] - (4-fluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-pyrrolidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-piperazin-1-yl-phenyl) -amine;

[4- (4-azetidin-1-yl-5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-piperazin-1-yl-phenyl) -amine;

n- {4- [4- ((R) -3-benzyloxymethyl-piperazin-1-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

{4- [ 5-cyclopropyl-4- ((R) -3-methanesulfonylmethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

n- {4- [ 5-cyclopropyl-4- ((R) -3-methanesulfonylmethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -acetamide;

{4- [ 5-cyclopropyl-4- ((R) -3-methanesulfonylmethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (4-fluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((R) -3-methanesulfonylmethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

cyclopropanecarboxylic acid {4- [ 5-cyclopropyl-4- ((R) -3-methanesulfonylmethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amide;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,4, 6-trifluoro-pyridin-2-yl) -amine;

n- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -N' -methyl-ethane-1, 2-diamine;

n- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -N ', N' -dimethyl-ethane-1, 2-diamine;

1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -azetidin-3-ol;

1- { 5-cyclopropyl-2- [2- (3-piperazin-1-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -azetidin-3-ol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-isopropyl-1H-pyrazol-3-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-ethyl-5-methyl-1H-pyrazol-3-yl) -amine;

[4- (5-cyclopropyl-4-piperidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [6- (4-methyl-piperazin-1-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperidin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [6- (4-methyl-piperazin-1-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 5-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,4, 6-trifluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

(R) -4- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperazine-2-carbonitrile;

{4- [ 5-cyclopropyl-4- (1,2,3, 6-tetrahydro-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl-amine;

{4- [ 5-cyclopropyl-4- (piperidin-4-ylsulfanyl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

(3S,4S) -1- (5-cyclopropyl-2- {2- [3- (4-methyl-piperazin-1-yl) -phenylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -pyrrolidine-3, 4-diol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-cyclopropyl-1H-pyrazol-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (tetrahydro-pyran-4-yl) -1H-pyrazol-4-yl ] -amine;

(1-cyclopentyl-1H-pyrazol-4-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

n- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -N, N' -trimethyl-ethane-1, 2-diamine;

{4- [ 5-cyclobutyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 6-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 6-difluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3-fluoro-pyridin-2-yl) -amine;

(6-chloro-3-fluoro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (3, 6-difluoro-pyridin-2-yl) -ethyl ] -amine;

n- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -N ', N' -dimethyl-butane-1, 4-diamine;

[4- (4-azepan-1-yl-5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

1- { 5-cyclopropyl-2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

(R) -1- { 5-cyclopropyl-2- [2- (6-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-ol;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclobutyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine;

((R) -1-cyclopropyl-ethyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

((R) -1-cyclohexyl-ethyl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(5-cyclopropyl-3-fluoro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

1- {4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -piperidin-1-yl } -2, 2-dimethyl-propan-1-one;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2,2, 2-trifluoro-ethyl) -piperidin-4-yl ] -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methanesulfonyl-piperidin-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2-fluoro-phenyl) -1H-pyrazol-4-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2, 6-difluoro-phenyl) -1H-pyrazol-4-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2,4, 6-trifluoro-phenyl) -1H-pyrazol-4-yl ] -amine;

1- { 5-cyclopropyl-2- [2- (2-methyl-2, 3-dihydro-1H-isoindol-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -3, 5-difluoro-benzamide;

(1S,2S,4R) -bicyclo [2.2.1] hept-2-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(1R,2R,4S) -bicyclo [2.2.1] hept-2-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-cyclopropyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (2-dimethylamino-ethoxy) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-trifluoromethyl-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- ((3R,5S) -3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (4, 7-diaza-spiro [2.5] oct-7-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (7-cyclopropyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (1-methyl-1H-pyrazol-3-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

1- { 5-cyclopropyl-2- [2- (3-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

((R) -1-cyclohexyl-ethyl) - {4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4, 6-difluoro-pyridin-2-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl-amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 6-difluoro-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (5-trifluoromethyl-pyridin-2-yl) -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3-fluoro-pyridin-2-yl) -amine;

-4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -N-methyl-benzamide;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-yl-amine;

{4- [ 5-cyclopropyl-4- ((3R,5S) -3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

6- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -nicotinamide;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,4, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (8-cyclopropyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

4- ((S) -3-benzyl-piperazin-1-yl) -2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine;

[2- (2-benzyl-morpholin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine;

(S)-N¹- (5-methoxy-2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -3-phenyl-propanesAlkane-1, 2-diamines;

5-methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-methoxy-2- (2-phenoxymethyl-morpholin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ (R) -4- (5-methoxy-2-morpholin-4-ylpyrido [3,4-d ] pyrimidin-4-yl) -piperazin-2-yl ] -methanol;

5-methoxy-2-morpholin-4-yl-4- ((R) -3-phenoxymethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

[ (S) -1- (5-methoxy-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperidin-3-yl ] -phenyl-amine;

4- [ (R) -3- (2-fluoro-phenoxymethyl) -piperazin-1-yl ] -5-methoxy-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine;

5-methoxy-4- ((R) -3-methoxymethyl-piperazin-1-yl) -2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine;

4- [ (R) -3- (4-fluoro-phenoxymethyl) -piperazin-1-yl ] -5-methoxy-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine;

(2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) - (R) -pyrrolidin-3-yl-amine;

[ 2-morpholin-4-yl-8- (2H-pyrazol-3-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine;

N⁴- ((S) -2-amino-3-phenyl-propyl) -2-morpholin-4-yl-pyrido [3,4-d]Pyrimidine-4, 8-diamine;

(S)-N¹- (2-morpholin-4-yl-pyrido [3, 4-d)]Pyrimidin-4-yl) -3-phenyl-propane-1, 2-diamine;

5-bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

synthesis of 5-cyclopropyl-2-morpholin-4-yl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

4- ((S) -3-benzyl-piperazin-1-yl) -5-cyclopropyl-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidine;

[ (S) -4- (5-cyclopropyl-2-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-4-yl) -piperazin-2-yl ] -acetonitrile;

5-methoxy-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-methoxy-2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-benzyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- [2- (2-fluoro-benzyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-ethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-methoxy-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-methoxy-4- ((R) -3-methoxymethyl-piperazin-1-yl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ (R) -4- [ 5-methoxy-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -methanol;

4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(R) -pyrrolidin-3-yl- [2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -amine;

5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

8-chloro-5-cyclopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-isopropyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(5-cyclopropyl-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -4- ((R) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -4- ((S) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4- ((S) -3-cyclopropyl-piperazin-1-yl) -2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -4- (3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

4- ((S) -3-benzyl-piperazin-1-yl) -5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4- ((S) -3-cyclopropyl-piperazin-1-yl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ (S) -4- [ 5-cyclopropyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazin-2-yl } -acetonitrile;

5-cyclopropyl-4-piperazin-1-yl-2- (2-thiophen-2-yl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (2-cyclopropyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

4- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-1-carboxylic acid ethyl ester;

5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-ol;

5-cyclopropyl-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4-morpholin-4-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4-piperazin-1-yl-2- (2-trideuteromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-5-chloro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (4-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (5-fluoro-2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(+/-) - (cis) -1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

(+/-) - (trans) -1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-3, 4-diol;

5-cyclopropyl-4- (3-trifluoromethyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4-piperidin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4-piperazin-1-yl-2- [2- (1-trifluoromethyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol;

5-cyclopropyl-2- [2- (1-phenyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidine-4-carbonitrile;

{1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-yl } -methanol;

{1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -azetidin-3-yl } -methanol;

1- { 5-cyclopropyl-2- [2- (1-phenyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ol;

5-cyclopropyl-4- (1, 1-dioxo-1. lamda.)⁶-thiomorpholin-4-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b]Pyridin-4-yl) -pyrido [3,4-d]A pyrimidine;

5-cyclopropyl-4-thiomorpholin-4-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

1- [2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol;

4-azetidin-1-yl-5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

1- [2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] - [1,4] diazepan-5-one;

(R) -1- [2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -pyrrolidin-3-ol;

5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) spiro [1, 3-dihydropyrrolo [2,3-b ] pyridine-2, 1' -cyclohexane ];

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole;

1- [ 5-cyclopropyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-ol;

4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -9H-pyrido [2,3-b ] indole; or a salt form thereof.

56. A compound of formula (I) or a salt form thereof according to claim 1, wherein R²⁴Independently at each occurrence, selected from H, and optionally substituted with 1-13R⁴⁹Substituted C_1-6An alkyl group; and is

R²⁸Selected from the group consisting of optionally substituted 1-28R⁴⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R⁴⁹Substituted 4-21 membered heterocycloalkylalkyl and optionally substituted with 1-11R⁴⁹Substituted byC_6-11And (4) an aryl group.

57. A compound of formula (I) or a salt form thereof according to claim 1 or 56, wherein R¹²And R¹³Together form an optionally substituted 1-21R¹⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R¹⁹Substituted 3-15 membered heterocycloalkyl or optionally substituted with 1-15R¹⁹Substituted 5-15 membered heteroaryl.

58. A compound of formula (I) or a salt form thereof according to claim 1 or 56, wherein R¹²、R¹⁴And R¹⁵Each is H and R¹³is-NR²²R²³。

59. A compound selected from:

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -N, N-dimethyl-benzamide;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,4, 6-trifluoro-pyridin-2-yl) -amine;

(+/-) -cis-1- { 5-cyclopropyl-2- [2- (3-morpholin-4-yl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidine-3, 4-diol;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - ((R) -1-cyclopropyl-ethyl) -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - ((R) -1-phenyl-ethyl) -amine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclobutyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- {2- [1- (2-fluoro-phenyl) -cyclopropyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4, 6-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-cyclopropyl- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

(5-cyclobutyl-3-fluoro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{ 5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

(4-chloro-1-ethyl-1H-pyrazol-3-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2,2, 2-trifluoro-ethyl) -1H-pyrazol-3-yl ] -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - [1- (2,2, 2-trifluoro-ethyl) -1H-pyrazol-3-yl ] -amine;

{4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (1-isopropyl-1H-pyrazol-3-yl) -amine;

{ 5-cyclopropyl-2- [2- (3,4, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

{ 5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl-amine;

{ 5-cyclopropyl-2- [2- (3,4, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -pyrrolidin-3-yl-amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-morpholin-4-yl-phenyl) -amine;

5-cyclobutyl-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-pyrrolidin-3-yl-amine;

azetidin-3-yl- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5, 8-difluoro-9H-pyrido [2,3-b ] indole;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclobutyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

azetidin-3-yl- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine;

[ 4-chloro-1- (2,2, 2-trifluoro-ethyl) -1H-pyrazol-3-yl ] - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -8-fluoro-9H-pyrido [2,3-b ] indole;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (8-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (7-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (S) -pyrrolidin-3-yl-amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -7, 8-difluoro-9H-pyrido [2,3-b ] indole;

{4- [ 5-cyclopropyl-4- ((cis) -3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3,4, 6-trifluoro-pyridin-2-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (2, 2-dimethyl-piperidin-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6, 8-difluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (5-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-phenyl-ethyl) -amine;

(4-chloro-1-ethyl-1H-pyrazol-3-yl) - {4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amine;

benzo (b) isAzol-2-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine;

benzothiazol-2-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methyl-1H-benzimidazol-2-yl) -amine;

(5-cyclopropyl-3, 6-difluoro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

5-cyclopropyl-2- {2- [1- (4-fluoro-phenyl) -cyclopropyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{4- [ 5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - [1- (2,2, 2-trifluoro-ethyl) -piperidin-4-yl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -naphthalen-2-yl-amine;

biphenyl-3-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{4- [ 5-cyclopropyl-4- ((R) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - [3- (4-methyl-piperazin-1-yl) -phenyl ] -amine;

{4- [ 5-cyclopropyl-4- ((R) -3-trifluoromethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (1-methyl-1H-pyrazol-3-yl) -amine;

{ 5-cyclopropyl-2- [2- (3,4, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ 2-fluoro-4- (2-methyl-2H-pyrazol-3-yl) -phenyl ] -amine;

{ 5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (R) -pyrrolidin-3-yl-amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl- (R) -pyrrolidin-3-yl-amine;

azepan-4-yl- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -naphthalen-1-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-D ] pyrimidin-2-yl) -pyridin-2-yl ] -iso [ D3-4] quinolin-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1-methyl-1H-indazol-3-yl) -amine;

{ 5-cyclopropyl-2- [2- (3,4, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl-amine;

5-cyclopropyl-4-piperazin-1-yl-2- [2- (2,2, 2-trifluoro-1, 11-dimethyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (1-phenyl-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (tetrahydro-furan-2-yl) -ethyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (2-fluoro-phenyl) -ethyl ] -amine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-4-yl-amine;

(R) -pyrrolidin-3-yl-amine, [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ];

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

8-chloro-5-cyclopropyl-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazolo [1,5-a ] pyridin-2-yl-amine;

{4- [ 5-cyclopropyl-4- ((cis) -3, 5-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - [1- (2,2, 2-trifluoro-ethyl) -piperidin-4-yl ] -amine;

2- (2-chloro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (2-methoxymethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

4- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ylamino } -piperidin-2-one;

[ 5-cyclopropyl-2- (1-methyl-2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (R) -pyrrolidin-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-D ] pyrimidin-2-yl) -pyridin-2-yl ] - [ D3-4] quinolin-2-yl-amine;

(±) -2- ((endo) -2-bicyclo [2.2.1] hept-2-yl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-methoxymethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl- (1-methyl-piperidin-4-yl) -amine;

5-cyclobutyl-4-piperazin-1-yl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl- (1-methyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (1-methyl-piperidin-4-yl) -amine;

1- (4- { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-ylamino } -piperidin-1-yl) -ethanone;

5-cyclopropyl-2- [2- (1-methyl-1-phenyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (3-chloro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl- (R) -pyrrolidin-3-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-D ] pyrimidin-2-yl) -pyridin-2-yl ] -iso [ D3-4] quinolin-1-yl-amine;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole

4- (4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole;

8-chloro-5-cyclopropyl-2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(±) -exo- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -7-oxa-bicyclo [2.2.1] hept-2-yl-amine;

(2, 6-difluoro-phenyl) - [4- (4-piperazin-1-yl-5-vinyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

1- [4- ({ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -piperidin-1-yl ] -ethanone;

1- [4- ({ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -piperidin-1-yl ] -ethanone;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (R) -indan-1-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (S) -indan-1-yl-amine;

[4- (8-chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-8-fluoro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

5-cyclopropyl-8-fluoro-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(1-cyclobutyl-piperidin-4-ylmethyl) - { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

benzo [1,2, 5] s]Oxadiazol-4-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-)Pyrido [3,4-d]Pyrimidin-2-yl) -pyridin-2-yl]-an amine;

5-cyclopentyl-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- (2-difluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-4-ylmethyl-amine;

5-cyclopropyl-2- [2- (2-methoxy-1, 1-dimethyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (2-methoxy-1, 1-dimethyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(1-cyclobutyl-piperidin-4-yl) - { 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amine;

5-cyclopropyl-4-piperazin-1-yl-2- [2- (tetrahydro-pyran-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (1-phenyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-difluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (1-isopropyl-piperidin-4-yl) -methyl-amine;

benzo [1,2, 5] s]Oxadiazol-5-yl- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3, 4-d)]Pyrimidin-2-yl) -pyridin-2-yl]-an amine;

5-bromo-4-piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -8-chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-8-fluoro-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-bromo-2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(±) -exo-5-cyclopropyl-2- [2- (7-oxa-bicyclo [2.2.1] hept-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(±) -exo-5-cyclobutyl-2- [2- (7-oxa-bicyclo [2.2.1] hept-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2, 6-difluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - [1- (2, 2-difluoro-ethyl) -piperidin-4-yl ] -methyl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -indan-5-yl-amine;

(5-cyclopropyl-3, 6-difluoro-pyridin-2-yl) - {4- [ 5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -amine;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -2, 2-difluoro-2-phenyl-acetamide;

5-cyclopropyl-2- [2- (1-fluoro-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{4- [ 5-cyclopropyl-4- (1-methyl-piperidin-4-ylsulfanyl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (2, 6-difluoro-phenyl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl- (1-methyl-piperidin-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ 2-fluoro-4- (1-methyl-1H-pyrazol-4-yl) -phenyl ] -amine;

{4- [ 5-cyclopropyl-4- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [ 5-cyclopropyl-4- (hexahydro-pyrrolo [3,4-c ] pyrrol-2-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 5-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ]]Pyrimidin-2-yl) -pyridin-2-yl]- (2-trifluoromethyl-benzoOxazol-5-yl) -amine;

5-cyclopropyl-4- (piperidin-4-ylsulfanyl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(±) -endo-2- (2-bicyclo [2.2.1] hept-2-yl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(8-chloro-5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (1,2,3, 4-tetrahydro-naphthalen-2-yl) -amine;

{ 5-cyclopropyl-2- [2- ([ D3-4] quinolin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-D ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-ylmethyl-amine;

(1S,2R) -1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -indan-2-ol;

(1S,2S) -1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -indan-2-ol;

(1R,2S) -1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -indan-2-ol;

(1R,2R) -1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -indan-2-ol;

5-cyclobutyl-2- [2- (2, 6-difluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (2, 6-difluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- (2-cyclobutyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-cyclobutyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (8-chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 5-difluoro-pyridin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-methyl-3H-benzimidazol-5-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [4- (2,2, 2-trifluoro-ethoxy) -phenyl ] -amine;

{2- [2- (5-chloro-3-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

5-cyclopropyl-2- (2-cyclohexyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-cyclohexyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ 3-chloro-1- (5-trifluoromethyl-pyridin-2-yl) -1H-pyrazol-4-yl ] - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-difluoro-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-difluoro-piperidin-4-yl) -amine;

{ 5-cyclobutyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

trans-2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -indan-1-ol;

(R) -2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -2-phenyl-ethanol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-naphthalen-2-yl-ethyl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (2-fluoro-phenyl) -ethyl ] -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethoxy-phenyl) -amine;

{ 5-cyclobutyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

(S) -2- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-ylamino ] -2-phenyl-ethanol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-naphthalen-1-yl-ethyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 2-difluoro-2-phenyl-ethyl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-ylmethyl-amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (tetrahydro-pyran-4-yl) -amine;

{ 8-chloro-5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

{ 8-chloro-5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

(5-chloro-3-fluoro-pyridin-2-yl) - [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl- (tetrahydro-pyran-4-yl) -amine;

(4- { 5-cyclopropyl-4- [3- (tetrahydro-pyran-4-yl) -pyrrolidin-1-yl ] -pyrido [3,4-d ] pyrimidin-2-yl } -pyridin-2-yl) - (3, 5-difluoro-pyridin-2-yl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (3,5, 6-trifluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 3-dimethyl-indan-1-yl) -amine;

[4- (8-chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

5-cyclopropyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (1-phenyl-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4-piperazin-1-yl-2- [2- (2,2, 2-trifluoro-1, 1-dimethyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4-piperazin-1-yl-2- [2- (1-trifluoromethyl-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4-piperazin-1-yl-2- [2- (tetrahydro-furan-3-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4-piperazin-1-yl-2- [2- (tetrahydro-furan-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3-fluoro-piperidin-4-yl) -amine;

[4- (5, 8-bicyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

[4- (5, 8-bicyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3, 5-difluoro-pyridin-2-yl) -amine;

[4- (5, 8-bicyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2, 6-difluoro-phenyl) -amine;

2- (2-tert-butyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5, 8-bicyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridazin-3-yl) -amine;

5-cyclopropyl-4-piperazin-1-yl-2- [2- (tetrahydro-furan-3-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

(2, 6-difluoro-phenyl) - [4- (4-piperazin-1-yl-5-trifluoromethyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

(3, 5-difluoro-pyridin-2-yl) - [4- (4-piperazin-1-yl-5-trifluoromethyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -amine;

[4- (4-piperazin-1-yl-5-trifluoromethyl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3,5, 6-trifluoro-pyridin-2-yl) -amine;

{ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

5-cyclopropyl-2- (2, 2-dimethyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{4- [4- (3-amino-piperidin-1-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 5-difluoro-pyridin-2-yl) -amine;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -6,7,8, 9-tetrahydro-5H-pyrido [2,3-b ] indole;

6-chloro-4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole;

5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{4- [ 5-cyclopropyl-4- (3-methylamino-piperidin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 5-difluoro-pyridin-2-yl) -amine;

n- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -N' -methyl-benzene-1, 4-diamine;

5-cyclopropyl-4-piperazin-1-yl-2- [2- (1-trifluoromethyl-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -6,7,8, 9-tetrahydro-5H-pyrido [2,3-b ] indole;

2- (3-chloro-2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (tetrahydro-pyran-4-yl) -amine;

4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -3, 3-dimethyl-1, 3-dihydro-pyrrolo [2,3-b ] pyridin-2-one;

or a salt thereof.

60. A compound selected from:

4- ({ 8-chloro-2- [2- (5-chloro-3-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -piperidine di-trifluoroacetate;

4- { 8-chloro-2- [2- (5-chloro-3-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } -piperazine di-trifluoroacetate;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-pyridin-2-yl-ethyl) -amine;

2- (2-cyclopentyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2-cyclopentyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (3, 3-difluoro-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (3, 3-difluoro-cyclobutyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - ((R) -1-phenyl-propyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [ (R) -1- (2-methoxy-phenyl) -ethyl ] -amine;

4- {2- [2- (5-chloro-3-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclobutyl-pyrido [3,4-d ] pyrimidin-4-yl } -piperazine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-fluoro-quinolin-2-yl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-phenoxy-ethyl) -amine;

4- ({2- [2- (5-chloro-3-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclobutyl-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -piperidine;

((R) -1- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-yl);

5-cyclobutyl-2- (3-methoxy-2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (2, 2-dimethyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

4- { [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-amino) -piperidine;

{ 5-cyclopropyl-2- [2- ([1,2,4] triazolo [1,5-a ] pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

5-cyclobutyl-2- (6-fluoro-9H-pyrido [2,3-b ] indol-4-yl) -N-methyl-N- (4-piperidinyl) pyrido [3,4-d ] pyrimidin-4-amine;

{ 5-cyclopropyl-2- [2- ((R) -1-phenyl-ethylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

[ 5-cyclobutyl 2- (7-fluoro-9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

{ 5-cyclopropyl-2- [2- (4-trifluoromethoxy-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

{ 5-cyclopropyl-2- [2- (3-methyl-3H-benzoimidazol-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

((S) -1- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-yl);

((R) -1- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-yl) -methyl;

[ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

{ 5-cyclopropyl-2- [2- (4-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethoxy-phenyl) -amine;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -6-fluoro-9H-pyrido [2,3-b ] indole;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -7-fluoro-9H-pyrido [2,3-b ] indole;

((S) -1- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-yl) -methyl;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5-fluoro-9H-pyrido [2,3-b ] indole;

4- ({ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -3-methyl-piperidine;

{ 5-cyclopropyl-2- [2- (4-isopropyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

1- (5-cyclopropyl-2-spiro [1, 3-dihydropyrrolo [2,3-b ] pyridine-2, 1' -cyclohexane ] -4-yl-pyrido [3,4-d ] pyrimidin-4-yl) piperidin-3-amine;

4- ({2- [2- (5-chloro-3-fluoro-pyridin-2-ylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -3, 3-dimethyl-piperidine;

(5-cyclopropyl-2- {2- [1- (2,2, 2-trifluoro-ethyl-) -piperidin-4-ylamino ] -pyridin-4-yl } -pyrido [3,4-d ] pyrimidin-4-yl) -methyl-piperidin-4-yl-amine;

{ 5-cyclopropyl-2- [2- (1-cyclopropyl-piperidin-4-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

(1- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -4-fluoro-piperidin-3-yl);

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-3-yl ] -phenyl-amine;

5-cyclopropyl-2- (3-phenyl-pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(±) -3, 4-trans-4- { [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-amino } -1-methyl-pyrrolidin-3-ol;

(±) -3, 4-trans-4- ({ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -1-methyl-pyrrolidin-3-ol;

(±) -3, 4-trans-4- ({ 5-cyclopropyl-2- [2- ((R) -1-phenyl-ethylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -1-methyl-pyrrolidin-3-ol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-3-yl ] - (2, 6-difluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-3-yl ] - (3, 5-difluoro-pyridin-2-yl) -amine;

2- [2- (2-tert-butyl-thiazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2-phenoxy-ethylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

2- (3-bromo-pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (1-methyl-1-phenyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-fluoro-4-trifluoromethoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methoxy-4-trifluoromethoxy-phenyl) -amine;

(±) - { 5-cyclopropyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

4- ({ 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -3-methoxy-cyclohexane;

2- (3-bromo-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

n1 x- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -ethane-1, 2-diamine;

(±) - { 5-cyclopropyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

(±) - [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -amine;

n (1) - [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -ethane-1, 2-diamine;

{4- [ 5-cyclopropyl-4- (1-oxy-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 5-difluoro-pyridin-2-yl) -amine;

(±) - [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

(4-methyl-piperidin-4-yl) -5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -amine;

(S) -1- [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ylamine;

4- [ 5-cyclobutyl-4- (1-oxy-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -9H-pyrido [2,3-b ] indole;

4- [ 5-cyclobutyl-7-oxy-4- (1-oxy-piperazin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -9H-pyrido [2,3-b ] indole;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -5,6,7, 8-tetrahydro-cyclopenta [4,5] pyrrolo [2,3-b ] pyridine;

{4- [4- ((S) -3-amino-piperidin-1-yl) -5-trifluoromethyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -phenyl-amine;

{4- [4- ((S) -3-amino-piperidin-1-yl) -5-trifluoromethyl-pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } - (3, 5-difluoro-pyridin-2-yl) -amine;

5-cyclopropyl-4- ((S) -2-methyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4- ((S) -2-methyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

[ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (4-methyl-piperidin-4-yl) -amine;

5-cyclopropyl-2- [3- (3-fluoro-phenyl) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [3- (4-fluoro-phenyl) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [3- (2-fluoro-phenyl) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4- ((R) -3-trifluoromethyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

(±) - [ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

[ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (4-methyl-piperidin-4-yl) -amine;

(±) - (5-aza-spiro [2.5] oct-8-yl) - [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -amine;

(±) - (5-aza-spiro [2.5] oct-8-yl) - [ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -amine;

5-cyclopropyl-2- [2- [ (1R,2S,4S) -norbornane-2-yl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- [ (1S,2R,4R) -norbornane-2-yl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ 5-cyclopropyl-2- (3-phenyl-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

[2- (3-bromo-pyridin-4-yl) -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-piperidin-4-yl-amine;

(±) -3, 4-trans-4- { [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-amino } -pyrrolidin-3-ol;

(±) - (3, 4-trans) -4- { [ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -methyl-amino } -pyrrolidin-3-ol;

1- [4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] -cyclobutanol;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (3-trifluoromethoxy-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-methyl-4-trifluoromethoxy-phenyl) -amine;

(S) -1- [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ylamine;

(R) -1- [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ylamine;

4- (5-cyclobutyl-4-morpholin-4-yl-pyrido [3,4-d ] pyrimidin-2-yl) -9H-pyrido [2,3-b ] indole;

(5-aza-spiro [2.5] oct-8-yl) - [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -amine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4- ((S) -3-methyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

n- { 5-cyclopropyl-2- [2- (3, 5-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -cyclohexane-1, 3-diamine;

n- [ 5-cyclopropyl-2- (2-phenylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -cyclohexane-1, 3-diamine;

2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-4- ((S) -2-methyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

(±) - (3, 4-trans) -4- ({2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -pyrrolidin-3-ol;

5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4- ((R) -3-trifluoromethyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine; complexing with trifluoroacetic acid;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (2-trifluoromethoxy-phenyl) -amine;

(±) - {2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

(±) - {2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

(±) - { 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

(±) - { 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4- ((S) -3-methyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4- (3, 3-dimethyl-piperazin-1-yl) -2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazolo [1,5-a ] pyridin-5-yl-amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazolo [1,5-a ] pyridin-6-yl-amine;

(±) - (3, 4-trans) -4- ({ 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } -methyl-amino) -pyrrolidin-3-ol;

5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4- ((S) -2-methyl-piperazin-1-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

(S) -1- {2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-ylamine;

(S) -1- { 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-ylamine;

5-cyclobutyl-2- [2- (2-methyl-tetrahydro-furan-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (2-methyl-tetrahydro-furan-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (2, 2-difluoro-1-methyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [2- (2, 2-difluoro-1-methyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] -cyclobutanol;

1- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -3-phenylurea;

5-cyclopropyl-2- [2- (4-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (4-isopropyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- ([1,2,4] triazolo [1,5-a ] pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

(±) - { 5-cyclobutyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

(5-aza-spiro [2.5] oct-8-yl) - { 5-cyclopropyl-2- [2- (3, 6-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

{2- [2- (4-chloro-phenylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

2- (3-chloro-2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(±) - [ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - ((3, 4-trans) -4-methoxy-pyrrolidin-3-yl) -amine;

(±) - [ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - ((3, 4-trans) -4-methoxy-pyrrolidin-3-yl) -amine;

[ 5-cyclopropyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - ((3R,4S) -3-methoxy-piperidin-4-yl) -amine;

[ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - ((3R,4S) -3-methoxy-piperidin-4-yl) -amine;

[ 5-cyclopropyl-2- (2-p-tolylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -amine;

5-cyclopropyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4- ((S) -2-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [2- (3-fluoro-pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4- ((S) -2-methyl-piperazin-1-yl) -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (3, 6-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

(5-aza-spiro [2.5] oct-8-yl) - { 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-6-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -amine;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-6-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -amine;

{ 5-cyclobutyl-2- [2- (2, 2-difluoro-1-methyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

5-cyclobutyl-2- [2- (1-fluoromethyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

3- [4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] -tetrahydro-furan-3-ol;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

5-cyclopropyl-2- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-5-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

(S) -1- [ 5-cyclopropyl-2- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ylamine;

5-cyclopropyl-4- (2, 6-diaza-spiro [3.3] hept-2-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (pyrazolo [1,5-a ] pyridin-6-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

4- [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperazine-2-carboxylic acid;

{ 5-cyclopropyl-2- [2- (3, 6-difluoro-pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (4-methyl-piperidin-4-yl) -amine;

{ 5-cyclopropyl-2- [2- (2, 2-difluoro-1-methyl-cyclopropyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } -methyl-piperidin-4-yl-amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-fluoro-phenyl) -amine;

[4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-oxetan-3-yl-phenyl) -amine;

5-cyclobutyl-N-methyl-2- [2- (1-methyl-1-phenyl-ethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -N- (4-piperidinyl) pyrido [3,4-d ] pyrimidin-4-amine;

5-cyclopropyl-4- (octahydro-pyrrolo [3,2-c ] pyridin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

(S) -1- [ 5-cyclobutyl-2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] -piperidin-3-ylamine;

2- [3- (2-chloro-phenyl) -pyridin-4-yl ] -5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-4-piperazin-1-yl-2- (3-o-tolyl-pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclopropyl-2- [3- (2-methoxy-phenyl) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

(S) -2-amino-6- [ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-ylamino ] -hexanoic acid;

5-cyclopropyl-4- ((R) -2-methyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4- ((R) -2-methyl-piperazin-1-yl) -2- (2-trifluoromethyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (4-fluoro-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

{2- [2- (4-chloro-phenylamino) -pyridin-4-yl ] -5-cyclopropyl-pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

{ 5-cyclopropyl-2- [2- (4-isopropyl-phenylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

{ 5-cyclopropyl-2- [2- ([1,2,4] triazolo [1,5-a ] pyridin-2-ylamino) -pyridin-4-yl ] -pyrido [3,4-d ] pyrimidin-4-yl } - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

5-cyclobutyl-4- ((S) -2-methyl-piperazin-1-yl) -2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-4- ((R) -2-methyl-piperazin-1-yl) -2- (2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -pyrazin-2-yl-amine;

2- (3-bromo-pyridin-4-yl) -5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- [3- (2-fluoro-phenyl) -pyridin-4-yl ] -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

5-cyclobutyl-2- (3-phenyl-pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

[ 5-cyclopropyl-2- (2-p-tolylamino-pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -6-trifluoromethoxy-9H-pyrido [2,3-b ] indole;

(3, 3-dimethyl-piperidin-4-yl) -5-cyclopropyl-2- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -methyl-amine;

[ 5-cyclopropyl-2- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -amine;

4- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-3-yl ] -benzamide;

[ 5-cyclopropyl-2- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (4-methyl-piperidin-4-yl) -amine;

[ 5-cyclobutyl-2- (9H-pyrido [2,3-b ] indol-4-yl) -pyrido [3,4-d ] pyrimidin-4-yl ] - (3, 3-dimethyl-piperidin-4-yl) -amine;

5-cyclobutyl-2- (2-thiophenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

n- [4- (5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] -benzenesulfonamide;

5-cyclopropyl-2- (3-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

{ 5-cyclopropyl-2- [2- (2-fluoro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } - ((3R,4R) -4-methoxy-pyrrolidin-3-yl) -amine;

{2- [2- (2-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -5-cyclopropyl-3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } - ((3R,4R) -4-methoxy-pyrrolidin-3-yl) -amine;

5-cyclobutyl-4-piperazin-1-yl-2- (1H-pyrazolo [3,4-b ] pyridin-4-yl) -pyrido [3,4-d ] pyrimidine;

4- [ 5-cyclobutyl-4- (octahydro-pyrrolo [3,2-c ] pyridin-1-yl) -pyrido [3,4-d ] pyrimidin-2-yl ] -9H-pyrido [2,3-b ] indole;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

n- {4- [ 5-cyclopropyl-4- (methyl-piperidin-4-yl-amino) -pyrido [3,4-d ] pyrimidin-2-yl ] -pyridin-2-yl } -benzenesulfonamide;

5-cyclopropyl-2- [2- (2-methoxy-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -4-piperazin-1-yl-3, 4-dihydro-pyrido [3,4-d ] pyrimidine;

(S) -1- { 5-cyclopropyl-2- [2- (2-methoxy-phenyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] -3, 4-dihydro-pyrido [3,4-d ] pyrimidin-4-yl } -piperidin-3-ylamine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - (6-fluoro-pyridin-2-yl) -amine;

[4- (5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidin-2-yl) -pyridin-2-yl ] - [1- (2,2, 2-trifluoro-ethyl) -piperidin-4-yl ] -amine;

2- (2-benzenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -5-cyclobutyl-4-piperazin-1-yl-pyrido [3,4-d ] pyrimidine;

or a salt thereof.

61. A compound as defined in claim 1, wherein R is¹⁹Independently at each occurrence is selected from the group consisting of optionally substituted 1-13R³⁹Substituted C_1-6Alkyl, optionally substituted with 1-11R³⁹Substituted C_6-11Aryl, optionally substituted with 1-19R³⁹Substituted C_7-16Arylalkyl, optionally substituted with 1-21R³⁹Substituted C_3-11Cycloalkyl optionally substituted by 1-28R³⁹Substituted 3-15 membered heterocycloalkyl, optionally substituted with 1-40R³⁹Substituted 4-21 membered heterocycloalkylalkyl, optionally substituted with 1-15R³⁹Substituted 5-15 membered heteroaryl, halogen, -CN, -C (═ O) OR³⁰、-NR³²R³³、–OR³⁰、＝O、–S(＝O)_nR³⁰Wherein n is 0, 1, or 2.

62. A compound as defined in any one of claims 1, 56, or 61, wherein G is formula (la)A group of (a); and R is⁷Is optionally substituted by 1-21R¹⁹Substituted C_3-11Cycloalkyl radical and R⁸And R⁹Is H.

63. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

64. Use of a compound of formula (I) according to any one of claims 1-62, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an aPKC-dependent disorder or condition in a subject.

65. The use of claim 64, wherein the aPKC-dependent disorder or condition is cancer.