HK1201829B

HK1201829B - Novel heterocyclic carboxamides as modulators of kinase activity

Info

Publication number: HK1201829B
Application number: HK15102308.6A
Authority: HK
Inventors: B‧R‧胡克; X‧陈; Y‧肖; R‧兰; L‧C‧德塞尔姆; C‧尼古; J‧布特尼克; S‧R‧卡拉; T‧L‧约翰逊
Original assignee: 默克专利有限公司
Priority date: 2011-12-22
Filing date: 2012-12-17
Publication date: 2018-02-02

Description

Novel heterocyclic carboxamides as modulators of kinase activity

Technical Field

The present invention relates to a series of heterocyclic carboxamide compounds useful in the treatment of hyperproliferative diseases, such as cancer, in mammals. The invention also includes the use of the compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing the compounds.

Background

Protein kinases constitute a large family of structurally related enzymes responsible for The control of a variety of signal transduction processes within cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase products book.I and II, Academic Press, san Diego, Calif.). Kinases can be grouped into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that generally correspond to families of these kinases have been identified (e.g., Hanks, S.K., Hunter, T., FASEB J., 9: 576-596 (1995); Knighton, et al, Science, 253: 407-414 (1991); Hiles et al, Cell, 70: 419-429 (1992); Kunz et al, Cell, 73: 585-596 (1993); Garcia-Butoes, et al, EMBO J., 13: 2352-2361 (1994)).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. A single protein kinase may be regulated by more than one mechanism.

By adding phosphate groups to target proteins, kinases can regulate many different cellular processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes. These phosphorylation events act as molecular on-off switches that can modulate or modulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stress, etc. Suitable protein kinases function in signaling pathways to activate or inactivate (directly or indirectly) e.g. metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation is implicated in a variety of diseases including, for example, inflammation, cancer, allergy/asthma, immune system diseases and disorders, central nervous system diseases and disorders, and angiogenesis.

Protein kinase 70S6K, 70kDa ribosomal protein kinase p70S6K (also known as SK6, p70/p85S6 kinase, p70/p85 ribosomal S6 kinase and pp70S6K) is a member of the AGC subfamily of protein kinases. p70S6K is a serine-threonine kinase that is part of the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is a downstream part of PI3K and is activated in response to phosphorylation at multiple sites by various mitogens, hormones, and growth factors. Since rapamycin acts to inhibit p70S6K activity, p70S6K activity is also controlled by the mTOR-containing complex (TORC 1). p70S6K is regulated by PI3K downstream targets AKT and PKC ζ. Akt directly phosphorylates and inactivates TSC2, thereby activating mTOR. Furthermore, studies of mutant alleles of p70S6K that are inhibited by wortmannin but not rapamycin indicate that the PI3K pathway can exert effects on p70S6K independent of the regulation of mTOR activity.

The enzyme p70S6K regulates protein synthesis by phosphorylation of the S6 ribosomal protein. S6 phosphorylation is associated with increased translation of the mRNA coding component of the translation apparatus (translational appatatus) including ribosomal proteins and translation elongation factors (the increased expression of which is essential for cell growth and proliferation). These mrnas contain an oligopyrimidine tract at their 5 'transcription start (called 5' TOP), which has been shown to be essential for their regulation at the translation level.

In addition to being involved in translation, p70S6K activation is also involved in cell cycle control, neural cell differentiation, regulation of cellular motility and cellular responses important in tumor metastasis, immune responses, and tissue repair. The p70S6K antibody disrupted the mitogenic response driven by rat fibroblasts into S phase, indicating that p70S6K function is essential in the progression from G1 to S phase in the cell cycle. Furthermore, it has been determined that inhibition of cell cycle proliferation by rapamycin from the G1 to S phase of the cell cycle is a result of its inhibition to produce the hyperphosphorylated, activated form of p70S 6K.

The role of p70S6K in tumor cell proliferation and protection from apoptosis is supported based on its involvement in growth factor receptor signaling, overexpression and activation in tumor tissues. For example, northern and Western blot analyses showed that Amplification of the PS6K gene was accompanied by a corresponding increase in mRNA and protein expression, respectively (Cancer Res. (1999) 59: 1408-11-PS6K localized to the Chromosomal Region17q23 in breast Cancer and Determination of Its Amplification (Localization of PS6K to chromosome Region17q23and Determination of Its Amplification in Breast Cancer)).

Chromosome 17q23 was amplified in the following tumors and cancers: up to 20% of primary breast tumors, 87% of breast tumors containing a mutation in BRCA2 and 50% of tumors containing a mutation in BRCA1, as well as other Cancer types, such as pancreatic Cancer, bladder Cancer and neuroblastoma (see m.barlund, o.monni, j.kononen, r.cornelison, j.torhorrst, g.sauter, o. -p.kallidimemi and kallidimemi a., Cancer res., 2000, 60: 5340-. Studies have shown that 17q23 amplification in breast Cancer involves the PAT1, RAD51C, PS6K and SIGMA1B genes (Cancer Res (2000): 60, pp 5371-5375).

The p70S6K gene has been identified as a target for amplification and overexpression at these sites, and a statistically significant correlation between amplification and poor prognosis was observed. Clinical inhibition of p70S6K activation was observed in renal cancer patients treated with CCI-779 (rapamycin ester), an inhibitor of the upstream kinase mTOR. A significant linear correlation between disease progression and inhibition of p70S6K activity was reported. Tumor suppressor LKB1 activates AMPK in response to energy stress, which phosphorylates TSC1/2 complex and renders it inactive the mTOR/p70S6K pathway. Mutations in LKB1 cause poietz-yersinie syndrome (Peutz-jegherssydrome PJS), and patients with PJS develop 15 times as likely cancer as the general population. In addition, 1/3 lung adenocarcinoma was latent with the unactivated LKB1 mutation. p70S6K is involved in metabolic diseases and disorders. The lack of p70S6K was reported to avoid age and diet induced obesity while increasing insulin sensitivity. Based on these findings, the role of p70S6K in metabolic diseases and disorders such as obesity, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperaminoemia, and hyperlipidemia is supported.

Compounds described as suitable for inhibiting p70S6K are disclosed in WO03/064397, WO04/092154, WO05/054237, WO05/056014, WO05/033086, WO05/117909, WO05/039506, WO06/120573, WO06/136821, WO06/071819, WO06/131835, WO08/140947 and PCT/US 10/000313.

Disclosure of Invention

It is an object of the present invention to provide novel compounds that modulate kinase activity. Such protein kinase modulation includes, but is not limited to, p70S6K inhibition and AKT inhibition, which are useful in the treatment of hyperproliferative diseases, especially those associated with hyperactivity of the above-mentioned protein kinases, such as cancer in mammals, said compounds having superior pharmacological properties with respect to activity as well as solubility, metabolic clearance and bioavailability characteristics.

Accordingly, the present invention provides novel heterocyclic carboxamides and their pharmaceutically acceptable salts, solvates or prodrugs, which are kinase inhibitors and useful in the treatment of the diseases mentioned above.

The compound is a compound shown in a general formula (I) and a pharmaceutically acceptable salt, a solvate of salt or a prodrug thereof,

wherein:

x is N, or C-R⁴；

Y is N-R⁵O, or absent;

R¹is L¹-R⁶、L¹-R⁶-L²-R⁷；

R²Is H, Hal, OH, OA, CN, NH₂Or NHA;

R³is H, CH₃Or C (Hal)₃；

R⁴Is H, Hal, OH, COOH, NH₂Or CN;

R⁵is H, LA or is a monocycloalkyl having 3,4,5, 6 or 7 ring atoms, of which 1 or 2 CH₂The radical may be replaced by-NH-, or

R⁵、R¹Together form a monocyclic alkyl radical having 3,4,5, 6 or 7 ring atoms, of which 1 or 2 CH₂The radicals being substituted by O atoms and/or-NH-, -NA-, -N (L)¹-R⁶)-、-CHA-、-CA₂-、CH(L¹-R⁶) -or-CO-group, and the monocycloalkyl group may be replaced by NH₂Substitution;

L¹、L²independently a single bond, or an unbranched or branched alkyl radical having 1,2,3, 4 or 5C atoms which may be unsubstituted or substituted by Hal, OH, NH₂、NH(LA)、N(LA)₂Mono-or di-substituted, in which 1 or 2 CH₂The radicals being substituted by O atoms or by-CO-, -NH-, -N (LA) -, -CONH-, -N (LA) COO-or-NHCO-group;

R⁶is Ar or is a monocycloalkyl group having 3,4,5, 6 or 7 ring atoms, of which 1 or 2 CH₂The radicals may be replaced by O atoms and/or by-NH-, -NA-, -CHA-, -CO-or-CONHA-groups;

ar is a monocyclic or bicyclic, aromatic carbocyclic or heterocyclic ring having 0, 1,2,3 or 4N, O and/or S atoms and 5, 6, 8, 9 or 10 framework atoms, which carbocyclic or heterocyclic ring may be unsubstituted or, independently of one another, Hal, A, OA, OH, NH₂Or NHA mono-, di-or tri-substituted;

a is an unbranched or branched, linear or cyclic alkyl radical having 1,2,3, 4,5 or 6C atoms, in which 1 or 2 CH₂The group may be replaced by an O atom and/or a-NH-, -NHCOAr or-CONHAR group, wherein 1-3H atoms may be replaced by Hal, and wherein 1 or 2 CH₃The radical being optionally substituted by NH₂OH, NH (LA) or N (LA)₂Substituted by a group;

LA is an unbranched or branched, linear alkyl group having 1,2,3 or 4C atoms, wherein 1,2 or 3H atoms may be replaced by Hal (e.g. methyl, ethyl and trifluoromethyl); and

hal is F, Cl, Br or I.

In general, all residues occurring more than once may be the same or different, i.e. they are independent of each other. Unless otherwise indicated, residues and parameters in the context have the meaning as indicated under the general formula (I).

The invention therefore relates in particular to compounds of the general formula (I) in which at least one of the radicals has the preferred meanings indicated below.

"Hal" denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

"A" denotes, for example, methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1,2-, 1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl.

"A" also denotes an alkyl group as defined above, wherein one or two CH' s₂Groups can be replaced by O or S atoms and/or by NH, N (LA), CONH, NHCO or-CH ═ CH-groups, and/or further 1 to 3H atoms can be replaced by F and/or Cl, for example trifluoromethyl, pentafluoroethyl, 1, 1-difluoromethyl, 1,1, 1-trifluoroethyl, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In other examples of "A", one or two CH₃The radicals being substituted by OH, SH, NH₂，N(LA)H，N(LA)₂Or CN, for example N, N' -dimethylaminoalkyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 3-aminomethylcyclobutyl or cyanoalkyl. Cyclic a preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

"LA" denotes unbranched or branched, linear alkyl having 1,2,3 or 4C atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

"Ar" represents, for example, unsubstituted phenyl, naphthyl or biphenyl, and further preferably, for example, phenyl, naphthyl or biphenyl, each of which is mono-, di-or trisubstituted with A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonylamino, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl.

"Ar" also means o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-acetylaminophenyl, o-, m-or p-methoxyphenyl, M-or p-ethoxyphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulfonylamino) phenyl, o-, m-or p- (methylsulfonyl) phenyl, preference is also given to 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2,4, 5-dichloro-4-bromophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, and mixtures thereof, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl, (4-methoxyphenyl) methyl, (3-methoxyphenyl) methyl, (4-methoxyphenyl) ethyl, (3-methoxyphenyl) ethyl.

"Ar" also preferably represents 2-, 3-or 4-phenyl, 2-, 3-or 4-phenylmethyl, 2-, 3-or 4-phenylethyl, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 3-or 4-pyridylmethyl, 2-, 3-or 4-pyridylethyl, 2-, 4-, 5-or 6-pyrimidinyl, 2-, 3-, 5-or 6-pyrazin-1-or 4-yl, furthermore preferably represents 1,2, 3-triazol-1-, -4-or 5-yl, 1,2, 4-triazol-1-, -3-or 5-yl, 1-or 5-tetrazolyl, 1,2, 3-oxadiazol-4-or 5-yl, 1,2, 4-oxadiazol-3-or 5-yl, 1,3, 4-oxadiazol-2-yl, 1,3, 4-thiadiazol-2-or 5-yl, 2-, 4-pyrazin-1-or 4-yl, 1,2,3, 4-thiadiazol-1-or 5-yl, or mixtures thereof, 1,2, 4-thiadiazol-3-or-5-yl, 1,2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-or 5-isoindolyl, 2-, 6-or 8-purinyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, diazo-1, 2,4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, quinoxalin-2-, 3-, 4-or 5-yl, 4-, 5-or 6-phthalazinyl, 2-, 3-, or, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, preferably also 1, 3-benzodioxol-2-, 4-or 5-yl, thiophen-2-or 3-yl, 1, 4-benzodioxan-6-yl, 2,1, 3-benzothiadiazol-4-or-5-yl or 2,1, 3-benzooxadiazol-5-yl, furan-2-or 3-yl, 2, 3-dihydro-benzofuran-2-, 3-, 4-or 5-yl, each of which is unsubstituted or may be substituted, for example, by carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl, phenyl, benzyl, -CH₂Cyclohexyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetylamino, ureidoMethanesulfonylamino, formyl, acetyl, aminosulfonyl and/or methanesulfonyl are mono-, di-or trisubstituted.

Particularly preferred are compounds corresponding to sub-formulae 1 to 10 of the general formula (I) in which:

in the sub-formula 1, the first,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

In the sub-formula 2, the first,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

R⁵、R¹Together form a monocyclic alkyl radical having 3,4,5, 6 or 7 ring atoms, of which 1 or 2 CH₂The radicals may be substituted by-NH-, -NA-, -N (L)¹-R⁶)-、-CHA-、-CA₂-、CH(L¹-R⁶) -or-CO-group, and the monocycloalkyl group may be replaced by NH₂The substitution is carried out by the following steps,

in the sub-formula 3, the first,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

R⁵、R¹Together form a monocycloalkyl group having 4,5 or 6 ring atoms, of which 1 CH₂The group may be substituted by-N (L)¹-R⁶) -a group and the monocycloalkyl group may be replaced by NH₂The substitution is carried out by the following steps,

in the sub-formula 4, the group,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

R⁵、R¹Together form a monocycloalkyl group having 4,5 or 6 ring atoms, of which 1 CH₂The group may be substituted by-N (L)¹-R⁶) -is replaced by a group, and the said monoCycloalkyl radicals may be substituted by NH₂The substitution is carried out by the following steps,

L¹is a bond, -CONH-, -NHCO-, -CONHCH₂-、CH₂CONH-，

In the sub-formula 5, the compound represented by the general formula,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

R⁶is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、C(Hal)₃O is mono-, di-or tri-substituted,

in the sub-formula 6, the compound represented by the general formula,

x is a group of atoms selected from the group consisting of N,

y is N-R⁵，

X is a group of atoms selected from the group consisting of N,

y is N-R⁵，

L¹is the key, -CONH-, -NHCO-, -CONHCH₂-、CH₂CONH-，

R⁶Is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-, di-or tri-substituted,

in the sub-formula 7, the group,

x is a group of atoms selected from the group consisting of N,

y is a radical of NH,

R¹is L¹-R⁶-L²-R⁷，

L¹，L²Is the presence of an inverted or small molecule of an amino acid,

R⁶is a monocycloalkyl group having 4,5 or 6 ring atoms, of which 1 CH₂The group may be replaced by an-NH group,

R⁷is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-, di-or tri-substituted,

in the sub-formula 8, the group,

x is a group of atoms selected from the group consisting of N,

y is a radical of NH,

R¹is L¹-R⁶-L²-R⁷，

L¹，L²Is the presence of an inverted or small molecule of an amino acid,

R⁶is a piperidinyl group or a pyrrolidinyl group,

R⁷is phenyl, said phenyl being substituted by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-substituted or di-substituted,

in the sub-formula 9, the compound represented by the general formula,

x is a group of atoms selected from the group consisting of N,

y is a radical of NH,

R¹is L¹-R⁶-L²-R⁷，

L¹，L²Is the presence of an inverted or small molecule of an amino acid,

R⁶is thatOr

in the sub-formula 10, the group,

x is a group of atoms selected from the group consisting of N,

y is a radical of NH,

R¹is L¹-R⁶，

R⁶Is phenyl, said phenyl being unsubstituted or independently by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-, di-or tri-substituted,

the remaining residues have the meanings indicated above for formula (I).

The compounds of the present invention may be in the form of prodrug compounds. "prodrug compound" means a derivative that can be converted into the biologically active compound of the present invention in an organism under physiological conditions, for example, by oxidation, reduction, hydrolysis, and the like, each of which can be carried out with or without the participation of an enzyme. Examples of prodrugs are the compounds of the following cases: wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino; or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted to a boronic ester, for example acetyloxy, palmitoyloxy, pivaloyloxy, succinoyloxy, fumaroyloxy, alanoyloxy; or wherein the carboxyl group is esterified or amidated; or wherein the thiol group forms a disulfide bridge with a carrier molecule (e.g., a peptide) that selectively delivers the drug to the target and/or to the cytosol. These compounds can be prepared from the compounds of the present invention according to known methods. Further examples of prodrugs are compounds wherein the carboxylic acid ester in the compounds of the invention is for example converted into alkyl-, aryl-, choline, amino, acyloxymethyl, linolenoyl-ester.

Metabolites of the compounds of the invention are also within the scope of the invention.

When tautomerism (e.g., keto-enol tautomerism) of the compounds of the present invention or prodrugs thereof exists, it is intended to claim both their individual forms (e.g., keto or enol forms), respectively, and mixtures thereof in any proportion. The same applies to their stereoisomers, e.g., enantiomers, cis/trans isomers, conformational isomers, and the like.

If desired, isomers can be separated according to methods known in the art (e.g., liquid chromatography). The same applies to their enantiomers, for example, using chiral stationary phase separation. Furthermore, enantiomers can be separated by conversion to diastereomers, i.e. coupling with enantiomerically pure auxiliary compounds, followed by separation of the resulting diastereomers and cleavage of the auxiliary residues. Alternatively, any enantiomer of a compound of the invention may be obtained by stereoselective synthesis using optically pure starting materials.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, especially their pharmaceutically acceptable salts. The compounds according to the invention which contain acidic groups can therefore be present in the form of salts and, according to the invention, can be used, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More specific examples of such salts include: sodium, potassium, calcium, magnesium or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine or amino acids). The compounds of the invention containing one or more basic groups, i.e. groups which can be protonated, can be present in the form of salts and, according to the invention, in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, napadisylic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, then, in addition to the salt forms, the invention likewise comprises internal salts or betaines (zwitterions). The salts can be prepared by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in solvents or dispersants, or by exchanging anions or cations with other salts. The invention likewise comprises all salts of the compounds of the invention which, owing to their low physiological compatibility, are not suitable for direct use in medicaments but can be used, for example, as chemical reaction intermediates or in the preparation of pharmaceutically acceptable salts.

The term "substituted" preferably means substituted by the above-mentioned substituents, wherein a plurality of different degrees of substitution are possible, unless otherwise specified.

All physiologically acceptable salts, derivatives, solvates of salts and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.

The compounds of formula (I) may have one or more chiral centres. The compounds may thus occur in a variety of enantiomeric forms and may be in racemic or optically active form. The invention therefore also relates to the optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

Because there may be differences in the pharmaceutical activity of racemates or stereoisomers of the compounds of the present invention, it may be desirable to use enantiomers. In these cases, the final products and even intermediates can be resolved into enantiomeric compounds using chemical or physical methods known to those skilled in the art or even employed directly synthetically.

In the case of racemic amines present in the molecular structure, the mixture can form diastereomers with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid and lactic acid in R or S form, suitable N-protected amino acids (e.g.N-benzoylproline or N-phenylsulphonylproline), or various optically active camphorsulphonic acids. Chromatographic resolution of the enantiomers with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylic acid polymers, immobilized on silica gel, is also advantageous. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example ethane/isopropanol/nitrile, for example in a ratio of 82: 15: 3. One elegant way to resolve racemates containing ester groups (e.g., acetyl esters) is to use enzymes, particularly esterases.

In addition, the present invention relates to a pharmaceutical composition comprising the compound of the present invention or a prodrug compound thereof or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient and a pharmaceutically acceptable carrier.

"pharmaceutical composition" means one or more active ingredients and one or more inert ingredients that make up the carrier, as well as any product obtained directly or indirectly from: any two or more components are combined, complexed, aggregated, or one or more components are dissociated, or one or more components are otherwise reacted or interacted with. Thus, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may additionally contain one or more other compounds as active ingredients, for example one or more additional compounds of the present invention, prodrug compounds or other p70S6K inhibitors.

Pharmaceutical compositions include suitable compositions for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ocular), pulmonary (nasal or buccal inhalation) or nasal administration, the most suitable route in any known case depending on the nature and severity of the condition being treated and on the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art.

In one embodiment, the compounds and pharmaceutical compositions are useful for treating the following diseases: cancers, for example brain cancer, lung cancer, colon cancer, epidermoid cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, uterine cancer, rectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, melanoma, hematological malignancies, such as acute myelogenous leukemia, multiple myeloma, chronic myelogenous leukemia, myeloid leukemia, glioma, kaposi's sarcoma, or any other type of solid or liquid tumor. Preferably, the cancer treated is selected from breast, colorectal, lung, prostate or pancreatic cancer or glioblastoma.

The invention also relates to the use of the compounds of the invention in the preparation of medicaments for the treatment of hyperproliferative diseases associated with overactivity of p70S6K and diseases modulated by the p70S6K cascade in mammals or for the treatment of disorders mediated by abnormal proliferation, such as cancer and inflammation.

The present invention also relates to compounds or pharmaceutical compositions for treating diseases associated with angiogenesis or vasculogenesis in a mammal comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, prodrug or hydrate thereof and a pharmaceutically acceptable carrier.

In one embodiment, the compound or pharmaceutical composition may be used to treat the following diseases: tumor angiogenesis, chronic inflammation (e.g., rheumatoid arthritis, inflammatory bowel disease), atherosclerosis, skin diseases (e.g., psoriasis, eczema, and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration.

The present invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate or prodrug thereof and an amount of an additional anti-cancer therapeutic agent, wherein the amount of the compound, salt, solvate or prodrug together with the amount of the chemotherapeutic agent is effective to inhibit abnormal cell growth. Many anti-cancer therapeutic agents are currently known in the art. In one embodiment, the anti-cancer therapeutic is a chemotherapeutic agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. In another embodiment, the anti-cancer therapeutic is an antibody selected from the group consisting of: bevacizumab, CD 40-specific antibody, chTNT-1/B, desuzumab, zamumab, IGF 1R-specific antibody, lintuzumab, ibritumomab, WX G250, rituximab, tiximumab, trastuzumab, and cetuximab. In another embodiment, the anti-cancer therapeutic is an inhibitor of another protein kinase, such as Akt, Axl, Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt-3, PDK1, and Erk.

The present invention also relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with surgery or radiation therapy, wherein the amount of the compound, salt, solvate or prodrug in combination with the radiation therapy is effective to inhibit abnormal cell growth or treat the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques may be used in the combination therapies described herein. In such combination therapy, administration of a compound of the invention may be determined as described herein. It is believed that the compounds of the present invention may render abnormal cells more susceptible to radiation therapy, thereby killing and/or inhibiting the growth of such cells.

Accordingly, the present invention also relates to a method of sensitizing abnormal cells in a mammal to radiation therapy comprising administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, effective to sensitize the abnormal cells to radiation therapy. The amount of a compound, salt or solvate in the present methods can be determined according to the methods described herein for determining an effective amount of the compound. The present invention also relates to a method of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, prodrug or isotopically labeled derivative thereof, and an amount of one or more agents selected from the group consisting of an anti-angiogenic agent, a signaling inhibitor and an antiproliferative agent.

In practice, the compounds of the present invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. In the case of oral liquid preparations, any conventional pharmaceutical media can be used, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. In the case of oral solid preparations, the compositions may be presented as, for example, powders, hard and soft capsules, and tablets, with solid oral dosage forms being preferred over liquid dosage forms.

Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. The compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of active compound in these compositions may vary and may advantageously range from about 2% to about 60% by weight. The amount of active compound in the therapeutically useful composition is such that an effective dose is obtained. The active compounds can likewise be administered intranasally, for example, as liquid drops or as sprays.

Tablets, pills, capsules, and the like may likewise comprise: binders, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid; lubricants, such as magnesium stearate; and sweetening agents such as sucrose, lactose or saccharin. Where the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the unit dose. For example, tablets may be coated with shellac, sugar coating or both. A syrup or elixir may contain, in addition to the active ingredient: sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, a coloring agent and a flavoring (e.g., cherry or orange flavor).

The compounds of the invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared by appropriate mixing in water with a surfactant, such as hydroxy-propylcellulose. Dispersions can be prepared from glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile injectable aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the forms must be sterile and must be sufficiently fluid to allow them to be easily injected. In the case of preparation and storage, the form must be stable and must be capable of resisting contamination by microorganisms, such as bacteria and fungi. The carrier can include solvents or dispersion media such as water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may provide a mammalian, especially human, effective dose of a compound of the invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. administration is possible. The dosage forms comprise tablets, buccal tablets, dispersing agents, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably, the compounds of the invention are administered orally.

The effective amount of the active ingredient administered may depend on the particular compound being administered, the mode of administration, the condition being treated, and the severity of the condition being treated. The dosage can be readily determined by one skilled in the art.

In the treatment or prevention of cancer, inflammation or other proliferative diseases for which the compounds of the invention are indicated, substantially satisfactory results are obtained when a daily dose of from about 0.01mg to about 100mg per kg of animal body weight is administered, preferably a single daily dose. For large mammals, the total daily dosage is from about 0.1mg to about 1000mg, preferably from about 0.2mg to about 50 mg. In the case of a 70kg adult, the total daily dose is approximately about 0.2mg to 200 mg. The dosage regimen may be adjusted to provide the optimum therapeutic response.

The invention also relates to a kit (kit) comprising the following individual packages:

a) an effective amount of a compound of the present invention or a physiologically acceptable salt, solvate or prodrug thereof; and

b) an effective amount of an additional pharmaceutically active ingredient.

The kit comprises a suitable container, such as a box, a separate bottle, a bag or an ampoule. The kit may comprise, for example, separate ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further pharmaceutically active ingredient, in dissolved or lyophilised form.

Detailed Description

Experimental part

Some abbreviations that may appear in this application are as follows:

abbreviations

Name (R)
		ACN	Acetonitrile
AcOH	Acetic acid
		AIBN	Azobisisobutyronitrile
ATP	Adenosine triphosphate
		b	Broad peak
Bop-Cl	Bis (2-oxo-3-oxazolidinyl) phosphoryl chloride
		Conc.	Concentrating
d	Double peak
		DCM	Methylene dichloride
DCE	Dichloroethane
		DMAP	Dimethylaminopyridine
DMF	Dimethyl formamide
		DMSO	Dimethyl sulfoxide
DIEA/DIPEA	N, N-diisopropylethylamine
		DTT	Dithiothreitol

EDTA	Ethylenediaminetetraacetic acid
		equiv./eq.	Equivalent weight
Et	Ethyl radical
		h	Hour(s)
HEPES	4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
		HPLC	High pressure liquid chromatography
LC/MS	Liquid chromatography-mass spectrometry
		LiOH	Lithium hydroxide
m	Multiple peaks
		M	Molecular ion
m/z	Mass to charge ratio
		Me	Methyl radical
MeOH	Methanol
		min	Minute (min)
MS	Mass spectrometry
		N	Equivalent (concentration unit)
NaOH	Sodium hydroxide
		NBS	N-bromosuccinimide
NMO	4-methylmorpholine N-oxide
		NMP	N-methyl-2-pyrrolidone
NMR	Nuclear magnetic resonance
		PG	Protecting group
psi	Pounds per square inch
		q	Quartet peak
Rf	Retention factor
		RT/rt	At room temperature
Rt.	Retention time
		s	Single peak
T3P	Propyl phosphoric cyclic anhydride

TBAF	Tetrabutylammonium fluoride
		Tert	Tertiary amine
TEA	Triethylamine
		TFA	Trifluoroacetic acid
THAB	Tetrahexylammonium bromide
		THF	Tetrahydrofuran (THF)
UV	Ultraviolet light
		VIS	It can be seen that

The compounds of the present invention may be prepared according to the methods of the schemes and examples below, using appropriate materials, as further illustrated in the specific examples below.

In addition, other compounds claimed herein can be readily prepared by using the methods described herein, in conjunction with conventional techniques in the art. However, the compounds illustrated in the examples are not to be construed as being the only type of the present invention. The examples also illustrate a detailed description of the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations of the conditions and procedures of the following preparative procedures can be used to prepare these compounds.

The compounds of the invention are typically isolated in the form of their pharmaceutically acceptable salts, such as those described above. The base corresponding to the isolated salt as the free amine can be prepared by neutralization with a suitable base such as aqueous sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, extraction of the liberated base as the free amine with an organic solvent and subsequent evaporation. The free amine isolated in this way can be further converted into other pharmaceutically acceptable salts by dissolving it in an organic solvent, followed by addition of the appropriate acid, and finally evaporation, precipitation or crystallization.

The invention is illustrated but not limited by the specific embodiments described in the following schemes and examples. Unless otherwise stated in the flow chart, any variables have the same meaning as described above.

Unless otherwise stated, all starting materials were from commercial suppliers and used without further purification. Unless otherwise indicated, all temperatures are expressed in ° c and all reactions are carried out at room temperature. The compounds were purified by silica chromatography or preparative HPLC.

The invention also relates to a process for the preparation of the compounds of general formula (I) according to the scheme and the working examples described below.

Synthetic schemes describing intermediate and end product compounds

Quinazoline bromide intermediate 1a was prepared by a commercially available 2-amino-3-methylbenzoic acid according to the 8-step synthesis described in scheme 1.

Scheme 1

Quinoline intermediates 9a, 10a were purchased commercially and 11a was prepared according to the 5-step synthesis described in scheme 2.

Scheme 2

Amine intermediates were either purchased commercially or prepared according to the following synthetic routes (scheme 3, scheme 4, scheme 5 and scheme 6).

Scheme 3

Protection of the amino group of compound 3a with Toc affords 3 b. 3b is hydrolyzed to release carboxylic acid 3 c. 3c with an amine and then removing Toc the protecting group to yield amine intermediate e.

Scheme 4

Aromatic aldehyde 4a reacts with nitromethane under alkaline conditions to give hydroxy derivative 4b, which 4b is converted to alkene 4c under elimination conditions promoted by acetic anhydride. Cyclization of 4c with N-benzyl-1-methoxy-N- ((trimethylsilyl) methyl) methylamine yields pyrrolidine derivative 4 d. Reduction of the nitro group of 4d with Raney nickel as catalyst followed by Teoc protection of the amino moiety with N- [2- (trimethylsilyl) ethoxycarbonyloxy ] succinimide gave 4 f. The N-benzyl group of 4f was removed under hydrogenation conditions and protected with di-tert-butyl dicarbonate to give 4 h. The Teoc-protected primary amine was released 4h after tetra-n-butylammonium fluoride treatment to give amine intermediate 4 i.

Scheme 5

Amino acid 5a was protected with Boc to afford 5 b. 5b is then reacted with an amine to form the amide 5 c. Removal of the Cbz group under hydrogenation conditions yields the desired amine intermediate 5 d.

Scheme 6

The amino group of amino acid 6a is selectively protected with Teoc and the acid moiety is coupled to an amine to form amide 6 c. Removal of the Teoc with TBAF afforded amine intermediate 6 d.

Scheme 7

Under reductive amination conditions, 7a and 7b react to produce 7c, which is then treated with acid to give the deprotected pyrrolidine intermediate 7d as the trifluoroacetate salt.

Scheme 8

Coupling of bromide intermediate 1a with amine 8b, where necessary P is a protecting group, produces 8 c. The nitrile intermediate 8c is hydrolyzed under basic conditions and with the aid of hydrogen peroxide to give the amide 8d, which is then deprotected to give the desired compound 8 e.

Scheme 9

9a is subjected to oxidative hydrolysis with hot concentrated sulfuric acid to convert the nitrile to the carboxamide 9 b. Coupling of 9b with a carboxylic acid affords 9 c. Deprotection of 9c affords 9d, the desired compound.

Scheme 10

Benzyl bromide 10a is reacted with aniline 9b to produce the desired compound 10 b.

Scheme 11

The 5-bromoquinoline-8-carbonitrile 11a reacts with an aminopyrrolidine derivative under Buckwald Harting coupling reaction conditions to give 11 b. The nitrile moiety is converted to the carboxamide using hot concentrated sulfuric acid to provide compound 11 c.

Scheme 12

Under Buckwald Harting coupling reaction conditions, 5-bromoquinoline-8-carboxylic acid methyl ester 12a reacts with amine intermediate 8b to give 12 b. 12b are treated with ammonia in methanol to yield carboxamide 12c, and the protecting group of 12c is removed to yield 12 d.

Analytical method

Analytical LC/MS was performed using the following three methods:

method A: using DiscoveryC¹⁸5 μm, 3 × 30mm column, flow rate 400 μ L/min, sample loop 5 μ L, mobile phase (A) containing 0.1% formic acid in water, and mobile phase (B) containing 0.1% formic acid in methanol; the retention time is in minutes. Detailed description of the method: (I) using a Quaternary Pump G1311A (Agilent), equipped with a UV/VIS diode array detector G1315B (Agilent) and a Finnigan LCQ Duo MS detector (ESI + mode), UV-detection at 254 and 280nm, gradient: 15-95% (B)3.2 min linear gradient, (II) 1.4 min hold at 95% (B), (III) 0.1 min linear gradient from 95-15% (B), and (IV) 2.3 min hold at 15% (B).

Method B: using a Waters Symmetry C18, 3.5 μm, 4.6x75mm column, flow rate 1 mL/min, loop 10 μ L was injected, mobile phase (a) was water with 0.05% TFA, mobile phase (B) was ACN with 0.05% TFA; the retention time is in minutes. Detailed description of the method: (I) binary Pump G1312A (Agilent) was used, with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B (SL) MS detector (ESI + mode), UV-detection at 254 and 280nm, gradient: 20-85% (B)10 min linear gradient, (II) hold at 85% (B) for 1 min, (III) 0.2 min linear gradient from 85-20% (B), and (IV) hold at 20% (B) for 3.8 min.

Method C: gradient: 4.2 min/flow rate: 2 ml/min 99: 01-0: 100% water + 0.1% by volume TFA; acetonitrile + 0.1% by volume of TFA; 0.0 to 0.2 minutes: 99: 01; 0.2 to 3.8 minutes: 99: 01 → 0: 100(ii) a 3.8 to 4.2 minutes: 0: 100, respectively; column: chromolith Performance RP18 e; the length is 100mm, and the diameter is 3 mm; wavelength: 220 nm.

Analytical chiral HPLC

Analytical chiral HPLC was performed in an Agilent1100 series system using a chiral Pak AD-H column (250X4.6mm) from Daicel Chemical Industries, Ltd. The method used a 5.0 μ L injection volume, a flow rate of 1 mL/min, a 100% methanol run at 25 ℃ for 15 min, and UV-detection at 254 and 280 nm.

Preparative HPLC

Using Waters Atlantis dC₁₈OBD^TM10 μ M (30X250mm) column or Waters Sunfire PrepC₁₈OBD10 μ M (30X250mm) column for preparative HPLC. The column was used at a flow rate of 60 mL/min on a Waters Prep LC4000System equipped with a sample injection loop (10mL) and ISCOIA-6 UV/Vis detector. The mobile phase was aspirated from two solvent bottles containing (a) water and (B) HPLC-grade acetonitrile. Typical preparations use a linear gradient (e.g., 0-60% solvent B over 60 minutes).

Examples

The following working examples are intended to illustrate specific embodiments of the invention and are not intended to limit the scope of the specification or claims in any way. These working examples describe methods of synthesizing certain agents useful for preparing heterocyclic carboxamide compounds for the treatment of hyperproliferative diseases and methods of synthesizing these heterocyclic quinazoline and quinoline carboxamide compounds.

Preparation of intermediates

An intermediate A:5-bromoquinazoline-8-carbonitriles

Step 1: 8-methyl-quinazolin-4 (3H) -ones

2-amino-3-methylbenzoic acid (100g, 0.66mol), formamidine acetate (206g, 1.98mol) and formamide (26mL, 0.6600mol) were mixed together in a 2L round bottom flask equipped with a mechanical stirrer. The reaction mixture was heated at 160 ℃ for 16 hours. Completion of the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with 2n naoh solution (300 mL). After stirring at the same temperature for 15 minutes, the reaction mixture was neutralized with 1.5N HCl solution. The solid precipitate was filtered off, washed with ice-cold water and dried in vacuo to give the title compound (90g, 86% yield) as a cream solid.¹HNMR(DMSO-d₆，400MHz)12.21(bs，1H)，8.10(s，1H)，7.95-7.93(dd，J＝8.8,7.9Hz，1H)，7.65-7.63(d，J＝7.9Hz，1H)，7.39-7.35(t，J＝15.2Hz，1H)，2.51(s，3H)。

Step 2: 4-chloro-8-methyl quinazoline

Under nitrogen atmosphere, POCl is added₃(300mL) was placed in a 2L round bottom flask. 8-Methylquinazolin-4 (3H) -one (45g) was added portionwise. The reaction mixture was refluxed at 120 ℃ for 12 hours. Completion of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The resulting residue was dissolved in DCM (500mL) and frozen saturated K was poured in under constant stirring₂CO₃In solution. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated in vacuo to give (45g, 90% yield) the title compound as a yellow solid. This compound was used in the next step without further purification.¹H NMR(CDCl3，400MHz)9.03(s，1H)，8.08-8.06(dd，J＝8.9，8.4Hz，1H)，7.77-7.76(d，J＝7.1Hz，1H)，7.59-7.56(d，J＝15.5Hz，1H)，2.75(s，3H)。

And step 3: 8-methyl quinazoline

To a solution of 4-chloro-8-methyl quinazoline (45g, 0.252mol) in DCM (700mL) was added p-toluenesulfonyl hydrazide (65.9g, 0.353mol) in portions with stirring under a nitrogen atmosphere. The reaction mixture was heated at 45 ℃ for 12 hours. By TLC and LCMS monitors whether the reaction is complete. After the reaction was complete, the reaction mixture was cooled to room temperature and the solvent was evaporated to dryness. The resulting residue was dissolved in ethanol (500mL), and 2N NaOH solution (300mL) was added to the solution and the mixture was refluxed for 6 hours. After confirmation by LCMS, the reaction mixture was cooled to room temperature and extracted with MTBE (3 × 600 mL). The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The residue obtained was filtered by column chromatography using neutralized silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent to give (15g, 27% yield) the title compound as a low melting point yellow solid.¹H NMR(DMSO-d₆，400MHz)9.54(s，1H)，9.31(s，1H)，7.97-7.94(dd，J＝8.8,8.1Hz，1H)，7.87-7.84(m，1H)，7.65-7.62(d，J＝15.2Hz，1H)，2.67(s，3H)。

And 4, step 4: 5-bromo-8-methyl quinazoline

8-Methylquinazoline (10g, 0.0694mol) in portions at 0 ℃ in concentrated H₂SO₄(100mL) silver sulfate (34.64g, 0.1111mol) was added. Bromine (4.4mL, 0.0832mol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS periodically. After 16 h LCMS showed 42% starting material and 51% product. Adding ice to the reaction mixture and reacting with NH₄Basifying the OH solution. The aqueous layer was extracted with ethyl acetate (4 × 500mL), washed with water and brine solution. Na for organic layer₂SO₄Drying and vacuum concentrating. The crude product was purified by column chromatography using neutralized silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent to give (51% yield) the title compound as a pale yellow liquid.¹H NMR(DMSO-d₆，400MHz)9.60-9.58(s，1H)，9.40-9.38(s，1H)，7.93-7.91(d，J＝7.72Hz，1H)，7.77-7.75(d，J＝7.72Hz，1H)，2.62(s，3H)。

And 5: 5-bromo-8- (dibromomethyl) quinazoline

5-bromo-8-methyl quinazoline (46g, 0.206mol) was stirred in CCl under a nitrogen atmosphere₄(800mL) was added N-bromosuccinimide (80.4g, 0.451mol) and AIBN (6.74g, 0.041 mol) at room temperature). The reaction mixture was heated at 90 ℃ for 12 hours. After the end reaction, the reaction mixture is cooled to room temperature, filtered off and washed with CCl₄And (6) washing. The filtrate was concentrated to dryness to give (61g) the title compound as a yellow liquid. The crude product was used in the next step without purification.¹HNMR(DMSO-d₆，400MHz)9.73(s，1H)，9.53(s，1H)，8.45-8.43(d，J＝8.04Hz，1H)，8.22-8.20(d，J＝8.04Hz，1H)，8.02(s，1H)。

Step 6: 5-bromoquinazoline-8-carbaldehyde

To a solution of 5-bromo-8- (dibromomethyl) quinazoline (61g, crude mixture) in acetone (500mL) and water (100mL) was added silver nitrate (61g) in portions with stirring at 0 ℃. The reaction mixture was stirred at room temperature for 6 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered off and the filtrate was extracted with ethyl acetate (3 × 500 mL). The organic layer was washed with 10% NaHCO₃The solution, water and brine solution were washed. Na as solvent₂SO₄Dried and concentrated in vacuo to give the crude product which was purified by HPLC (56%) (25g, 65%), preparative HPLC conditions: column: xterra, C18(19X300mm), 10 microns, mobile phase: 0.1% TFA; b: methanol to isolate the compound. NH for the solid obtained₄Basification of OH and extraction with ethyl acetate. The organic layer was washed with water. Na as solvent₂SO₄Drying and concentration in vacuo gave (6.2g) the title compound as a pale yellow solid.¹H NMR(DMSO-d₆，400MHz)11.14(s，1H)，9.80(s，1H)，9.58(s，1H)，8.30-8.27(d，J＝12.3Hz，2H)。

And 7: 5-bromo-quinazoline-8-carbaldehyde oxime

To a suspension of 5-bromo-quinazoline-8-carbaldehyde (2400.00 mg; 10.12 mmol; 1.00eq.) in acetonitrile (10ml) was added hydroxylamine hydrogen chloride (773.90 mg; 11.14 mmol; 1.10eq.), followed by triethylamine (1.57 ml; 11.14 mmol; 1.10 eq.). The reaction mixture was stirred at 100 ℃ for 1 hour and LCMS showed MS270/272(M + 18). The reaction mixture was cooled, filtered, the filtrate was washed with ether and 3000mg of the product 5-bromo-quinazoline-8-carbaldehyde oxime was collected in 117% yield (¹HNMR showed 1eq triethylamine hydrochloride).

And 8: 5-bromoquinazoline-8-carbonitriles

To a solution of 5-bromo-quinazoline-8-carbaldehyde oxime (3000.00 mg; 11.90 mmol; 1.00eq.) in DMF (15ml) was added a 50% solution of 2,4, 6-tripropyl- [1,3,5,2,4,6] trioxatriphosphane 2,4,6 trioxide (10.42 ml; 17.85 mmol; 1.50eq.) in DMF. The resulting mixture was stirred at 100 ℃ for 45 minutes and LCMS showed a major peak (MS: 252/254,234/236) and a minor peak (MS: 208/209). The reaction mixture was cooled, poured into water, extracted with ethyl acetate, dried, and concentrated to give a viscous solid which was washed with ether and the title product was collected (1665mg. yield 59.6%). LC-MS (232/234and 250/252).

An intermediate B:5-Bromoquinoline-8-carboxylic acid methyl ester

Step 1: 5-bromo-8-methylquinoline

To 8-methylquinoline (30g, 0.209mol) in concentrated H at 0 deg.C₂SO₄(300ml) silver sulfate (97.98g, 0.314mol) was added portionwise and bromine (10.74ml, 0.209mol) was added dropwise. After completion of the addition of bromine, the reaction mixture was stirred at room temperature for 4 hours, and completion of the reaction was confirmed by TLC. After the reaction is complete, ice is added to the reaction mixture, with NH₄Basifying the OH solution and extracting with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, and concentrated to give (43g, 92.4% yield) a dark brown liquid. The crude product was used in the next step without purification.¹H NMR(DMSO-d₆，400MHz)：8.97-8.96(dd，J＝4.16,5.8Hz，1H)，8.45-8.42(dd，J＝8.56,10.2Hz，1H)，7.81-7.79(d，J＝7.68Hz，1H)，7.67-7.64(dd，J～8.52,12.64Hz，1H)，7.53-7.51(dd，J＝7.64,8.52Hz，1H)，2.66(s，3H)。

Step 2: 5-bromo-8- (dibromomethyl) quinoline

To 5-bromo-8-methylquinoline (86g, 0.387mol) in CCl at room temperature₄To a solution (700ml) was added N-bromosuccinamide (144g, 0.813mol), followed by benzoyl peroxide (8.6g), and the reaction mixture was heated at 90 ℃ for 12 hours. Completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction mixture was filtered off and concentrated to give (140g, 95% yield) as a pale orange solid, which was used in the next step without purification.¹H NMR(DMSO-d₆，400MHz)：9.1-9.08(dd，J＝4.16,5.8Hz，1H)，8.59-8.57(dd，J＝8.56,10.2Hz，1H)，8.25-8.23(d，J＝8.04Hz，1H)，8.16-8.11(t，J＝19.08Hz，2H)，7.82-7.79(dd，J＝8.6,12.8Hz，1H)。

And step 3: 5-bromoquinoline-8-carbaldehyde

To a solution of 5-bromo-8- (dibromomethyl) quinoline (75g, 0.197mol) in acetone (400mL) and water (100mL) was added silver nitrate (75g) in portions over 10 minutes at 0 ℃. The reaction mixture was stirred at room temperature for 6 hours. Completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction mixture was filtered off and the filtrate was extracted with MTBE (1000 ml). The organic layer was washed with 10% NaHCO₃The solution, water and brine solution were washed. Na for organic layer₂SO₄Drying and concentration gave (15g, 32% yield) the title compound as a white solid.¹H NMR(DMSO-d₆，400MHz)：11.272-11.27(s，1H)，9.17-9.15(dd，J＝4.2,5.8Hz，1H)，8.64-8.62(dd，J＝8.6,10.3Hz，1H)，8.17-8.15(d，J＝7.84,1H)，8.09-8.07(d，J＝7.88Hz，1H)，7.85-7.82(dd，J＝8.64,12.84Hz，1H)。

And 4, step 4: 5-bromoquinoline-8-carboxylic acid

To a solution of 5-bromoquinoline-8-carbaldehyde (10g, 0.039mol) in THF (300ml) was added aqueous NaOH (30g) in portions at room temperature over 10 minutes, followed by silver nitrate (10.79g, 0.0635mol), and the reaction mixture was stirred at room temperature for 30 minutes. Completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction mixture was filtered off. The black solid was washed with THF, methanol and DMF (50ml each). (Note: the product was not dissolved in any of the above solvents, and the filtrate and washing solution were discarded).The black solid was dried to give the title compound (crude-30 g). The crude product was used in the next step without purification.¹H NMR(DMSO-d₆，400MHz)：8.92-8.91(dd，J＝4.12,5.8Hz，1H)，8.49(s，1H)，8.46-8.44(dd，J＝8.56,10.2Hz，1H)，7.83-7.81(dd，J＝7.6，Hz，1H)，7.63-7.6(dd，J＝8.52,12.68Hz，1H)，7.46-7.44(d，J＝7.6Hz，1H)。

And 5: 5-Bromoquinoline-8-carboxylic acid methyl ester

To a solution of 5-bromoquinoline-8-carboxylic acid (30g, 0.119mol, unpurified) in DMF (400ml) was added potassium carbonate (41.12g, 0.297mol) and methyl iodide (MeI) (22.3ml, 0.357mol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and confirmed by TLC whether the reaction was complete. After completion of the reaction, the reaction mixture is filtered off and evaporated. The reaction mixture was washed with 10% NaHCO₃Basified and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound as a brown liquid (4.6 g). LCMS: found (M +, 268).¹H NMR(DMSO-d₆，400MHz)：9.04-9.02(dd，J＝3.92,5.68，Hz，1H)，8.58-8.56(m，1H)，8.05-8.03(d，J＝7.72Hz，1H)，7.87-7.86(d，J＝7.76Hz，1H)，7.78-7.75(dd，J＝8.6,12.8Hz，1H)，3.91(s，3H)。

Representative Synthesis of intermediate C (scheme 4)

3-amino-4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester(trans, racemate)

Step 1: 1- (3-trifluoromethoxy-phenyl) -2-nitro-ethanol

A solution of 3-fluoromethoxybenzaldehyde (21.37 ml; 201.43 mmol; 1.00eq.) and nitromethane (13.06 ml; 241.71 mmol; 1.20eq.) in methanol (40ml) was cooled to-10 ℃. A solution of NaOH (8.46 g; 211.50 mmol; 1.05eq.) in water (20ml) was added over 10 minutes, maintaining the temperature below-5 ℃. The reaction mixture was stirred at-5 ℃ for 15 minutes, during which time the reaction solution solidified to a white solid. The temperature of the reaction mixture was raised to 0 ℃ and diluted with water (150 ml). After all the solids had dissolved, HCl (4M, 100ml) was added. The reaction mixture was extracted with DCM (300ml x 2). The combined extracts were washed with brine and concentrated to give 34.8g of the desired 1- (3-trifluoromethoxy-phenyl) -2-nitro-ethanol, 93% yield.

Step 2: 1-trifluoromethoxy-3- ((E) -2-nitro-vinyl) -benzene

N, N-dimethylpyridin-4-amine (2.30 g; 18.80mmol) was added to a solution of 1- (3-fluoromethoxyphenyl) -2-nitroethanol (34.80 g; 187.95mmol) in acetic anhydride (35.53 ml; 375.90mmol) at 0 ℃ and stirred at room temperature for 72 hours. The reaction mixture was poured into NaHCO under vigorous stirring₃Saturated solution (400 mL). The desired intermediate was extracted with ethyl acetate (3 × 100 mL). The organic extract was washed with saturated NaHCO₃The solution, washed with brine, MgSO₄Drying, filtration and concentration gave 26.0g of the desired 1-trifluoromethoxy-3- ((E) -2-nitro-vinyl) -benzene, 83% yield.

And step 3: trans-1-benzyl-3- (3-trifluoromethoxy-phenyl) -4-nitro-pyrrolidine

Reacting N-benzyl-1-methoxy-N- [ (trimethylsilyl) methyl group]Methylamine was added to a solution of 1-trifluoromethoxy-3- ((E) -2-nitro-vinyl) -benzene (6.00 g; 35.90mmol) in DCM (50 ml). The reaction solution was cooled to 0 ℃ and TFA (0.30 ml; 3.95mmol) was added dropwise thereto, followed by stirring at room temperature overnight. The reaction solution was washed with water and brine, MgSO₄Drying, filtering, and concentrating. The crude material was purified by Biotage (340g column) eluting with 5% ethyl acetate in hexane to give 5.5g of the desired product in 51% yield.

And 4, step 4: (trans-1-benzyl-4- (3-trifluoromethoxy-phenyl) -pyrrolidin-3-ylamine

Trans-1-benzyl-3- (3-trifluoromethoxyphenyl) -4-nitropyrrolidine (5.50 g; 18.31mmol) was dissolved inMethanol (300 mL). Addition of NH₃(30ml, 2.0M solution in methanol) the solution was passed through an H cube reactor (flow rate 1.5min/min, perhydro, 50 ℃). The reaction solution was concentrated to give 4.6g of (trans-1-benzyl-4- (3-trifluoromethoxy-phenyl) -pyrrolidin-3-ylamine, yield 92%.

And 5: 2- (trimethylsilyl) ethyl [ trans-1-benzyl-4- (3-trifluoromethoxy-phenyl) -pyrrolidin-3-yl ] -carbamate

1- ({ [2- (trimethylsilyl) ethoxy) at 0 deg.C]Carbonyl } oxy) pyrrolidine-2, 5-dione (4.5 g; 17.37mmol) was added trans-1-benzyl-4- (3-trifluoromethoxyphenyl) pyrrolidinyl-3-amine (4.5 g; 16.87mmol) and DIEA (4.5 ml; 25.30mmol) in DCM (50 ml). The reaction mixture was heated to room temperature and stirred at room temperature for 1 hour. The reaction solution was washed with brine, MgSO₄Drying, filtering and concentrating. The crude material was purified by Biotage eluting with a gradient of 30% to 60% ethyl acetate in hexanes to give 6.0g of the title compound in 99% yield.

Step 6: 2- (trimethylsilyl) ethyl [ trans-4- (3-trifluoromethoxy-phenyl) -pyrrolidin-3-yl ] -carbamate

Acetic acid (2mL) was added to a solution of 2- (trimethylsilyl) ethyl [ trans-benzyl-4- (3-trifluoromethoxyphenyl) pyrrolidin-3-yl ] carbamate (2.50 g; 6.03mmol) in ethanol (150 mL). Pd/C (1.25g, wet, 10% Pd) was added and the reaction mixture was placed in a parr shaker apparatus (pressure 60Psi) and allowed to react for 2 hours. The reaction mixture was filtered off, and the filtrate was concentrated to give the title compound (1.96g, quantitative yield).

And 7: trans-3- (3-trifluoromethoxyphenyl) -4- ({ [2- (trimethylsilyl) ethoxy ] carbonyl } amino) -pyrrolidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (1.27 g; 5.82mmol) was added to a solution of 2- (trimethylsilyl) ethyl [ trans-4- (3-fluoromethoxyphenyl) pyrrolidin-3-yl ] carbamate (1.80 g; 5.55mmol) and DIEA (2.2 ml; 12.26mmol) in DCM (100ml) and stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by Biotage eluting with a gradient of 20% to 60% ethyl acetate in hexane to give the title compound 2.0g, 85% yield.

And 8: 3-amino-4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (trans, racemate)

Trans-3- (3-trifluoromethoxyphenyl) -4- ({ [2- (trimethylsilyl) ethoxy)]Carbonyl } amino) -pyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g; 5.76mmol) and N, N-tributylbutane-1-ammonium fluoride (20.00 ml; 1.00M; 20.00mmol) was dissolved in methanol and stirred at room temperature overnight. The crude product was purified by Biotage eluting with a gradient of 5% to 10% methanol in DCM to give the title compound (1.61g, 79% yield). LC-MS (M + H346, obsd 347).¹HNMR(DMSO-d6)1.39(s，9H)，1.55(s，1H)，2.90-2.99(m，2H)，3.24-3.26(m，1H)，3.33-3.37(m，1H)，3.55-3.57(m，1H)，3.60-3.68(m，1H)，3.70-3.72(m，1H)，7.05-7.06(m，1H)，7.13-7.15(m，2H)，7.35-7.36(m，1H)。

Representative Synthesis of intermediate D (scheme 6)

((3- (phenylcarbamoyl) piperidin-3-yl) methyl) carbamic acid benzyl ester (racemate)

Step 1: 3- ((((benzyloxy) carbonyl) amino) methyl) -1- ((2- (trimethylsilyl) ethoxy) -carbonyl) piperidine-3-carboxylic acid

To a solution of 3- (benzyloxycarbonylamino-methyl) -piperidine-3-carboxylic acid hydrochloride (2000.00 mg; 6.08 mmol; 1.00eq.) in DME (60ml) was added DIEA (3.82 ml; 21.29 mmol; 3.50 eq.). After stirring for 15 min, 3-trimethylsilanyl-propionic acid 2, 5-dioxo-pyrrolidin-1-yl ester (1628.18 mg; 6.69 mmol; 1.10eq.) was added. The reaction mixture was stirred at room temperature overnight. An additional 50ml of DME was added to the reaction solution, which was washed with 1% citric acid, brine, dried and concentrated to give a residue showing a clean mass spectrum peak as the title compound (2462mg, yield 85%) which was used directly in the next step reaction.

Step 2: 2- (trimethylsilyl) ethyl 3- ((((benzyloxy) carbonyl) amino) methyl) -3- (phenylcarbamoyl) piperidine-1-carboxylic acid ester

To a solution of 3- ((((benzyloxy) carbonyl) amino) methyl) -1- ((2- (trimethylsilyl) ethoxy) carbonyl) piperidine-3-carboxylic acid (2462.00 mg; 5.64 mmol; 1.00eq.) in DCE (4.0ml) was added bis (2-oxo-1, 3-oxazolidin-3-yl) hypophosphoryl chloride (1435.59 mg; 5.64 mmol; 1.00 eq.). After stirring for 15 min at room temperature, DIEA (1.52 ml; 8.46 mmol; 1.50eq.) and phenylamine (525.18 mg; 5.64 mmol; 1.00eq.) were added. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added 50ml of DCM, washed with brine, dried and concentrated. The residue was purified using a SNAP column (100g) eluting with 20-50% ethyl acetate in hexanes to give the title compound (2600mg, 90.1% yield).

And step 3: ((3- (phenylcarbamoyl) piperidin-3-yl) methyl) carbamic acid benzyl ester

A reaction mixture of 2- (trimethylsilyl) ethyl 3- ((((benzyloxy) carbonyl) amino) methyl) -3- (phenylcarbamoyl) piperidine-1-carboxylic acid ester (1200.00 mg; 2.35 mmol; 1.00eq.) and TBAF (10.00 ml; 9.38 mmol; 4.00eq.) in THF was stirred at room temperature overnight. The crude product was purified by preparative HPLC to give the title compound (600mg, 69.6%).

Representative Synthesis of intermediate E (scheme 5)

3-aminomethyl-3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester(racemate)

Step 1: 3- (Benzyloxycarbonylamino-methyl) -pyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester

A reaction mixture of 3- (benzyloxycarbonylamino-methyl) -pyrrolidine-3-carboxylic acid hydrochloride (2000.00 mg; 6.35 mmol; 1.00eq.) and di-tert-butyl dicarbonate (1.77 ml; 8.26 mmol; 1.30eq.) was suspended in N-butanol (25.00ml) and treated with 2N aqueous NaOH (3.97 ml; 7.94 mmol; 1.25 eq.). The reaction mixture was heated to 75 deg.C (bubbling was immediately observed) for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (100ml), washed with water and brine, MgSO₄Drying, concentration and drying gave 1-tert-butyl 3- (benzyloxycarbonylamino-methyl) -pyrrolidine-1, 3-dicarboxylate (2200mg, 89.4%).

Step 2: 3- (Benzyloxycarbonylamino-methyl) -3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1-tert-butyl 3- (benzyloxycarbonylamino-methyl) -pyrrolidine-1, 3-dicarboxylate (2200.00 mg; 5.81 mmol; 1.00eq.) in DCE (40.0ml) was added bis (2-oxo-1, 3-oxazolidin-3-yl) phosphoryl chloride (1627.95 mg; 6.40 mmol; 1.10 eq.). After stirring for 15 min, DIEA (1.25 ml; 6.98 mmol; 1.20eq.) and phenylamine (595.55 mg; 6.40 mmol; 1.10eq.) were added. The reaction mixture was stirred at room temperature overnight. 50ml of DCM were added. The solution was washed with brine, dried and concentrated to give the crude product which was purified with biotage, eluent 20-50% ethyl acetate in hexanes to give the title compound (1800mg, 68.3%).

And step 3: 3-aminomethyl-3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3- (benzyloxycarbonylamino-methyl) -3-phenylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1200.00 mg; 2.65 mmol; 1.00eq.) in 30ml of methanol was added ammonium formate (1668.40 mg; 26.46 mmol; 10.00eq.) and 10% Pd/C (wet) 1.2 g. The mixture was stirred at 65 ℃ for 1 hour, then filtered and concentrated to give the crude product, which was dissolved in DCM and washed with 5% NaHCO₃Washed with brine, dried and concentrated to give the title compound (820mg, 97%).

Representative Synthesis of intermediate F (scheme 3)

3-amino-4- ((3-fluorophenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester(racemate)

Step 1: 4- (2-trimethylsilyl-ethoxycarbonylamino) -pyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester

4- (2-trimethylsilyl-ethoxycarbonylamino) -pyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (4443.00 mg; 11.04 mmol; 1.00eq.) LiOH₂A reaction mixture of O (1389.45 mg; 33.11 mmol; 3.00eq.) in water (16.50ml) and methanol (16.50ml) was stirred at 45 ℃ overnight. After removal of part of the solvent, the mixture was extracted with DCM, washed with 5% citric acid, dried and concentrated to give a pale yellow oil as the title compound (3200mg, 77.4%).

Step 2: 3- (3-fluoro-phenylcarbamoyl) -4- (2-trimethylsilyl-ethoxycarbonylamino) -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (2-trimethylsilyl-ethoxycarbonylamino) -pyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester (3200.00 mg; 8.54 mmol; 1.00eq.) in DCE (40.0ml) was added bis (2-oxo-1, 3-oxazolidin-3-yl) phosphoryl chloride (2392.68 mg; 9.40 mmol; 1.10 eq.). After stirring for 15 min, DIEA (1.69 ml; 9.40 mmol; 1.10eq.) and 3-fluoro-phenylamine (1044.40 mg; 9.40 mmol; 1.10eq.) were added. The reaction mixture was stirred at 45 ℃ overnight. The reaction solution was diluted with ethyl acetate, washed, dried, and concentrated to give a crude product which was purified using a SNAP (100g) column (eluent was 20-50% ethyl acetate in hexane) to give the title compound (1700mg, 42.5%).

And step 3: 3-amino-4- (3-fluoro-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester

To 3- (3-fluoro-phenylcarbamoyl) -4- (2-trimethylsilyl-ethoxycarbonylamino) -pyrrolidine-1-carboxylic acid tert-butyl ester (1700.00 mg; 3.64 mmol; 1.00eq.) was added TBAF (2851.67 mg; 10.91 mmol; 3.00eq.) (1.0M in THF11 ml). The resulting mixture was stirred overnight. The reaction mixture was poured into water, washed with brine, 5% NaHCO₃Washed with brine, dried and concentrated to give a crude product to which ether (5ml) was added. The white precipitated solid was filtered off to give the title compound (710mg, 60.4%).

Representative Synthesis of intermediate G (scheme 7)

N- (3, 4-dichlorobenzyl) pyrrolidin-3-amine(racemate)

Step 1: 3- ((3, 4-Dichlorobenzyl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g; 8.05 mmol; 1.00eq.) and 3, 4-dichlorobenzaldehyde (1339.00 mg; 7.65 mmol; 0.95eq.) in methanol (10.00ml) and acetic acid (1.00ml) was stirred at room temperature for 30 minutes, followed by addition of sodium cyanoborohydride (9.66 ml; 9.66 mmol; 1.20 eq.). The reaction mixture was stirred at room temperature for 2 more hours, during which time an aqueous ammonia solution (30mL) was poured into the reaction mixture. The resulting inorganic precipitate was filtered off and washed with dichloromethane (50 mL). The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane (50mL x 3). The organic extracts were combined, washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by flash column chromatography on silica eluting with a gradient of ethyl acetate in hexane to give the desired intermediate tert-butyl 3- ((3, 4-dichlorobenzyl) amino) pyrrolidine-1-carboxylate (2.47 g; 7.16 mmol; 88.9%) as a clear viscous oil. LC-MS (M + H346, obsd 288 (M-57)).

Step 2: n- (3, 4-dichlorobenzyl) pyrrolidin-3-amine

To a solution of tert-butyl 3- ((3, 4-dichlorobenzyl) amino) pyrrolidine-1-carboxylate (100 mg; 0.29 mmol; 1.00eq) in dichloromethane (3mL) was added trifluoroacetic acid (0.04 mL; 0.58 mmol; 2.00 eq). The reaction flask was equipped with an argon inlet and stirred until TLC confirmed completion of the reaction (10% methanol in dichloromethane). After completion of the reaction, the solution was concentrated in vacuo to give a dry residue, redissolved in dichloromethane and concentrated (× 3) to give the desired intermediate G as TFA salt in quantitative yield. LC-MS (M + H246, obsd 246).

Example Compounds of formula (I)

Example 15- ((4- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide(Trans-racemate)

Step 1: 3- ((8-cyano-quinazolin-5-yl) amino) -4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (trans racemate)

A reaction mixture of intermediate A (100.00 mg; 0.43 mmol; 1.00eq.) tert-butyl 3-amino-4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylate (trans racemate) (155.38 mg; 0.45 mmol; 1.05eq.) and DIEA (0.15 ml; 0.85 mmol; 2.00eq.) in NMP (2ml) was stirred at 120 ℃ overnight. The reaction mixture was purified by preparative HPLC to give the title compound (120mg, 56.8%).

Step 2: 3- ((8-carbamoyl-quinazolin-5-yl) amino) -4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (trans racemate)

3- (8-cyano-quinazolin-5-ylamino) -4- (4-trifluoromethoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (100.00 mg; 0.20 mmol; 1.00eq.) with 2.0M aqueous NaOH solution (1 ml; 2.00 mmol; 10.00eq.) and 35% H₂O₂Aqueous solution (0.19 ml; 2.00 mmol; 10.00 eq).) in DMSO (8ml) at 40 ℃ overnight. The crude product was purified by preparative HPLC to give the title compound (58mg, 56.0%).

And step 3: 5- ((4- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide (trans racemate)

To 58.0mg of tert-butyl 3- ((8-carbamoylquinazolin-5-yl) amino) -4- (4- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylate (trans racemate) was added 1ml of methanol, 1ml of 4.0m HCl in dioxane. The resulting mixture was stirred at room temperature for 3 hours. Removal of the solvent gave a crude product which was treated with acetonitrile to give example 1(42mg) as the hydrochloride salt. LC-MS (M + H418, obsd 418).¹HNMR：(DMSO)10.12(s，1H)，9.80(s，1H)，9.67(s，1H)，9.32(1s，1H)，8.49-8.51(d，2H)，8.05-8.07(d，1H)，7.67-7.70(d，2H)，7.38-7.40(d，2H)，6.72-6.7(d，1H)，4.65(t，1H)，3.77-3.81(m，3H)，3.35-3.40(m，1H)，3.15-3.25(m，1H)，3.20(s，1H)。

P70S6K IC₅₀：23nM

Example 25- ((4- (3-chloro-5-fluorophenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide(Trans-racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with tert-butyl 3-amino-4- (3-chloro-5-fluorophenyl) pyrrolidine-1-carboxylate (trans racemate). LC-MS (M + H386, obsd 386/388).

P70S6K IC₅₀：160nM

Example 35- ((4-phenylpiperidin-3-yl) amino) quinazoline-8-carboxamide(Trans-racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with tert-butyl 3-amino-4-phenylpiperidine-1-carboxylate (trans racemate). LC-MS (M + H348, obsd 348).

P70S6K IC₅₀：4.1nM

Example 45- ((4- (3-fluoro-4- (trifluoromethyl) phenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(Trans-racemate)

The title compound was synthesized by coupling reaction with tert-butyl 3-amino-4- (3-fluoro-4- (trifluoromethyl) phenyl) piperidine-1-carboxylate (trans racemate) according to the preparation method of example 1. LC-MS (M + H434, obsd 434).¹HNMR：(DMSO)9.85(s，1H)，9.20(s，1H)，9.24-9.26(d，2H)，8.50-8.52(d，1H)，7.73-7.75(m，1H)，7.47-7.49(d，1H)，7.29-7.30(d，1H)，6.88-6.90(d，1H)，4.50-4.55(d，1H)，3.58-3.60(m，1H)，3.46-3.49(m，1H)，3.35-3.40(m，2H)，3.12-3.14(m，1H)，2.80-2.84(m，1H)，2.30-2.35(m，1H)。

P70S6K IC₅₀：5.9nM

Example 55- (((3R) -4- (3-fluoro-4- (trifluoromethyl) phenyl) piperidin-3-yl) amino) quinazoline-8-carboxylic acid Amides of carboxylic acids(chiral, one of the enantiomers of example 4, not knowing the absolute configuration)

The title compound was isolated from example 4 by chiral chromatography. LC-MS (M + H434, obsd 434).

P70S6K IC₅₀：9.9nM

Example 65- (((3S,4S) -4- (3-fluoro-4- (trifluoromethyl) phenyl) piperidin-3-yl) amino) quinazoline-8- Carboxamides(chiral, second enantiomer of example 4, unknown absolute configuration)

P70S6K IC₅₀：54nM

Example 7(S) -5- ((1- (3-fluorophenyl) -2- (methylamino) ethyl) amino) quinazoline-8-carboxamide (chiral amine) Character)

A reaction mixture of intermediate A (100.00 mg; 0.43 mmol; 1.00eq.), N- [ (S) -2-amino-2- (3-fluoro-phenyl) -ethyl ] -4-nitro-benzenesulfonamide (152.24 mg; 0.45 mmol; 1.05eq.) and DIEA (0.15 ml; 0.85 mmol; 2.00eq.) in NMP (1ml) was stirred at 120 ℃ overnight. The reaction solution was cooled, poured into water and extracted with ethyl acetate, washed with brine, dried and concentrated to give the crude product which was purified by SNAP column (25g, eluent 20-80% ethyl acetate in hexane) to give N- [ (S) -2- (8-cyano-quinazolin-5-ylamino) -2- (3-fluoro-phenyl) -ethyl ] -N-methyl-4-nitro-benzenesulfonamide (120 mg).

Stirring N- [ (S) -2- (8-cyano-quinazolin-5-ylamino) -2- (3-fluoro-phenyl) -ethyl]A solution of-N-methyl-4-nitro-benzenesulfonamide (120.00 mg; 0.24 mmol; 1.00eq.) in DMSO (8ml) was added 2.0M aqueous NaOH (0.59 ml; 1.18 mmol; 5.00eq.) and 35% aqueous hydrogen peroxide (0.14 ml; 1.42 mmol; 6.00eq.), and stirring was continued overnight at 40 ℃. The crude product was purified by preparative HPLC to give the desired product, to which was added acetonitrile (2ml), thiophenol (0.1ml), CsCO₃(200mg) was stirred at 40 ℃ overnight. The crude product was purified by preparative HPLC to give the title product. LC-MS (M + H434, obsd 434).

P70S6K IC₅₀：>1000nM

Example 85- (4- (2-amino-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) quinazoline-8-carboxylic acid Amine (racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 4-nitro-N- (2- (piperazin-1-yl) -2- (4- (trifluoromethyl) phenyl) ethyl) benzenesulfonamide, followed by hydrolysis and deprotection. LC-MS (M + H445, obsd 445).

P70S6K IC₅₀：210nM

Example 95- (3-amino-3- ((2, 4-difluorobenzoylamino) methyl) pyrrolidin-1-yl) quinazoline-8-carboxylic acid Amide (racemate)

The title compound was synthesized by coupling reaction with N- ((3-aminopyrrolidin-3-yl) methyl) -2, 4-difluorobenzamide followed by nitrile hydrolysis according to the preparation method of example 1. LC-MS (M + H427, obsd 427).

p70S6K IC₅₀：>1000nM

Example 105- (3-amino-3- ((4-fluoro-2-hydroxybenzoylamino) methyl) pyrrolidin-1-yl) quinazoline- 8-carboxamides (racemates)

The title compound was isolated as a by-product of Synthesis example 9. LC-MS (M + H425, obsd 425).

p70S6K IC₅₀：>1000nM

Example 115- (3- (aminomethyl) -3- (phenylcarbamoyl) piperidin-1-yl) quinazoline-8-carboxamide (racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with benzyl ((3- (phenylcarbamoyl) piperidin-3-yl) methyl) carbamate, followed by hydrolysis and deprotection. LC-MS (M + H404, obsd 405).

p70S6K IC₅₀：>1000nM

Example 125- (((3- (phenylcarbamoyl) pyrrolidin-3-yl) methyl) amino) quinazoline-8-carboxamide (racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with tert-butyl 3- (aminomethyl) -3- (phenyl-carbamoyl) pyrrolidine-1-carboxylate (racemate). LC-MS (M + H390, obsd 391).

p70S6K IC₅₀：650nM

Example 135- ((-4- ((3-fluorophenyl) carbamoyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxylic acid Amines as pesticides(Trans-racemate)

The title compound was synthesized by coupling reaction with tert-butyl 3-amino-4- ((3-fluorophenyl) carbamoyl) pyrrolidine-1-carboxylate (trans racemate) according to the preparation method of example 1. LC-MS (M + H395, obsd 395).

p70S6K IC₅₀：290nM

Example 145- (((4- (phenylcarbamoyl) piperidin-4-yl) methyl) amino) quinazoline-8-carboxamide (racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2- (trimethylsilyl) ethyl 4- (aminomethyl) -4- (phenylcarbamoyl) piperidine-1-carboxylic acid ester (racemate). LC-MS (M + H404, obsd 405).

p70S6K IC₅₀：>1000nM

Example 155- (3-amino-3- (phenylcarbamoyl) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with tert-butyl (3- (phenylcarbamoyl) pyrrolidin-3-yl) carbamate (racemate). LC-MS (M + H377, obsd 377).

p70S6K IC₅₀：2300nM

Example 16(S) -5- ((1- (3-fluorophenyl) -2- (methylamino) ethyl) amino) quinoline-8-carboxamide (chiral amine) Character)

The reaction mixture of methyl 5-bromo-quinoline-8-carboxylate (600.00 mg; 2.25 mmol; 1.00eq.), N- [ (S) -2-amino-2- (3-fluoro-phenyl) -ethyl ] -N-methyl-4-nitro-benzenesulfonamide (876.48 mg; 2.48 mmol; 1.10eq.), tripotassium phosphate (957.26 mg; 4.51 mmol; 2.00eq.), dicyclohexyl- (2',4',6' -triisopropyl-biphenyl-2-yl) -phosphine (214.99 mg; 0.45 mmol; 0.20eq.), dipotassium acetate (50.62 mg; 0.23 mmol; 0.10eq.) and toluene (5ml) was placed in a microwave tube and stirred overnight at 100 ℃. The crude product was purified by preparative HPLC (basic conditions) to give (S) -5- {1- (3-fluoro-phenyl) -2- [ methyl- (4-nitro-benzenesulfonyl) -amino ] -ethylamino } -quinoline-8-carboxylic acid methyl ester (250 mg). LC-MS (M + H339, obsd 339).

The methyl ester (250.00 mg; 0.46 mmol; 1.00eq.) was added to a solution of 7.0M ammonia in methanol (15.00ml) and stirred at 50 ℃ for 5 days. The reaction mixture was concentrated and purified by preparative HPLC to give (S) -5- {1- (3-fluoro-phenyl) -2- [ methyl- (4-nitro-benzenesulfonyl) -amino]-Ethylamino } -quinoline-8-carboxamide, which was dissolved in acetonitrile (5ml), thiophenol (204.58 mg; 1.86 mmol; 4.00eq.) and Cs were added₂CO₃(605.00 mg; 1.86 mmol; 4.00 eq.). The reaction mixture was stirred at room temperature overnight. After workup by the general procedure, the residue was purified by preparative HPLC to give example 16(30mg, 19%). LC-MS (M + H339, obsd 339).

p70S6K IC₅₀：>1000nM

Example 175- ((-4- (quinolin-7-yl) pyrrolidin-3-yl) amino) quinoline-8-carboxamide(Trans-racemate)

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 3-amino-4- (quinolin-7-yl) pyrrolidine-1-carboxylate (trans racemate), conversion of the methyl ester to the amide using a solution of ammonia in methanol and N-Boc deprotection to provide example 17. LC-MS (M + H384, obsd 384).

p70S6K IC₅₀：190nM

Example 185- (3-phenylpiperazin-1-yl) quinoline-8-carboxamide (racemate)

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 2-phenylpiperazine-1-carboxylate, conversion of the methyl ester to the amide using a solution of ammonia in methanol and deprotection of N-Boc to afford example 18. LC-MS (M + H333, obsd 333).

p70S6K IC₅₀：670nM

Example 195- ((3-phenylazetidin-3-yl) amino) quinoline-8-carboxamide

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 3-amino-3-phenylazetidine-1-carboxylate (racemate), conversion of the methyl ester to the amide using a solution of ammonia in methanol and deprotection of N-Boc to afford example 19. LC-MS (M + H319, obsd 319).

p70S6K IC₅₀：>1000nM

Example 205- (((3- (phenylcarbamoyl) pyrrolidin-3-yl) methyl) amino) quinoline-8-carboxamide(racemate)

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 3- (aminomethyl) -3- (phenylcarbamoyl) pyrrolidine-1-carboxylate (racemate), conversion of the methyl ester to the amide using a solution of ammonia in methanol and deprotection of N-Boc to afford example 20. LC-MS (M + H390, obsd 390).

p70S6K IC₅₀：>1000nM

Example 215- ((-4- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinoline-8-carboxamide(racemate _ trans)

5-bromo-quinoline-8-carbonitrile (200.00 mg; 0.86 mmol; 1.00eq), (3-amino-4- (3-trifluoromethoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (0.41 ml; 1.03 mmol; 1.20eq.) (trans-racemate), sodium 2-methyl-propan-2-ol (181.43 mg; 1.89 mmol; 2.20eq.) and dicyclohexyl- (2',4',6' -triisopropyl-biphenyl-2-yl) -phosphine (122.73 mg; 0.26 mmol; 0.30eq.) and toluene (5ml) the reaction mixture was placed in a microwave tube, degassed for 10 min, then placed in a microwave at 100 ℃ for 20 min, the reaction mixture was concentrated, redissolved in DMSO, purified by preparative HPLC (basic conditions, 70% -75% acetonitrile in water), yield 3- (8-cyano-quinolin-5-ylamino) -4- (3-trifluoromethoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (trans racemate) (150mg, 35%).

The methyl ester (250.00 mg; 0.46 mmol; 1.00eq.) was added to a solution of 7.0M ammonia in methanol (15.00ml) and stirred at 50 ℃ for 5 days. The reaction mixture was concentrated and purified by preparative HPLC to give (S) -5- {1- (3-fluoro-phenyl) -2- [ methyl- (4-nitro-benzenesulfonyl) -amino]-Ethylamino } -quinoline-8-carboxamide, which was dissolved in acetonitrile (5ml), thiophenol (204.58 mg; 1.86 mmol; 4.00eq.) and Cs were added₂CO₃(605.00 mg; 1.86 mmol; 4.00 eq.). The reaction mixture was stirred at room temperature overnight. After workup by the general procedure, the residue was purified by preparative HPLC to give example 16(30mg, 19%).

A reaction mixture of 3- (8-cyano-quinolin-5-ylamino) -4- (3-trifluoromethoxy-phenyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (trans racemate) (136.00 mg; 0.27 mmol; 1.00eq.) in concentrated sulfuric acid (2.00 ml; 37.52 mmol; 137.53eq.) was heated at 100 ℃ for 1 hour. The reaction solution was cooled and poured into crushed ice. Solid sodium hydroxide was added to adjust the PH to 9. The oil was separated and purified by preparative HPLC to give example 21(15 mg). LC-MS (M + H417, obsd 417).

p70S6K IC₅₀：22nM

Example 225- (((4S) -4- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinoline-8-carboxylic acid Amines as pesticides(chiral, first enantiomer of example 21, unknown absolute configuration)

The title compound was isolated from racemate example 21 by chiral chromatography. LC-MS (M + H417, obsd 417).

p70S6K IC₅₀：31nM

Example 235- (((3S,4R) -4- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinoline-8-carboxylic acid Amides of carboxylic acids(chiral, second enantiomer of example 21, unknown absolute configuration)

The title compound was isolated from racemate example 21 by chiral chromatography. LC-MS (M + H417, obsd 417).¹HNMR：(DMSO)9.92(s，1H)，9.76(s，1H)，8.20-8.23(d，1H)，7.98-8.00(d，1H)，7.30-7.32(d，1H)，7.25(s，1H)，7.15(t，1H)，6.80-6.82(d，1H)，4.60-4.63(m，1H)，3.80-3.90(m，2H)，3.65(t，1H)，3.30(t，1H)，3.20-3.25(m，1H)。

p70S6K IC₅₀：690nM

Example 245- ((-4- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinoline-8-carboxamide(racemate _ cis)

The title compound was isolated as a by-product from Synthesis example 21. LC-MS (M + H417, obsd 417).

p70S6K IC₅₀：23nM

Example 255- ((4- (3-fluorophenyl) piperidin-3-yl) amino) quinoline-8-carboxamide(racemate _ trans)

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 3-amino-4- (3-fluorophenyl) piperidine-1-carboxylate (trans racemate), conversion of the methyl ester to the amide using ammonia in methanol and deprotection of N-Boc to afford example 25. LC-MS (M + H365, obsd 365).

p70S6K IC₅₀：520nM

Example 265- (((4R) -4- (3-chloro-5-fluorophenyl)Pyrrolidin-3-yl) amino) quinoline-8-carboxamides(racemate _ trans)

The title compound was synthesized according to the procedure for the preparation of example 16 using a coupling reaction of methyl 5-bromoquinazoline-8-carboxylate with tert-butyl 3-amino-4- (3-chloro-5-fluorophenyl) pyrrolidine-1-carboxylate (trans racemate), conversion of the methyl ester to the amide with ammonia in methanol, and N-Boc deprotection to provide example 26. LC-MS (M + H385, obsd 384/386).

p70S6K IC₅₀：350nM

Example 275- ((4S) -4- (3-fluorophenyl) pyrrolidine-3-carboxamido) quinoline-8-carboxamide(Absolute chirality)

A reaction mixture of 5-amino-quinoline-8-carbonitrile (1000.00 mg; 4.29 mmol; 1.00eq.) in sulfuric acid (5.00 ml; 93.80 mmol; 21.86eq.) was stirred at 100 ℃ for 1 h. The reaction mixture was cooled and poured into ice and neutralized with 2N sodium hydroxide to PH 9. The precipitate was filtered off, washed with water and dried to give 5-aminoquinoline-8-carboxamide (800mg, yield 74.3%).

To a solution of (3R,4S) -4- (3-fluoro-phenyl) -pyrrolidine-1, 3-dicarboxylic acid tert-butyl ester (125.00 mg; 0.40 mmol; 1.00eq.) in DCE (4.0ml) was added bis (2-oxo-1, 3-oxazolidin-3-yl) phosphinic acid chloride (102.87 mg; 0.40 mmol; 1.00 eq.). After stirring for 15 min at room temperature, DIEA (0.15 ml; 0.81 mmol; 2.00eq.) and 5-aminoquinoline-8-carboxamide (75.65 mg; 0.40 mmol; 1.00eq.) were added. The reaction mixture was stirred at 60 ℃ overnight. The crude product was purified by preparative PLC to give tert-butyl (4S) -3- ((8-carbamoylquinolin-5-yl) carbamoyl) -4- (3-fluorophenyl) pyrrolidine-1-carboxylate, which was added to 1ml of 4.0M HCl and 1ml of methanol and stirred at room temperature for 3 hours. The reaction mixture was concentrated, neutralized to Ph7 and purified by preparative HPLC to afford example 27. (M + H479, obsd 479).

p70S6K IC₅₀：>1000nM

Example 285- ((4S) -4-phenylpyrrolidine-2-carboxamido) quinoline-8-carboxamide(Absolute chirality)

The title compound was synthesized according to the procedure for the preparation of example 27, coupling of 5-aminoquinoline-8-carboxamide with (4S) -1- (tert-butoxycarbonyl) -4-phenylpyrrolidine-2-carboxylic acid, followed by deprotection to afford example 28. LC-MS (M + H361, obsd 361).

p70S6K IC₅₀：578nM

Example 295- (2-amino-2-phenylacetylamino) quinoline-8-carboxamide (racemate)

The title compound was synthesized according to the procedure for the preparation of example 27 using a coupling reaction of 5-aminoquinoline-8-carboxamide with 2- ((tert-butoxycarbonyl) amino) -2-phenylacetic acid and deprotection of the protecting groups to afford example 29. LC-MS (M + H321, obsd 321).

p70S6K IC₅₀：>1000nM

Example 305- ((3S) -3-phenylazetidine-2-carboxamido) quinoline-8-carboxamide(Absolute chirality)

The title compound was synthesized according to the procedure for the preparation of example 27 using a coupling reaction of 5-aminoquinoline-8-carboxamide with (3S) -1- (tert-butoxycarbonyl) -3-phenylazetidine-2-carboxylic acid followed by removal of the Boc protecting group to afford example 30. LC-MS (M + H347, obsd 347).

p70S6K IC₅₀：>1000nM

Example 315- (4-fluorobenzylamino) -quinoline-8-carboxamide

To a solution of 5-aminoquinoline-8-carboxamide (120mg, 0.64mmol) in anhydrous DMF (2mL) was added 4-fluorobenzyl bromide (242.34mg, 1.28mmol) and potassium carbonate (531.56mg, 3.85 mmol). The suspension was heated at 50 ℃ overnight. The mixture was diluted with methanol (4mL) and the solid was filtered off. The crude product was purified by reverse phase HPLC to afford example 31(90 mg). LC-MS (M + H296, obsd 296).

p70S6K IC₅₀：875nM

Example 325- (2-fluorobenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H296, obsd 296).

p70S6K IC₅₀：>1000nM

Example 335- (3-fluorobenzylamino) -quinoline-8-carboxamide

p70S6K IC₅₀：369nM

Example 345- (3-chlorobenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H312, obsd 312).

p70S6K IC₅₀：140nM

Example 355- (3, 4-difluorobenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H314, obsd 314).

p70S6K IC₅₀：>1000nM

Example 365- (3,4, 5-trifluorobenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H332, obsd 332).

p70S6K IC₅₀：>1000nM

Example 375- (4-fluoro-3-trifluoromethylbenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H364, obsd 364).

p70S6K IC₅₀：695nM

Example 385- (4-chloro-3-trifluoromethylbenzylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H380, obsd 380).

p70S6K IC₅₀：>1000nM

Example 395- ((1-phenyl-2 (pyrrolidin-1-yl) ethyl) amino-quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H361, obsd 361).

p70S6K IC₅₀：>1000nM

Example 405- (phenylethylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H292, obsd 292).

p70S6K IC₅₀：>1000nM

EXAMPLE 415- (phenylpropylamino) -quinoline-8-carboxamide

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H306, obsd 306).

p70S6K IC₅₀：>1000nM

Example 425- (benzylamino) quinoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 31. LC-MS (M + H278, obsd 278).

p70S6K IC₅₀：680nM

Example 435- [ 3-amino-3- [ (4-fluorophenyl) carbamoyl]Pyrrolidin-1-yl radical]Quinazoline-8-carboxylic acid acyl Amines as pesticides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 3-amino-N- (4-fluorophenyl) pyrrolidine-3-carboxamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H395, obsd 395).¹HNMR(400MHz，DMSO)13.03(s，0H)，9.76(d，J＝13.4Hz，2H)，9.24–9.17(m，1H)，8.54(t，J＝9.2Hz，1H)，7.75(dd，J＝9.0，5.0Hz，2H)，7.55(d，J＝4.1Hz，1H)，7.17(dd，J＝16.2,7.4Hz，2H)，6.88(t，J＝8.2Hz，1H)，4.36–4.26(m，1H)，4.11(dd，J＝16.7，9.7Hz，1H)，3.68(d，J＝10.4Hz，1H)，2.08(t，J＝8.5Hz，1H)，1.45–1.18(m，1H)。

p70S6K IC₅₀：1200nM

Example 445- (3-amino-3- ((3, 4-difluorophenyl) carbamoyl) pyrrolidin-1-yl) quinazolin-8- Carboxamides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 3-amino-N- (3, 4-difluorophenyl) pyrrolidine-3-carboxamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H413, obsd 413).¹H NMR(400MHz，DMSO)9.79–9.71(m，2H)，9.21(s，1H)，8.56(d，J＝8.9Hz，1H)，7.93(ddd，J＝13.3,7.5,2.5Hz，1H)，7.59–7.49(m，2H)，7.41(dd，J＝19.7，9.1Hz，1H)，6.89(d，J＝9.0Hz，1H)，4.31(d，J＝10.3Hz，1H)，4.10(dd，J＝16.5，9.7Hz，1H)，3.78(t，J＝8.0Hz，1H)，3.68(d，J＝10.3Hz，1H)，2.08(t，J＝8.5Hz，1H)。

p70S6K IC₅₀：1300nM

Example 455- (3-amino-3- ((3-fluorophenyl) carbamoyl) pyrrolidin-1-yl) quinazoline-8-carboxylic acid Amines as pesticides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 3-amino-N- (3-fluorophenyl) pyrrolidine-3-carboxamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H395, obsd 395).¹HNMR(400MHz，DMSO)13.48(s，1H)，9.76(d，J＝13.6Hz，2H)，9.21(d，J＝6.6Hz，1H)，8.55(t，J＝9.0Hz，1H)，7.74(d，J＝11.4Hz，1H)，7.54(dd，J＝28.9,10.7Hz，2H)，7.42–7.26(m，1H)，7.19(d，J＝8.8Hz，1H)，6.96–6.76(m，2H)，5.22(s，1H)，4.31(dd，J＝19.8,11.2Hz，2H)，4.11(s，1H)，3.93–3.73(m，2H)，3.69(d，J＝10.3Hz，1H)。

p70S6K IC₅₀：2000nM

Example 465- (3-amino-3- ((4-fluoro-3- (trifluoromethyl) phenyl) carbamoyl) pyrrolidin-1-yl) Quinazoline-8-carboxamides(racemate)

By reaction with 3-amino-N- (4-fluoro-3- (trifluoromethyl) -phenyl) pyrrolidine-3-carboxylic acidThe title compound was synthesized according to the preparation method of example 1 by subjecting the amide (racemate) to a coupling reaction and then hydrolyzing the nitrile intermediate. LC-MS (M + H395, obsd 395).¹H NMR(400MHz，DMSO)9.81–9.68(m，2H)，9.21(d，J＝7.7Hz，1H)，8.56(d，J＝8.9Hz，1H)，8.27(dd，J＝6.4,2.6Hz，1H)，8.10–8.00(m，1H)，7.60–7.46(m，2H)，6.88(t，J＝8.2Hz，1H)，4.32(d，J＝10.4Hz，1H)，4.10(dd，J＝16.7，9.7Hz，1H)，3.79(t，J＝8.0Hz，1H)，3.69(d，J＝10.1Hz，1H)，2.11(d，J＝5.1Hz，1H)。

p70S6K IC₅₀：270nM

Example 475- (3- (2-phenylacetamido) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2-phenyl-N- (pyrrolidin-3-yl) acetamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H376, obsd 376).¹H NMR(500MHz，dmso)9.75(d，J＝9.8Hz，2H)，9.21(d，J＝1.3Hz，1H)，8.59–8.52(m，1H)，8.43(d，J＝6.3Hz，1H)，7.57(s，1H)，7.23(td，J＝15.7,8.0Hz，5H)，6.88(d，J＝8.9Hz，1H)，4.37(s，1H)，4.03(dd，J＝10.2,6.0Hz，1H)，3.85(t，J＝8.5Hz，1H)，3.76(s，1H)，3.59–3.51(m，1H)，3.40(s，2H)，2.21(dd，J＝12.6,6.0Hz，1H)，2.00(d，J＝5.3Hz，1H)。

p70S6K IC₅₀：7900nM

Example 485- (3- (3- (trifluoromethyl) benzamido) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with N- (pyrrolidin-3-yl) -3- (trifluoromethyl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H430, obsd 430).¹HNMR(500MHz，dmso)9.81(s，1H)，9.74(s，1H)，9.22(s，1H)，8.90(d，J＝6.0Hz，1H)，8.56(d，J＝8.9Hz，1H)，8.22–8.13(m，2H)，7.92(d，J＝8.0Hz，1H)，7.73(t，J＝8.0Hz，1H)，7.57(s，1H)，6.91(d，J＝8.9Hz，1H)，4.66(d，J＝5.4Hz，1H)，4.17–4.08(m，1H)，3.93(s，1H)，3.87–3.74(m，2H)，2.99(s，0H)，2.54(s，2H)，2.33(d，J＝6.1Hz，1H)，2.20(s，1H)。

p70S6K IC₅₀：2200nM

Example 495- (3- (benzyl (2- (dimethylamino) ethyl) carbamoyl) pyrrolidin-1-yl) quinazolinone- 8-carboxamides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with N-benzyl-N- (2- (dimethylamino) ethyl) pyrrolidine-3-carboxamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H447, obsd 447).¹H NMR(400MHz，DMSO)9.74(s，2H)，9.21(d，J＝4.5Hz，1H)，8.54(t，J＝9.1Hz，1H)，7.55(s，1H)，7.41–7.20(m，5H)，6.88(dd，J＝23.8,8.7Hz，1H)，4.74(s，1H)，4.65(d，J＝15.0Hz，1H)，4.55(d，J＝14.6Hz，1H)，3.91(ddd，J＝23.2,16.7,8.5Hz，3H)，3.73(s，1H)，3.57(d，J＝44.4Hz，2H)，3.38(dd，J＝14.9，7.8Hz，2H)，3.00(s，1H)，2.54(d，J＝5.9Hz，1H)，2.43–2.28(m，3H)，2.12(d，J＝14.3Hz，5H)。

p70S6K IC₅₀：1600nM

Example 505- (3- (3, 4-difluorobenzoylamino) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 3, 4-difluoro-N- (pyrrolidin-3-yl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H398, obsd 398).¹H NMR(500MHz，dmso)9.81(s，1H)，9.74(s，1H)，9.22(s，1H)，8.71(d，J＝6.2Hz，1H)，8.56(d，J＝8.7Hz，1H)，7.97–7.88(m，1H)，7.76(s，1H)，7.56(dt，J＝16.9，8.6Hz，2H)，6.90(d，J＝8.9Hz，1H)，4.64–4.58(m，1H)，4.10(dd，J＝10.4,6.1Hz，1H)，3.97–3.88(m，1H)，3.82(s，1H)，3.74(dd，J＝10.7,4.3Hz，1H)，2.30(dd，J＝12.9，5.9Hz，1H)，2.17(d，J＝5.2Hz，1H)。

p70S6K IC₅₀：380nM

Example 515- (3- (2- (4-fluorophenyl) acetamido) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2- (4-fluorophenyl) -N- (pyrrolidin-3-yl) -acetamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H394, obsd 394).¹HNMR(400MHz，DMSO)9.76(s，2H)，9.21(s，1H)，8.55(d，J＝8.5Hz，1H)，8.44(d，J＝6.0Hz，1H)，7.59(s，1H)，7.25(s，2H)，7.08(t，J＝8.0Hz，2H)，6.88(d，J＝9.0Hz，1H)，4.36(s，1H)，4.04(d，J＝6.6Hz，1H)，3.85(s，1H)，3.77(s，1H)，3.54(d，J＝10.1Hz，1H)，3.38(d，J＝14.2Hz，2H)，2.20(s，1H)，1.99(s，1H)。

p70S6K IC₅₀：5400nM

Example 525- (3- ((3, 4-dichlorobenzyl) amino) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with N- (3, 4-dichlorobenzyl) pyrrolidin-3-amine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H417, obsd 417).¹H NMR(500MHz，dmso)9.73(s，2H)，9.18(s，1H)，8.52(d，J＝8.9Hz，1H)，7.59(d，J＝1.8Hz，1H)，7.55–7.47(m，2H)，7.34–7.28(m，1H)，6.82(d，J＝9.0Hz，1H)，3.91(dd，J＝10.4,5.5Hz，1H)，3.88–3.81(m，1H)，3.74(s，2H)，3.68(s，1H)，3.54(dd，J＝10.3,3.9Hz，1H)，3.38(s，1H)，2.63(s，1H)，2.13–2.04(m，1H)，1.94(d，J＝5.3Hz，1H)。

p70S6K IC₅₀：490nM

Example 535- (3- ((3, 4-dichlorobenzyl) (methyl) amino) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

By reaction with N- (3, 4-dichlorobenzyl) -N-methylThe title compound was synthesized according to the preparation method of example 1 by coupling pyrrolidine-3-amine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H431, obsd 431).¹HNMR(400MHz，DMSO)9.78(d，J＝17.6Hz，2H)，9.21(s，1H)，8.54(d，J＝8.7Hz，1H)，7.63–7.50(m，3H)，7.34(d，J＝8.1Hz，1H)，6.90(d，J＝8.9Hz，1H)，3.94–3.73(m，4H)，3.61(s，2H)，3.20(s，2H)，2.27(s，2H)，2.18(s，3H)，2.06–1.93(m，2H)，0.08(s，1H)。

p70S6K IC₅₀：570nM

Example 545- (3- ((3, 4-difluorobenzoylamino) methyl) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 3, 4-difluoro-N- (pyrrolidin-3-ylmethyl) -benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H412, obsd 412).¹H NMR(400MHz，DMSO)9.81(s，1H)，9.75(d，J＝4.0Hz，1H)，9.20(s，1H)，8.72(t，J＝5.6Hz，1H)，8.53(d，J＝8.9Hz，1H)，7.89(ddd，J＝11.5,7.8,2.0Hz，1H)，7.74(dd，J＝5.1,3.3Hz，1H)，7.62–7.50(m，2H)，6.85(d，J＝9.0Hz，1H)，3.92–3.74(m，3H)，3.65(dd，J＝10.2,7.0Hz，1H)，3.41(dtd，J＝19.7,13.3,6.1Hz，2H)，2.63(dt，J＝13.7,6.8Hz，1H)，2.16(td，J＝12.0，5.9Hz，1H)，1.85(dq，J＝15.2,7.5Hz，1H)。

p70S6K IC₅₀：233nM

Example 555- (3- ((2-fluoro-4- (trifluoromethyl) benzamido) methyl) pyrrolidin-1-yl) quinazoline- 8-carboxamides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2-fluoro-N- (pyrrolidin-3-ylmethyl) -4- (trifluoromethyl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H462, obsd 462).¹H NMR(400MHz，DMSO)10.87(s，1H)，9.80(s，1H)，9.75(d，J＝3.9Hz，1H)，9.19(s，1H)，8.53(d，J＝8.9Hz，1H)，7.89(d，J＝8.1Hz，1H)，7.52(d，J＝3.8Hz，1H)，6.90–6.80(m，2H)，6.72(d，J＝8.0Hz，1H)，3.87–3.77(m，3H)，3.61(dd，J＝10.1,7.3Hz，1H)，3.45(s，2H)，2.71–2.57(m，1H)，2.14(dt，J＝19.7,7.0Hz，1H)，1.93–1.79(m，1H)。

p70S6K IC₅₀：290nM

Example 565- (3- (aminomethyl) piperidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 3-N-boc-aminomethylpiperidine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H287, obsd 286.2/287.2).

P70S6K IC₅₀：56000nM AKT IC₅₀：>100000nM

Example 575- ((1- (m-tolyl) piperidin-4-yl) amino) quinazoline-8-carboxamide

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (m-tolyl) piperidin-4-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H363, obsd 362.2/363.3).

P70S6K IC₅₀：22000nM AKT IC₅₀：>100000nM

Example 585- ((1-methylpyrrolidin-3-yl) amino) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1-methylpyrrolidin-3-amine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H273, obsd 272.1/273.1).

P70S6K IC₅₀：20000nM AKT IC₅₀：>100000nM

Example 595- (3- ((methylamino) methyl) piperidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl methyl (piperidin-3-ylmethyl) carbamate (racemate) and hydrolyzing the nitrile intermediate. LC-MS (300M + H, 300.1/301.1).

P70S6K IC₅₀：5900nM AKT IC₅₀：18000nM

Example 60(R) -5- ((pyrrolidin-3-ylmethyl) amino) quinazoline-8-carboxamide(chirality)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl (S) -3- (aminomethyl) pyrrolidine-1-carboxylate and then hydrolyzing the nitrile intermediate. LC-MS (M + H273, obsd 272.1/273.1).

P70S6K IC₅₀：4800nM AKT IC₅₀：>100000nM

Example 61(S) -5- ((pyrrolidin-3-ylmethyl) amino) quinazoline-8-carboxamide(chirality)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl (R) -3- (aminomethyl) pyrrolidine-1-carboxylate and then hydrolyzing the nitrile intermediate. LC-MS (M + H273, obsd 272.1/273.1).

P70S6K IC₅₀：1700nM AKT IC₅₀：>100000nM

Example 625- ((pyridin-3-ylmethyl)) Amino) quinazoline-8-carboxamides

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with pyridin-3-ylmethylamine and hydrolyzing the nitrile intermediate. LC-MS (M + H279, obsd 280.1/281.1).

P70S6K IC₅₀：1600nM AKT IC₅₀：70000nM

Example 635- ((3-chlorobenzyl) amino) quinazoline-8-carboxamide

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with (3-chlorophenyl) methylamine and hydrolyzing the nitrile intermediate. LC-MS (M + H313, obsd 313.1/314.1).

P70S6K IC₅₀：59.2nM AKT IC₅₀：12000nM

Example 645- (3-phenethylpyrrolidin-1-yl) quinazoline-8-carboxamides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 3-phenethylpyrrolidine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H347, obsd 347.2/348.2).

P70S6K IC₅₀：240nM AKT IC₅₀：3100nM

Example 655- (3- (benzyloxy) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 3- (benzyloxy) pyrrolidine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H349, obsd 349.1/350.1).

P70S6K IC₅₀：710nM AKT IC₅₀：>100000nM

Example 665- (3-hydroxy-3-phenylpyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 3-phenylpyrrolidin-3-ol (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H335, obsd 335.1/336.1).

P70S6K IC₅₀：1800nM AKT IC₅₀：>100000nM

Example 675- ((3S,4R) -3- (hydroxymethyl) -4- (m-tolyl) pyrrolidin-1-yl) quinazoline-8-carboxylic acid Amides of carboxylic acids(chirality)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with ((3S,4R) -4- (m-tolyl) pyrrolidin-3-yl) methanol, followed by hydrolysis of the nitrile intermediate. LC-MS (M + H363, obsd 363.2/364.1).

P70S6K IC₅₀：190nM AKT IC₅₀：8200nM

Example 685- ((2- (3-chlorophenyl) -2- (dimethylamino) ethyl) amino) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (3-chlorophenyl) -N1, N1-dimethylethane-1, 2-diamine (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H370, obsd 370.1/371.1).

P70S6K IC₅₀：2600nM AKT IC₅₀：>100000nM

Example 695- ((2-phenyl-2- (piperazin-1-yl) ethyl) amino) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 4- (2-amino-1-phenylethyl) piperazine-1-carboxylate (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H363, obsd 363.2/364.1).

P70S6K IC₅₀：170nM AKT IC₅₀：10000nM

Example 705- ((3- (4-fluorophenyl) piperidin-4-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 4-amino-3- (4-fluorophenyl) piperidine-1-carboxylate (racemic mixture of diastereomers) and hydrolyzing the nitrile intermediate. LC-MS (M + H366, obsd 366.1/367.2).

P70S6K IC₅₀：550nM AKT IC₅₀：2500nM

Example 715- ((4- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (3- (trifluoromethyl) phenyl) pyrrolidine-1-carboxylate (racemic mixture of diastereomers) followed by hydrolysis of the nitrile intermediate. LC-MS (M + H402, obsd 402.2).

P70S6K IC₅₀：21nM AKT IC₅₀：4500nM

Example 725- ((4- (3- (trifluoromethoxy) phenyl)) Pyrrolidin-3-yl) amino) quinazoline-8-carboxamides(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (3- (trifluoromethoxy) phenyl) pyrrolidine-1-carboxylate (racemic mixture of diastereomers) followed by hydrolysis of the nitrile intermediate. LC-MS (M + H418, obsd 418.2/418.9).

P70S6K IC₅₀：100nM AKT IC₅₀：>100000nM

Example 735- ((4- (m-tolyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (m-tolyl) piperidine-1-carboxylate (racemic mixture of diastereomers) and hydrolyzing the nitrile intermediate. LC-MS (M + H-362, obsd-362.2/363.2).

P70S6K IC₅₀：390nM AKT IC₅₀：9000nM

Example 745- ((4- (3- (trifluoromethyl) phenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (3- (trifluoromethyl) phenyl) piperidine-1-carboxylate (racemic mixture of diastereomers) and hydrolyzing the nitrile intermediate. LC-MS (M + H416, obsd 416.2/417.2).

P70S6K IC₅₀：140nM AKT IC₅₀：2100nM

Example 755- ((4- (4-chloro-3-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the procedure for example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with a racemic mixture of 3-amino-4- (4-chloro-3-fluorophenyl) piperidine-1-carboxylic acid tert-butyl ester diastereomer) followed by hydrolysis of the nitrile intermediate. LC-MS (M + H400.8, obsd 400.2).

P70S6K IC₅₀：8.1nM AKT IC₅₀：130nM

Example 765- ((4- (3-chloro-4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (3-chloro-4-fluorophenyl) piperidine-1-carboxylate (racemic mixture of diastereomers) and hydrolyzing the nitrile intermediate. LC-MS (M + H400.8, obsd 400.1/401.1).

P70S6K IC₅₀：33nM AKT IC₅₀：570nM

Example 775- (((3R,4R) -4- (3-chloro-4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(chiral, one of the enantiomers of example 76, unknown absolute configuration)

The title compound was isolated from the mixture of diastereomers of example 76 by the chiral SFC method. LC-MS (M + H400.8, obsd 400.1/401.1).¹HNMR(MeOH-d4)1.16(m，1H)，1.31(m，1H)，1.78(m，1H)，2.34(m，1H)，2.89(m，1H)，3.20-3.32(m，3H)，6.29(m，1H)，6.97(m，1H)，7.25(m，1H)，7.39(m，1H)，8.33(m，1H)，9.21(s，1H)，9.93(s，1H)。

P70S6K IC₅₀：50nM AKT IC₅₀：850nM

Example 785- (((3S,4S) -4- (3-chloro-4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(chiral, one of the enantiomers of example 76, unknown absolute configuration)

The title compound was isolated from the mixture of diastereomers of example 76 by the chiral SFC method. LC-MS (M + H400.8, obsd 400.2).

P70S6K IC₅₀：350nM AKT IC₅₀：5700nM

Example 795- ((4- (4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(racemic mixture of diastereomers)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with tert-butyl 3-amino-4- (4-fluorophenyl) piperidine-1-carboxylate (racemic mixture of diastereomers) and hydrolyzing the nitrile intermediate. LC-MS (M + H366, obsd 366.1/367.1).

P70S6K IC₅₀：290nM AKT IC₅₀：2000nM

Example 805- (((3R,4R) -4- (4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(chiral, one of the enantiomers of example 79, not knowing the absolute configuration)

The title compound was isolated from the mixture of diastereomers of example 79 by the chiral SFC method. LC-MS (M + H366, obsd 366.2).

P70S6K IC₅₀：290nM AKT IC₅₀：2200nM

Example 815- (((3S,4S) -4- (4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide(chiral, one of the enantiomers of example 79, not knowing the absolute configuration)

The title compound was isolated from the mixture of diastereomers of example 79 by the chiral SFC method. LC-MS (M + H366, obsd 366.1).

P70S6K IC₅₀：52nM AKT IC₅₀：900nM

Example 825- (3-amino-4-phenylpiperidin-1-yl) quinazoline-8-carboxamides(racemate)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 4-phenyl-piperidin-3-ylamine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H347, obsd 348).

P70S6K IC₅₀：120nM

Example 835- (3-amino-4- (4- (trifluoromethyl) phenyl) piperidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 4- (4-trifluoromethyl-phenyl) -piperidin-3-ylamine and hydrolyzing the nitrile intermediate. LC-MS (M + H415, obsd 416).

P70S6K IC₅₀：350nM

Example 84(S) -5- (3-amino-3- (phenylcarbamoyl) pyri-dinePyrrolidin-1-yl) quinazoline-8-carboxamides(pure enantiomers, unknown absolute configuration)

The title compound was isolated from example 15 by chiral HPLC chromatography. LC-MS (M + H376, obsd 377).

P70S6K IC₅₀：2150nM

Example 85(R) -5- (3-amino-3- (phenylcarbamoyl) pyrrolidin-1-yl) quinazoline-8-carboxamide(pure enantiomers, unknown absolute Structure)

P70S6K IC₅₀：11500nM

Example 865- [ (3S,4R) -3-amino-4- (4-fluoro-phenyl) -piperidin-1-yl]-quinazoline-8-carboxylic acid amides(racemate _ cis)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with cis-4- (4-fluorophenyl) piperidin-3-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H366, obsd 366).

P70S6K IC₅₀：250nM

Example 875- [ (3R,4R) -3-amino-4- (4-fluoro-phenyl) -piperidin-1-yl]-quinazoline-8-carboxylic acid amides(racemate _ trans)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with trans-4- (4-fluorophenyl) piperidin-3-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H366, obsd 366).

P70S6K IC₅₀：7100nM

Example 885- [ (3S,4R) -3-amino-4- (3-fluoro-phenyl) -piperidin-1-yl]-quinazoline-8-carboxylic acid amides(racemate _ cis)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with cis-4- (3-fluorophenyl) piperidin-3-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H366, obsd 366).

P70S6K IC₅₀：17100nM

Example 895- [ (3R,4R) -3-amino-4- (3-fluoro-phenyl) -piperidin-1-yl]-quinazoline-8-carboxylic acid amides(racemate _ trans)

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with trans-4- (3-fluorophenyl) piperidin-3-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H366, obsd 366).

P70S6K IC₅₀：2400nM

Example 905- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (4-trifluoromethyl-phenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H402, obsd 402).

P70S6K IC₅₀：24000nM AKT IC₅₀：>100000nM

Example 915- [ 4-phenyl-piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1-phenylpiperazine and hydrolyzing the nitrile intermediate. LC-MS (M + H334, obsd 334).

P70S6K IC₅₀：3000nM AKT IC₅₀：15000nM

Example 925- [4- (3, 4-difluoro-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (3, 4-difluoro-phenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H370, obsd 370).

P70S6K IC₅₀：1000nM AKT IC₅₀：>100000nM

Example 935- [4- (4-chloro-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (4-chlorophenyl) piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H368, obsd 368).

P70S6K IC₅₀：1000nM

Example 945- [4- (3-chloro-4-fluorophenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (3-chloro-4-fluoro-phenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H386, obsd 386).

P70S6K IC₅₀：12000nM AKT IC₅₀：>100000nM

Example 955- [4- (3-fluoro-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (3-fluoro-phenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (352M + H, 352 obsd).

P70S6K IC₅₀：770nM AKT IC₅₀：6400nM

Example 965- [4- (3-chloro-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling 5-bromo-quinazoline-8-carbonitrile with 1- (3-chloro-phenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H368, obsd 368).

P70S6K IC₅₀：10000nM AKT IC₅₀：>100000nM

Example 975- (benzylamino) quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with benzylamine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H261, obsd 261).¹H NMR(400MHz，DMSO)9.96(s，1H)，9.30(s，1H)，8.83(t，J＝5.6Hz，1H)，8.11(d，J＝8.6Hz，1H)，7.42(d，J＝7.7Hz，2H)，7.35(t，J＝7.3Hz，2H)，7.27(t，J＝6.9Hz，1H)，6.62(d，J＝8.7Hz，1H)，4.64(d，J＝5.8Hz，2H)。

p70S6K IC₅₀：＝690nM AKT IC₅₀：＝57000nM

Example 985- (phenethylamino) quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2-phenethylamine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H293, obsd 293).¹H NMR(500MHz，dmso)9.84(s，1H)，9.69(d，J＝3.9Hz，1H)，9.26(s，1H)，8.56(d，J＝8.7Hz，1H)，7.86(t，J＝5.3Hz，1H)，7.52(d，J＝3.9Hz，1H)，7.39–7.27(m，4H)，7.26–7.19(m，1H)，6.85(d，J＝8.8Hz，1H)，3.62–3.52(m，2H)，3.04–2.97(m，2H)。

p70S6K IC₅₀：＝89nM；AKT IC₅₀：＝5600nM

Example 995- [2- (3-fluorophenyl) ethylamino]Quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2- (3-fluorophenyl) ethylamine and subsequent hydrolysis of the nitrile intermediate. LC-MS (M + H311, obsd 311).¹H NMR(500MHz，dmso)9.83(s，1H)，9.69(d，J＝3.9Hz，1H)，9.26(s，1H)，8.56(d，J＝8.7Hz，1H)，7.84(t，J＝5.5Hz，1H)，7.52(d，J＝3.9Hz，1H)，7.38–7.30(m，1H)，7.24–7.18(m，1H)，7.16(d，J＝7.6Hz，1H)，7.04(td，J＝8.6,2.5Hz，1H)，6.87(d，J＝8.8Hz，1H)，3.59(dd，J＝13.9，6.4Hz，2H)，3.06–2.98(m，2H)。

p70S6K IC₅₀：＝120nM AKT IC₅₀：＝2400nM

Example 1005- [2- (4-fluorophenyl) ethylamino]Quinazoline-8-carboxamides

The title compound was synthesized according to the preparation of example 1 by coupling with 2- (4-fluorophenyl) ethylamine and subsequent hydrolysis of the nitrile intermediate. LC-MS (M + H311, obsd 311).¹H NMR(500MHz，dmso)9.83(s，1H)，9.69(d，J＝3.9Hz，1H)，9.26(s，1H)，8.55(d，J＝8.7Hz，1H)，7.84(t，J＝5.4Hz，1H)，7.52(d，J＝3.8Hz，1H)，7.39–7.31(m，2H)，7.16–7.07(m，2H)，6.85(d，J＝8.8Hz，1H)，3.55(dd，J＝14.0，6.4Hz，2H)，3.03–2.95(m，2H)。

p70S6K IC₅₀：＝290nM AKT IC₅₀：＝4800nM

Example 1015- [2- (3, 4-difluorophenyl) ethylamino]Quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2- (3, 4-difluorophenyl) ethylamine and subsequent hydrolysis of the nitrile intermediate. LC-MS (M + H329, obsd 329).¹H NMR(500MHz，dmso)9.82(s，1H)，9.69(d，J＝3.9Hz，1H)，9.26(s，1H)，8.56(d，J＝8.7Hz，1H)，7.81(t，J＝5.3Hz，1H)，7.53(d，J＝3.7Hz，1H)，7.45(ddd，J＝12.0，7.9,2.0Hz，1H)，7.35(dt，J＝10.9，8.5Hz，1H)，7.15(s，1H)，6.87(d，J＝8.8Hz，1H)，3.57(dd，J＝13.7,6.4Hz，2H)，2.99(t，J＝7.3Hz，2H)。

p70S6K IC₅₀：＝360nM AKT IC₅₀：＝41000nM

Example 1025- (4-phenylbutylamino) quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 4-phenylbutan-1-amine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H321, obsd 321).¹H NMR(500MHz，dmso)9.86(s，1H)，9.68(d，J＝3.9Hz，1H)，9.24(s，1H)，8.53(d，J＝8.7Hz，1H)，7.74(t，J＝5.2Hz，1H)，7.50(d，J＝3.9Hz，1H)，7.27(t，J＝7.6Hz，2H)，7.22(d，J＝7.0Hz，2H)，7.17(t，J＝7.2Hz，1H)，6.75(d，J＝8.8Hz，1H)，3.34(dd，J＝12.1,6.8Hz，2H)，2.66(t，J＝7.1Hz，2H)，1.79–1.62(m，4H)。

p70S6K IC₅₀：＝87nM AKT IC₅₀：>100000nM

Example 1035- [ methyl (phenylethyl) amino group]Quinazoline-8-carboxamides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with N-methyl-2-phenylethylamine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H307, obsd 307).¹H NMR(500MHz，dmso)9.71(d，J＝2.5Hz，1H)，9.48(s，1H)，9.29(s，1H)，8.59(d，J＝8.4Hz，1H)，7.76(d，J＝2.4Hz，1H)，7.32–7.19(m，5H)，7.18(M，1H)，3.60(t，2H)，3.13(s，3H)，2.99(t，2H)。

p70S6K IC₅₀：＝220nM AKT IC₅₀：＝14000nM

Example 1045- [2- (3, 4-dichlorophenyl) ethylamino]Quinazoline-8-carboxamides

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling with 2- (3, 4-dichlorophenyl) ethylamine and subsequent hydrolysis of the nitrile intermediate. LC-MS (M + H-362, obsd-362).¹H NMR(500MHz，cd₃od)9.65(s，1H)，9.22(s，1H)，8.69(d，J＝8.8Hz，1H)，7.48(d，J＝1.9Hz，1H)，7.44(d，J＝8.2Hz，1H)，7.22(dd，J＝8.3,2.0Hz，1H)，6.89(d，J＝8.8Hz，1H)，3.71–3.64(m，2H)，3.05(t，J＝7.3Hz，2H)。

p70S6K IC₅₀：＝98nM AKT IC₅₀：>100000nM

Example 1055- [ phenethyl- [ (3R) -3-piperidinyl group]Amino group]Quinazoline-8-carboxamides (chiral)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with tert-butyl (R) -3- (phenethylamino) piperidine-1-carboxylate (scheme 7), followed by hydrolysis of the nitrile intermediate and deprotection. LC-MS (M + H376, obsd 376).¹H NMR(500MHz，dmso)10.34(s，1H)，8.39(s，1H)，7.95(d，J＝8.4Hz，1H)，7.41(s，1H)，7.32–7.06(m，5H)，6.88(d，J＝8.7Hz，1H)，5.56(s，1H)，3.57–3.47(m，1H)，3.26–3.10(m，2H)，2.93–2.74(m，3H)，2.68–2.60(m，1H)，2.42–2.33(m，1H)，2.07–1.99(m，1H)，1.93–1.75(m，2H)，1.74–1.56(m，2H)，1.27–1.19(m，1H)。

p70S6K IC₅₀：＝11000nM AKT IC₅₀：>100000nM

Example 1065- (3- ((2, 5-difluorobenzoylamino) methyl) pyrrolidin-1-yl) quinazoline-8-carboxamide(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2, 5-difluoro-N- (pyrrolidin-3-ylmethyl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H412, obsd 412). 1HNMR (400MHz, DMSO)9.81(s, 1H), 9.75(d, J ═ 4.2Hz, 1H), 9.21(s, 1H), 8.62(s, 1H), 8.54(d, J ═ 8.8Hz, 1H), 7.53(s, 1H), 7.49-7.32 (m, 4H), 6.85(d, J ═ 8.9Hz, 1H), 3.90-3.82 (m, 1H), 3.82-3.75 (m, 2H), 3.69-3.61 (m, 1H), 3.41(ddd, J ═ 34.0, 13.6,7.3Hz, 3H), 2.67-2.58 (m, 1H), 2.16(dd, J ═ 12.1,6.2, 1H), 1.90-1.79 (m, 1H).

p70S6K IC50：510nM

Example 1075- [ 3-amino-4- (3-trifluoromethyl-phenyl) -piperidin-1-yl]-quinazoline-8-carboxylic acid amides(racemate))

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and tert-butyl (4- (3- (trifluoromethyl) phenyl) piperidin-3-yl) carbamate, followed by hydrolysis of the nitrile intermediate and deprotection. LC-MS (M + H416, obsd 416).

P70S6K IC₅₀：380nM AKt IC₅₀：8100nM

Example 1085- [4- (4-fluorophenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (4-fluorophenyl) piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (352M + H, 352 obsd).

P70S6K IC₅₀：2300nM AKt IC₅₀：>100000nM

Example 1095- [4- (3-trifluoromethylphenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (3-trifluoromethylfluorophenyl) piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H402, obsd 402).

P70S6K IC₅₀：11000nM AKt IC₅₀：23000nM

Example 1105- [4- (3, 4-dichlorophenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the procedure for the preparation of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (3, 4-dichlorophenyl) -piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (M + H403, obsd 403).

P70S6K IC₅₀：>100000nM AKt IC₅₀：>100000nM

Example 1115- [4- (5-chloro-2-methylphenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (5-chloro-2-methylphenyl) piperazine followed by hydrolysis of the nitrile intermediate. LC-MS (382, obsd 382).

P70S6K IC₅₀：>100000nM AKt IC₅₀：>100000nM

Example 1125- {3- [ (2, 4-difluoro-benzoylamino) -methyl]-pyrrolidin-1-yl } -quinazoline-8- Carboxylic acid amides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2, 4-difluoro-N- (pyrrolidin-3-ylmethyl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H412, obsd 412).

p70S6K IC50：260nM

Example 1135- {3- [ (3-trifluoromethyl-benzoylamino) -methyl]-pyrrolidin-1-yl } -quinazoline- 8-Carboxylic acid amides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with N- (pyrrolidin-3-ylmethyl) -3- (trifluoromethyl) benzamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H444, obsd 444).

p70S6K IC50：nd nM

Example 1145- { (R) -3- [ (3, 4-difluoro-benzoylamino) -methyl]-pyrrolidin-1-yl } -quinazol Quinoline-8-carboxylic acid amides(pure enantiomers, unknown absolute Structure)

The title compound was isolated from example 54 by chiral HPLC chromatography. LC-MS (M + H412, obsd 412). 1H NMR (400MHz, DMSO)9.77(d, J ═ 26.9Hz, 2H), 9.20(s, 1H), 8.71(s, 1H), 8.53(d, J ═ 7.2Hz, 1H), 7.95-7.83 (m, 1H), 7.70(d, J ═ 13.6Hz, 4H), 7.61-7.45 (m, 2H), 6.84(d, J ═ 8.5Hz, 1H), 4.30-3.97 (m, 4H), 3.84(dd, J ═ 23.0, 14.6Hz, 3H), 3.68-3.59 (m, 1H), 3.44(s, 1H), 2.63(dd, J ═ 17.2,8.6Hz, 1H), 2.14(s, 1H), 1.82(s, 18H), 2.6H, 18H, 15H, 18H, 15H, 18H, 15H, 1H, and 1H.

p70S6K IC₅₀：470nM

Example 1155- { (S) -3- [ (3, 4-difluoro-benzoylamino) -methyl]-pyrrolidin-1-yl } -quinazol Quinoline-8-carboxylic acid amides(pure enantiomers, unknown absolute Structure)

The title compound was isolated from example 54 by chiral HPLC chromatography. LC-MS (M + H412, obsd 412).¹H NMR(400MHz，DMSO)9.82(s，1H)，9.75(s，1H)，9.21(s，1H)，8.79(s，1H)，8.54(d，J＝8.8Hz，2H)，7.91(s，1H)，7.76(s，1H)，7.56(d，J＝10.0Hz，2H)，6.86(d，J＝9.2Hz，1H)，4.37(s，4H)，3.83(d，J＝28.4Hz，3H)，3.64(s，2H)，3.45(d，J＝6.2Hz，5H)，3.15(d，J＝29.4Hz，2H)，2.94(s，1H)，2.15(s，2H)，1.88(s，1H)，1.59(s，2H)，1.25(s，4H)，1.05(dd，J＝18.1,12.1Hz，9H)，0.84(s，2H)。

p70S6K IC₅₀：450nM

Example 1165- [ (S) -3-amino-3- (4-fluoro-3-trifluoromethyl-phenylcarbamoyl) -pyrrolidine-1- Base of]-quinazoline-8-carboxylic acid amides(pure enantiomers, unknown absolute Structure)

The title compound was isolated from example 46 by chiral HPLC chromatography. LC-MS (M + H463, obsd 463).¹H NMR(400MHz，DMSO)9.77(d，J＝12.8Hz，2H)，9.22(s，1H)，8.56(d，J＝9.0Hz，1H)，8.28(s，1H)，8.06(s，1H)，7.61–7.46(m，2H)，6.90(d，J＝8.7Hz，1H)，4.33(d，J＝10.7Hz，1H)，4.11(s，2H)，3.79(s，1H)，3.70(d，J＝9.1Hz，1H)，2.10(s，2H)。

p70S6K IC₅₀：520nM

Example 1175- [ (R) -3-amino-3- (4-fluoro-3-trifluoromethyl-phenylcarbamoyl) -pyrrolidine-1- Base of]-quinazoline-8-carboxylic acid amides(pure enantiomers, unknown absolute Structure)

The title compound was isolated from example 46 by chiral HPLC chromatography. LC-MS (M + H463, obsd 463).¹H NMR(400MHz，DMSO)9.76(d，J＝12.2Hz，2H)，9.22(s，1H)，8.56(d，J＝7.4Hz，1H)，8.27(s，1H)，8.05(s，1H)，7.62–7.44(m，2H)，6.89(d，J＝8.8Hz，1H)，4.32(d，J＝9.8Hz，1H)，4.10(d，J＝8.5Hz，1H)，3.79(s，1H)，3.69(d，J＝10.3Hz，1H)，2.10(s，2H)。

p70S6K IC₅₀：380nM

Example 1185- {3- [ (2, 4-difluoro-benzoylamino) -methyl]-pyrrolidin-1-yl } -quinazoline-8- Carboxylic acid amides(racemate)

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 2-phenyl-N- (pyrrolidin-3-ylmethyl) acetamide (racemate) and hydrolyzing the nitrile intermediate. LC-MS (M + H390, obsd 390).¹H NMR(400MHz，DMSO)9.81–9.70(m，2H)，9.21(s，1H)，8.53(d，J＝8.9Hz，1H)，8.22(t，J＝5.5Hz，1H)，7.54(d，J＝3.7Hz，1H)，7.33–7.24(m，4H)，7.24–7.16(m，1H)，6.81(d，J＝8.9Hz，1H)，3.76(dd，J＝14.9，8.1Hz，3H)，3.54(dd，J＝10.2,7.2Hz，1H)，3.43(s，2H)，3.21(dtd，J＝19.7,13.3,6.2Hz，2H)，2.08(dd，J＝11.8,5.9Hz，1H)，1.83–1.67(m，1H)。

p70S6K IC₅₀：260nM

Example 1195- [4- (2-chloro-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (2-chloro-phenyl) -piperazine followed by hydrolysis. LC-MS (M + H368, obsd 368).

P70S6K IC₅₀：400nM

Example 1205- [4- (2-methyl-phenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (2-methyl-phenyl) -piperazine followed by hydrolysis. LC-MS (M + H348, obsd 348).

P70S6K IC₅₀：980nM

Example 1215- [4- (2-fluorophenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (2-fluorophenyl) -piperazine followed by hydrolysis. LC-MS (352M + H, 352 obsd).

P70S6K IC₅₀：12000nM

Example 1225- [4- (2-methoxyphenyl) -piperazin-1-yl]-quinazoline-8-carboxylic acid amides

The title compound was synthesized according to the preparation method of example 1 by coupling reaction with 5-bromo-quinazoline-8-carbonitrile and 1- (2-methoxyphenyl) -piperazine followed by hydrolysis. LC-MS (M + H364, obsd 364).

P70S6K IC₅₀：11000nM

Biological activity

P70S6K enzyme assay

P70S6K inhibitor compounds were diluted and plated in 96-well plates. Adding a reaction mixture comprising the following components to the compound plate to start an enzymatic reaction; P70S6K (3nM, T412E mutant, Millipore) was mixed with 24 μ MATP in assay buffer containing 100mM Hepes (pH7.5), 5mM MgCl₂1 mdtt, 0.015% Brij and 1 μ M substrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from the S6 ribosomal protein sequence, FITC-fluorescein isothiocyanate, AHA-6-aminocaproic acid). The reaction was incubated at 25 ℃ for 90 minutes, after which time10mM EDTA was added to stop the reaction. The ratio of substrate and product (phosphorylated) peptides was analyzed at a Caliper Life Sciences Lab Chip3000 at-1.4 psi, downstream and downstream voltages of-3000 and-700, respectively. On the chromatogram obtained, the product peak is resolved before the substrate peak.

AKT enzyme assay

125nl of an appropriate concentration of inhibitor in 100% DMSO was placed in each well of a 384-well plate using a TTP Mosquito liquid handling instrument (used to plot dose response curves). To the reaction were added the components to a final concentration of 12.5 μ l:

0.1 ng/. mu.l His-AKT (full Length), (Invitrogen, Part # P2999, Lot #641228C)

160uM ATP(Fluka，02055)

1mM DTT(Sigma，D0632)

1mM MgCl2(Sigma，M1028)

mu.M substrate Peptide (sequence FITC-AHA-GRPRTSSFAEG-NH2), synthesized by Tufts Peptide Synthesis

100mM HEPES pH7.5(Calbiochem，391338)

0.015％Brij-35(Sigma，B4184)

The reaction was incubated at 25 ℃ for 90 minutes, and then 70. mu.l of a stop buffer (100mM HEPES pH7.5, 0.015% Brij-35,10mM EDTA (Sigma, E7889)) was added to stop the reaction.

The orifice plate was read using a Caliper LC3000 in an Off-chip mobility shift assay format (Off-chip shift assay format) using a chip with 12 suction pins with the following parameters: the screening pressure was-2.3 psi, upstream voltage-500, downstream voltage-3000. These conditions allow the non-phosphorylated substrate and the phosphorylated product to be resolved in different peaks, so that the percentage of substrate converted to product can be directly measured. Percent conversion is plotted against inhibitor concentration to give a sigmoidal dose-response curve, based on which IC can be calculated₅₀The value is obtained.

Claims

1. A compound represented by the following general formula (I) or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing,

wherein:

x is N;

y is N-R⁵；

R¹Is L¹-R⁶Or L¹-R⁶-L²-R⁷；

R²Is H or Hal;

R³is H;

L¹、L²independently a single bond, or an unbranched or branched alkyl radical having 1,2,3, 4 or 5C atoms which may be unsubstituted or mono-or disubstituted by Hal, wherein 1 or 2 CH₂The group may be replaced by a-CO-, -NH-, -N (LA) -, -CONH-, -N (LA) COO-or-NHCO-group;

R⁶is Ar or is a monocycloalkyl group having 3,4,5, 6 or 7 ring atoms, of which 1 or 2 CH₂The groups may be replaced by-NH-or-NA-groups;

R⁷is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、CH₃O, or C (Hal)₃O is mono-, di-or tri-substituted;

a is an unbranched or branched, linear or cyclic alkyl radical having 1,2,3, 4,5 or 6C atoms, in which 1 or 2 CH₂The groups being replaced by O atoms and/or-NH-, -NHCO or-CONH groups, 1 to 3 of which being pro-HA subunit may be replaced by Hal, and 1 or 2 of these CH₃The radical being optionally substituted by NH₂OH, NH (LA) or N (LA)₂Substituted by a group;

LA is an unbranched or branched, linear alkyl group having 1,2,3 or 4C atoms, wherein 1,2 or 3H atoms may be replaced by Hal; and

hal is F, Cl, Br or I.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is N-R⁵。

3. The compound of claim 1, wherein the compound is selected from the group consisting of:

5- ((4- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4-phenylpiperidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4- (3-fluoro-4- (trifluoromethyl) phenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4- (4-chloro-3-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4- (3-chloro-4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide,

5- (((3R,4R) -4- (3-chloro-4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide,

5- ((4- (4-fluorophenyl) piperidin-3-yl) amino) quinazoline-8-carboxamide,

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is N-R⁵；R⁵And R¹Together form a ring having 45 or 6 ring atoms, one CH₂The group is-N (L)¹-R⁶) -substituted, and said monocycloalkyl ring may optionally be replaced by NH₂And (4) substitution.

5. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is N-R⁵；R⁵And R¹Together form a monocycloalkyl ring having 4,5 or 6 ring atoms, one CH of which₂The group is-N (L)¹-R⁶) -substituted, and said monocycloalkyl ring may optionally be replaced by NH₂Substitution; and L is¹Is a bond, -CONH-, -NHCO-, -CONHCH₂-or CH₂CONH-。

6. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is N-R⁵；R⁵And R¹Together form a monocycloalkyl ring having 4,5 or 6 ring atoms, one CH of which₂The group is-N (L)¹-R⁶) -substituted, and said monocycloalkyl ring may optionally be replaced by NH₂Substitution; and R is⁶Is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、C(Hal)₃O is mono-, di-or tri-substituted.

7. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is N-R⁵；R⁵And R¹Together form a monocycloalkyl ring having 4,5 or 6 ring atoms, of which 1 CH₂The group may be substituted by-N (L)¹-R⁶) -is replaced by a group, and the monocycloalkyl ring may optionally be replaced by NH₂Substitution; and, L¹Is the key, -CONH-, -NHCO-, -CONHCH₂-or CH₂CONH-；R⁶Is benzeneSaid phenyl group may be unsubstituted or independently be Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-, di-or tri-substituted.

8. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is NH; r¹Is L¹-R⁶-L²-R⁷；L¹And L²Is a bond; r⁶Is a monocycloalkyl ring having 4,5 or 6 ring atoms, of which 1 CH₂The group is replaced by an-NH-group; r⁷Is phenyl which may be unsubstituted or independently by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O is mono-, di-or tri-substituted.

9. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is NH; r¹Is L¹-R⁶-L²-R⁷；L¹And L²Is a bond; r⁶Is piperidinyl or pyrrolidinyl; r⁷Is phenyl, said phenyl being substituted by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O mono-or di-substitution.

10. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is NH; r¹Is L¹-R⁶-L²-R⁷；L¹And L²Is a bond; r⁶Is thatR⁷Is phenyl, said phenyl being substituted by Hal, C (Hal)₃、CH₃、CH₃O、C(Hal)₃O mono-or di-substitution.

11. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is N; y is N-R⁵；R⁵And R¹Together form a monocycloalkyl ring having 3,4,5, 6 or 7 ring atoms, one or two CH₂Can be substituted by-NH-, -NA-, -N (L)¹-R⁶)-、-CHA-、-CA₂-、CH(L¹-R⁶) -or-CO-group, and said monocycloalkyl ring is optionally replaced by NH₂And (4) substitution.

12. A medicament comprising at least one compound according to any one of claims 1 to 11 and/or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, as active ingredient, and a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for the treatment of a hyperproliferative disease in which modulation of P70S6K or AKT kinase is indicated.

15. The use of claim 14, wherein the disease is cancer.

16. The use of claim 14, wherein the disease is melanoma or kaposi's sarcoma.

17. The use of a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for the treatment of a hyperproliferative disease in which inhibition of P70S6K or AKT kinase is indicated.

18. The use of claim 17, wherein the disease is cancer.

19. The use of claim 17, wherein the disease is melanoma or kaposi's sarcoma.

20. Use of a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for the treatment of inflammation, kidney disease, pain or prostate disease in which modulation of P70S6K or AKT kinase is indicated.

21. The use of claim 20, wherein the inflammation is pancreatitis.

22. Use of a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for the treatment of inflammation, kidney disease, pain or prostate disease in which inhibition of P70S6K or AKT kinase is indicated.

23. The use of claim 22, wherein the inflammation is pancreatitis.

24. A kit comprising the following individual packages: an effective amount of a compound according to any one of claims 1 to 11 and/or a stereoisomer or tautomer thereof or a pharmaceutically acceptable salt thereof, and an effective amount of a further pharmaceutically active ingredient.