HK1182379A - Inhibitors of protein tyrosine kinase activity - Google Patents

Description

Inhibitors of protein tyrosine kinase activity

Background

RELATED APPLICATIONS

This application claims priority from U.S. provisional application No. 61/324,803, filed on day 16, 4/2010. The entire teachings of the above referenced application are incorporated by reference.

Technical Field

The present invention relates to compounds that inhibit protein tyrosine kinase activity. The invention relates, inter alia, to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, thereby inhibiting receptor signaling, e.g., VEGF receptor signaling and HGF receptor signaling. More particularly, the present invention relates to compounds, compositions and methods for inhibiting VEGF receptor signaling.

Background

Tyrosine kinases can be classified as either growth factor receptor-type (e.g., EGFR, PDGFR, FGFR, and erbB2) or non-receptor-type (e.g., c-src and bcr-abl) kinases. Receptor-type tyrosine kinases make up about 20 different subfamilies. Non-receptor tyrosine kinases constitute a number of subfamilies. These tyrosine kinases have diverse biological activities. Receptor tyrosine kinases are extracellular binding domains that span the cell membrane and have growth factors, transmembrane domains, and large enzymes that act as kinases to phosphorylate specific tyrosine residues in proteins and thus influence the intracellular portion of cell proliferation. Abnormal or inappropriate protein kinase activity may contribute to the development of disease conditions associated with such abnormal kinase activity.

Angiogenesis is an important component of certain normal physiological processes such as embryogenesis and wound healing, but aberrant angiogenesis contributes to several pathological conditions and in particular to tumor growth. VEGF-A (vascular endothelial growth factor A) is a key factor in promoting tumor neovascularization (angiogenesis). VEGF induces endothelial cell proliferation and migration via two high affinity receptors (the fms-like tyrosine kinase receptor Flt-1 and the kinase insert domain containing receptor KDR) signaling. These signaling reactions are critically dependent on receptor dimerization and activation of intrinsic Receptor Tyrosine Kinase (RTK) activity. Homodimers binding to VEGF in a disulfide bond stimulate receptor dimerization and activation of the RTK domain. Kinases autophosphorylate cytoplasmic receptor tyrosine residues, which then serve as binding sites for molecules involved in the propagation of signaling cascades. While it is possible to elucidate multiple pathways for both receptors, KDR signaling has been most extensively studied, suggesting that mitogenic responses involve ERK-1 and ERK-2 mitogen-activated protein kinases.

Interference of VEGF receptor signaling is a very attractive therapeutic target in cancer, since angiogenesis is a prerequisite for the growth of all solid tumors, and the mature endothelium remains relatively quiescent (except for the female reproductive system and wound healing). Many experimental approaches to inhibiting VEGF signaling have been investigated, including the use of neutralizing antibodies, receptor antagonists, soluble receptors, antisense constructs, and dominant negative strategies.

Although attractive solely from anti-angiogenic therapies that inhibit VEGF, several problems may limit this approach. The extent of VEGF expression can itself be increased by a number of different stimuli, and perhaps most importantly, the hypoxic condition of a tumor caused by inhibition of VEGFr can lead to induction of factors that themselves promote tumor invasion and metastasis, thus potentially affecting the role of VEGF inhibitors as cancer therapeutics.

HGF (hepatocyte growth factor) and the HGF receptor c-met are implicated in the ability of tumor cells to destroy inhibitory VEGF activity. HGF, derived from stromal fibroblasts surrounding tumor cells or expressed from the tumor itself, has been proposed to play a key role in tumor angiogenesis, invasion and metastasis. For example, the invasive growth of certain cancer cells is dramatically enhanced by tumor-matrix interactions involving the HGF/c-Met (HGF receptor) pathway. HGF, originally identified as a potent mitogen for hepatocytes, is secreted mainly from stromal cells, and the secreted HGF can promote motility and invasion of various cancer cells expressing c-Met in a paracrine manner. Binding of HGF to c-Met results in receptor phosphorylation and activation of the Ras/Mitogen Activated Protein Kinase (MAPK) signaling pathway, thereby enhancing cancer cells Sexual behavior. Furthermore, stimulation of the HGF/c-met pathway itself may lead to induction of VEGF expression, itself directly contributing to angiogenic activity.

Thus, an anti-tumor anti-angiogenesis strategy or method that targets VEGF/VEGFr signaling or HGF/c-met signaling may be an improved cancer therapy.

Tyrosine kinases also contribute to the pathogenesis of ophthalmic diseases, conditions and disorders such as age-related macular degeneration (AMD) and Diabetic Retinopathy (DR). Blindness resulting from these diseases is associated with abnormalities in retinal neovascularization. Neovascularization is regulated by growth factors such as VEGF and HGF, which activate receptor tyrosine kinases, initiating signaling pathways, leaking plasma to the macula, resulting in vision loss. Kinases are therefore attractive targets for the treatment of ocular diseases involving neovascularization.

Therefore, there is a need to develop a strategy to control ocular neovascularization and to develop a strategy to treat ocular diseases.

Disclosed herein are small molecules that are potent inhibitors of protein tyrosine kinase activity.

Summary of The Invention

The present invention provides novel compounds and methods for treating diseases responsive to inhibition of kinase activity, such as diseases responsive to inhibition of protein tyrosine kinase activity, for example, diseases responsive to inhibition of protein tyrosine kinase activity of growth factor receptors, for example, diseases responsive to inhibition of receptor type tyrosine kinase signaling, or for example, responsive to inhibition of VEGF receptor signaling. In some embodiments, the disease is a cell proliferative disease. In other embodiments, the disease is an ophthalmic disease. The compounds of the invention are inhibitors of kinase activity, e.g., protein tyrosine kinase activity, e.g., of growth factor receptors or e.g., receptor type tyrosine kinase signaling.

In a first aspect, the present invention provides compounds of formula (I):

and N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein D, M, Z, Ar and G are as defined herein. Because the compounds of the present invention are useful as kinase inhibitors, they are useful research tools for studying the role of kinases in both normal and disease states. In some embodiments, the present invention provides compounds useful as inhibitors of VEGF receptor signaling, and thus useful research tools for studying the role of VEGF in normal and disease states.

In a second aspect, the present invention provides a composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. For example, the present invention provides compositions comprising a compound that is an inhibitor of VEGF receptor signaling, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

In a third aspect, the invention provides a method of inhibiting kinase activity, e.g., tyrosine kinase activity of a protein tyrosine kinase, e.g., a growth factor receptor, comprising contacting the kinase with a compound of the invention or with a composition of the invention. In some embodiments of this aspect, the invention provides a method of inhibiting receptor type tyrosine kinase signaling, e.g., inhibiting VEGF receptor signaling. The inhibitory effect may be in a cell or a multicellular organism. If in a cell, the method of this aspect of the invention comprises contacting the cell with a compound of the invention or with a composition of the invention. If in a multicellular organism, the method of this aspect of the invention includes administering to the organism a compound of the invention or a composition of the invention. In some embodiments, the organism is a mammal, such as a primate, such as a human.

In a fourth aspect, the present invention provides a method of inhibiting angiogenesis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a therapeutically effective amount of a composition of the present invention. In some embodiments of this aspect, the angiogenesis to be inhibited is associated with tumor growth. In some other embodiments, the angiogenesis to be inhibited is retinal angiogenesis. In some embodiments of this aspect, the patient is a mammal, such as a primate, such as a human.

In a fifth aspect, the invention provides a method of treating a disease responsive to inhibition of kinase activity, for example a disease responsive to inhibition of protein tyrosine kinase activity of a growth factor receptor. In some embodiments of this aspect, the invention provides a method of treating a disease responsive to inhibition of receptor-type tyrosine kinase signaling, e.g., a disease responsive to inhibition of VEGF receptor signaling, comprising administering to an organism in need thereof a therapeutically effective amount of a compound of the invention or a composition of the invention. In some embodiments of this aspect, the organism is a mammal, such as a primate, such as a human.

In a sixth aspect, the present invention provides a method of treating a cell proliferative disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a therapeutically effective amount of a composition of the present invention. In some embodiments of this aspect, the cell proliferative disease is cancer. In some embodiments, the patient is a mammal, such as a primate, such as a human.

In a seventh aspect, the present invention provides a method of treating an ophthalmic disease, disorder, or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a therapeutically effective amount of a composition of the present invention. In some embodiments of this aspect, the disease is caused by choroidal angiogenesis. In some embodiments of this aspect, the patient is a mammal, such as a primate, such as a human.

In an eighth aspect, the present invention provides the use of a compound of the invention for or in the manufacture of a medicament for inhibiting kinase activity, e.g. inhibiting protein tyrosine kinase activity of a growth factor receptor. In some embodiments of this aspect, the invention provides the use of a compound of the invention for or in the manufacture of a medicament for inhibiting receptor-type tyrosine kinase signaling, e.g., inhibiting VEGF receptor signaling. In some embodiments of this aspect, the invention provides the use of a compound of the invention for or for the manufacture of a medicament for the treatment of a disease responsive to inhibition of kinase activity. In some embodiments of this aspect, the disease is responsive to inhibition of protein tyrosine kinase activity, such as inhibition of protein tyrosine kinase activity of growth factor receptors. In some embodiments of this aspect, the disease is responsive to inhibition of receptor type tyrosine kinase signaling, such as VEGF receptor signaling. In some embodiments of this aspect, the disease is a cell proliferative disease such as cancer. In some embodiments of this aspect, the disease is an ophthalmic disease, condition, or disorder. In some embodiments of this aspect, the ophthalmic disease, condition, or disorder is caused by choroidal angiogenesis. In some embodiments of this aspect, the disease is age-related macular degeneration, diabetic retinopathy, or retinal edema.

In a ninth aspect, the present invention provides the use of a compound of the present invention, or a composition thereof, to inhibit kinase activity, such as inhibiting receptor type tyrosine kinase activity, such as inhibiting protein tyrosine kinase activity of a growth factor receptor. In some embodiments of this aspect, the invention provides the use of a compound of the invention, or a composition thereof, to inhibit receptor-type tyrosine kinase signaling, such as to inhibit VEGF receptor signaling.

In a tenth aspect, the present invention provides the use of a compound of the invention, or a composition thereof, to treat a disease responsive to inhibition of kinase activity, such as a disease responsive to inhibition of protein tyrosine kinase activity of a growth factor receptor. In some embodiments of this aspect, the invention provides the use of a compound of the invention, or a composition thereof, to treat a disease responsive to inhibition of receptor-type tyrosine kinase signaling, such as a disease responsive to inhibition of VEGF receptor signaling. In some embodiments of this aspect, the disease is a cell proliferative disease, such as cancer. In some embodiments of this aspect, the disease is an ophthalmic disease, condition, or disorder. In some embodiments of this aspect, the ophthalmic disease, condition, or disorder is caused by choroidal angiogenesis.

The foregoing merely summarizes some aspects of the invention and is not limiting. These and other aspects and embodiments are described more fully below.

Detailed Description

The present invention provides compounds, compositions and methods for inhibiting kinase activity, such as protein tyrosine kinase activity, such as receptor protein kinase activity, such as VEGF receptor KDR. The invention also provides compounds, compositions and methods of inhibiting angiogenesis, treating diseases responsive to inhibition of kinase activity, treating cell proliferative diseases and conditions, and treating ophthalmic diseases, disorders and conditions. The patent and scientific literature referred to herein is available to those skilled in the art. Issued patents, published patent applications, and references cited herein are incorporated by reference to the same extent as if each patent, application, or reference were specifically and individually indicated to be incorporated by reference. In case of conflict, the present disclosure controls.

For the present invention, the following definitions will be used (unless specifically stated otherwise):

for simplicity, chemical moieties are defined primarily throughout and are referred to as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, these terms are also used to express the corresponding multivalent moieties in the context of appropriate structures as will be clear to those skilled in the art. For example, although "alkyl" moieties generally refer to monovalent radicals (e.g., CH) ₃-CH₂-) but in some cases the divalent linking moiety can be an "alkyl" in which case one of skill in the art would understand that the alkyl would be a divalent radical (e.g., -CH₂-CH₂-, which corresponds to the term "alkylene". Similarly, where a divalent moiety is required and stated as "aryl", those skilled in the art will appreciate that the term "aryl" refers to the corresponding divalent moiety arylene. It is understood that all atoms have the normal atomic valences to which they form a bond (i.e., carbon is 4, nitrogen is 3, oxygen is 2, and sulfur is 2, 4, or 6 depending on the oxidation state of S). A moiety may sometimes be defined as, for example, (A)_a-B-, wherein a is 0 or 1. In these cases, when a is 0, the moiety is B-, and when a is 1, the moiety is A-B-.

For simplicity, reference is made to "C_n-C_m"heterocyclic radical or" C_n-C_m"heteroaryl" refers to a heterocyclic or heteroaryl group having from "n" to "m" ring atoms, where "n" and "m" are integers. Thus, for example, C₅-C₆Heterocyclyl is a 5-or 6-membered ring having at least one heteroatom and includes pyrrolidinyl (C)₅) And piperazinyl and piperidinyl (C)₆)；C₆Heteroaryl groups include, for example, pyridyl and pyrimidinyl.

The term "hydrocarbyl" refers to a straight, branched or cyclic alkyl, alkenyl or alkynyl group, each as defined herein. "C ₀"hydrocarbyl group is used to refer to a covalent bond. Thus, "C₀-C₃Hydrocarbyl groups "include covalent bonds, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.

The term "alkyl" refers to a straight or branched chain aliphatic group having 1 to 12 carbon atoms, alternatively 1 to 8 carbon atoms, and alternatively 1 to 6 carbon atoms. In some embodiments, the alkyl group has 1 to 4 carbon atoms. In some embodiments, the alkyl group has 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms and alternatively 2 to 6 carbon atoms. In some embodiments, examples of alkyl groups having 2 to 4 carbons include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. "C₀"alkyl group (e.g." C)₀-C₃Alkyl "in) is a covalent bond.

The term "alkenyl" refers to an unsaturated straight or branched aliphatic group having one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively from 2 to 8 carbon atoms, and alternatively from 2 to 6 carbon atoms. In some embodiments, alkenyl groups have 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term "alkynyl" refers to an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively from 2 to 8 carbon atoms, and alternatively from 2 to 6 carbon atoms. In some embodiments, alkynyl groups have 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term "alkylene," "alkenylene," or "alkynylene," as used herein, refers to an alkyl, alkenyl, or alkynyl group, respectively, as defined above that is located between and used to link two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propynyl, and butynyl.

The term "carbocycle" as used herein refers to a cycloalkyl or aryl moiety group.

The term "cycloalkyl" refers to a saturated, partially unsaturated or unsaturated mono-, di-, tri-or polycyclic hydrocarbon group having about 3 to 15 carbons, alternatively 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and alternatively 5 or 6 carbons. In some embodiments, the cycloalkyl is fused to an aryl, heteroaryl, or heterocyclyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopent-2-enone, cyclopent-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.

The term "heteroalkyl" refers to a saturated, partially unsaturated, or unsaturated straight or branched chain aliphatic group in which one or more carbon atoms in the group are independently replaced with a heteroatom selected from O, S and N.

The term "aryl" refers to a mono, bi, tri, or polycyclic aromatic moiety containing 1 to 3 aromatic rings. In some embodiments, aryl is C₆-C₁₄Aromatic moieties, or aryl radicals, being C₆-C₁₀Aryl, or C₆And (4) an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

The term "aralkyl" or "arylalkyl" refers to a radical containing an aromatic hydrocarbonGroups are covalently linked to alkyl groups. If an aralkyl group is described as "optionally substituted" aralkyl, it is intended that one or both of the aryl and alkyl moiety groups may be independently optionally substituted or unsubstituted. In some embodiments, aralkyl is (C)₁-C₆) Alkyl radical (C)₆-C₁₀) Aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as "arylalkyl," this term and its related terms are intended to indicate that the order of the groups in the compound is "aryl-alkyl. Similarly, "alkyl-aryl" is intended to indicate that the order of groups in a compound is "alkyl-aryl".

The term "heterocyclyl" or "heterocycle" refers to a group having a mono, bi, or polycyclic structure of about 3 to about 14 atoms, alternatively 3 to 8 atoms, alternatively 4 to 7 atoms, alternatively 5 or 6 atoms, wherein one or more atoms, for example 1 or 2 atoms, are independently selected from N, O and S, and the remaining ring-forming atoms are carbon atoms. The ring structure may be saturated, unsaturated, or partially unsaturated. In some embodiments, the heterocyclyl is a non-aromatic heterocyclyl, in which case the group is also referred to as heterocycloalkyl. In some embodiments, the heterocyclyl is a spiroheterocyclyl, e.g., 2, 7-diazaspiro [4.4 [ ] -]Nonane, 2, 8-diazaspiro [5.5 ]]Undecane, 2, 8-diazaspiro [4.5 ]]Decane, 2, 7-diazaspiro [3.5 ]]Nonane, 2, 6-diazaspiro [3.4 ]]Octane, 2-oxa-7-azaspiro [4.4]Nonane, 2-oxa-8-azaspiro [5.5 ]]Undecane, 8-oxa-2-azaspiro [4.5 ]]Decane, 7-oxa-2-azaspiro [3.5 ]]Nonane, 6-oxa-2-azaspiro [3.4 ]]Octane, 1-oxa-7-azaspiro [4.4]Nonane, 2-oxa-8-azaspiro [5.5 ]]Undecane, 2-oxa-8-azaspiro [4.5 ]]Decane, 2-oxa-7-azaspiro [3.5 ]]Nonanes and 2-oxa-6-azaspiro [3.4 ]]Octane. In a bicyclic or polycyclic structure, one or more rings may be aromatic; for example, one or both rings of a bicyclic or tricyclic heterocycle may be aromatic, as in indane and 9, 10-dihydroanthracene. Examples of heterocyclyl groups include, but are not limited to, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, piperidinyl, piperazinyl, etc, Oxazolidinyl group,Oxazolidone group, N-morpholinyl group, thienyl group, pyridyl group, 1,2, 3-triazolyl group, imidazolyl group, isotriazolyl groupOxazolyl, pyrazolyl, piperazinyl, piperidinyl, N-piperidinyl, morpholinyl, homopiperazinyl, N-homopiperazinyl, thiomorpholinyl, N-thiomorpholinyl, tetrahydropyrrolyl and azepanyl. In some embodiments, the heterocyclyl is fused to an aryl, heteroaryl, or cycloalkyl. Examples of such fused heterocycles include, but are not limited to, tetrahydroquinoline and dihydrobenzofuran. In particular, compounds in which a ring O or S atom is adjacent to another O or S atom are excluded from the scope of this term.

In some embodiments, the heterocyclic group is heteroaryl. The term "heteroaryl" as used herein refers to a cyclic array having from 5 to 14 ring atoms, or 5, 6, 9 or 10 ring atoms having, for example, 6, 10 or 14 pi electrons shared; and a mono-, di-, tri-or polycyclic group having one or more heteroatoms independently selected from N, O and S in addition to carbon atoms. Such as heteroaryl groups including, but not limited to, pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl, and indolinyl. Other examples of heteroaryl groups include, but are not limited to, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, pyridyl, and the like, Azolyl, thiazolyl and isothiazolylAn azole group.

The terms "arylene", "heteroarylene" or "heterocyclene" refer to an aryl, heteroaryl or heterocyclyl group, respectively, as defined above, located between and used to link two other chemical groups.

Examples of heterocyclyl and heteroaryl groups include, but are not limited to, azepanyl, azetidinyl, acridinyl, azocinyl, benzindolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuranyl, benzothiophenyl, benzothiazophenyl, and the likeAzolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzotetrazolyl, benzisoxazolylAzolyl, benzisothiazolyl, benzimidazolinyl, benzoAzolyl, benzoOxadiazolyl, benzopyranyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, 1, 3-dioxolane, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] group]Tetrahydrofuranyl, dihydroisoindolyl, dihydroquinazolinyl (e.g. 3, 4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (e.g. furo [2,3-c ] ]Pyridyl, furo [3,2-b ]]Pyridyl or furo [2,3-b ]]Pyridyl), furyl, furazanyl, hexahydrodiazepineA group, imidazolidinyl group, imidazolinyl group, imidazolyl group, indazolyl group, 1H-indazolyl group, indolinyl group, indolizinyl group, indolyl group, 3H-indolyl group, isobenzofuranyl group, isochromanyl group, isoindolyl group, isoindolinyl group, isoindolyl group, isoquinolinyl group, isothiazolidinyl group, isoindolinyl group, indolinyl groupAzolinyl, isoOxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,Oxadiazolyl, l,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,3,4-A diazolyl group,Oxazolidinyl group,Azolyl group,Oxazolidinyl, oxetanyl, 2-oxazaYl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenothiazinyl, phenanthrinylThia-and coffee-baseOxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoOxazole, pyridoimidazole, pyridothiazole, pyridyl (pyridinyl, pyridil), pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H-pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalyl, quinuclidinyl, tetrahydro-1, 1-dioxothienyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrahydropyranyl, tetrazolyl, thiazolidinyl, 6H-1,2, 5-thiadiazinyl, thiadiazolyl (e.g. 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl), thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, thienyl, thiazolyl, thienyl, thienothiazolyl, thiazolylyl, Thieno Azolyl, thienoimidazolyl, thienyl, triazinyl, triazinylazazaA triazolyl group (e.g., 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl) and a xanthenyl group.

The term "oxazolyl" as used herein, refers to a 5-membered saturated or unsaturated heterocyclic group containing two or more heteroatoms selected from nitrogen, sulfur and oxygen as ring atoms, wherein at least one of the heteroatoms is a nitrogen atom. Examples of azole groups include, but are not limited to, optionally substituted imidazolyl,Azolyl, thiazolyl, pyrazolyl, isoAzolyl, isothiazolyl, 1,3, 4-thiadiazolyl, 1,2,4-Azolyl and 1,3,4-A diazolyl group.

As used herein and unless otherwise specified, when a moiety (e.g., alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as an "optionally substituted" moiety, it is meant that the group optionally has 1 to 4, alternatively 1 to 3, alternatively 1 or 2, independently selected non-hydrogen substituents. Suitable substituents include, but are not limited to, halogen, hydrocarbyl, oxo (oxo) (e.g., ring-CH-substituted with oxo is-C (O)), nitro, halocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, amido, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido.

Examples of substituents which are themselves not further substituted (unless otherwise specified) are:

(a) halogen, cyano, oxo, carboxyl, formyl, nitro, amino, carbamimidoyl, guanidino,

(b)C₁-C₅alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkylamino radical, C₁-C₈Alkoxycarbonyl, aryloxycarbonyl, C₂-C₈Acyl radical, C₂-C₈Amide group, C₁-C₈Alkylthio, arylalkylthio, arylThio radical, C₁-C₈Alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C₁-C₈Alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C₀-C₆N-alkylcarbamoyl, C₂-C₁₅-N, N-dialkylcarbamoyl radical, C₃-C₇Cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl fused to a cycloalkyl or heterocyclic group or to another aromatic ring, C₃-C₇Heterocyclic group, C₅-C₁₅Heteroaryl or any of these rings fused or spiro-fused to cycloalkyl, heterocyclyl or aryl, wherein each of the foregoing is further optionally substituted with one or more moieties as recited in (a) above; and

(c)-(CR³²R³³)_s-NR³⁰R³¹，

wherein s is 0 (in which case nitrogen is directly attached to the substituted moiety) to 6,

R³²And R³³Each independently is hydrogen, halogen, hydroxy or C₁-C₄Alkyl, and R³⁰And R³¹Each independently is hydrogen, cyano, oxo, hydroxy, C₁-C₈Alkyl radical, C₁-C₈Heteroalkyl group, C₂-C₈Alkenyl, carboxamide, C₁-C₃Alkyl-carboxamide, carboxamide-C₁-C₃Alkyl, amidino, C₂-C₈Hydroxyalkyl radical, C₁-C₃Alkyl heteroaryl, heteroaryl-C₁-C₃Alkyl radical, C₁-C₃Alkyl heteroaryl, heterocyclyl-C₁-C₃Alkyl radical, C₁-C₃Alkylheterocyclic group, heterocyclic group-C₁-C₃Alkyl radical, C₁-C₃Alkylcycloalkyl, cycloalkyl-C₁-C₃Alkyl radical, C₂-C₈Alkoxy radical, C₂-C₈alkoxy-C₁-C₄Alkyl radical, C₁-C₈Alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃Alkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-C₁-C₃Alkoxycarbonyl, C₁-C₈Acyl radical, C₀-C₈Alkyl-carbonyl, aryl-C₀-C₈Alkyl-carbonyl, heteroaryl-C₀-C₈Alkyl-carbonyl, cycloalkyl-C₀-C₈Alkyl-carbonyl, C₀-C₈alkyl-NH-carbonyl, aryl-C₀-C₈alkyl-NH-carbonyl, heteroaryl-C₀-C₈alkyl-NH-carbonyl, cycloalkyl-C₀-C₈alkyl-NH-carbonyl, C₀-C₈alkyl-O-carbonyl, aryl-C₀-C₈alkyl-O-carbonyl, heteroaryl-C₀-C₈alkyl-O-carbonyl, cycloalkyl-C₀-C₈alkyl-O-carbonyl, C₁-C₈Alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C₁-C₈alkyl-NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl, heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonylarylacyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C ₁-C₃Alkyl-, cycloalkyl-C₁-C₃Alkyl-, heterocyclyl-C₁-C₃Alkyl-, heteroaryl-C₁-C₃Alkyl-or a protecting group, wherein each of the foregoing is further optionally substituted with one or more moieties as listed in (a) above; or

R³⁰And R³¹Together with the N to which they are attached form a heterocyclyl or heteroaryl group, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of (a), protecting groups and (X) above³⁰-Y³¹-) wherein the heterocyclyl may also be bridged (with a methylene, ethylene or propylene bridge to form a bicyclic moiety); wherein

X³⁰Is selected from C₁-C₈Alkyl radical, C₂-C₈Alkenyl-, C₂-C₈Alkynyl-, -C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃Alkyl radical、C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃Alkyl radical, C₀-C₃alkyl-O-C₀-C₃Alkyl-, HO-C₀-C₃Alkyl-, C₀-C₄alkyl-N (R)³⁰)-C₀-C₃Alkyl-, N (R)³⁰)(R³¹)-C₀-C₃Alkyl-, N (R)³⁰)(R³¹)-C₀-C₃Alkenyl-, N (R)³⁰)(R³¹)-C₀-C₃Alkynyl-, (N (R)³⁰)(R³¹))₂-C=N-、C₀-C₃alkyl-S (O)_0-2-C₀-C₃Alkyl-, CF₃-C₀-C₃Alkyl-, C₁-C₈Heteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C₁-C₃Alkyl-, cycloalkyl-C₁-C₃Alkyl-, heterocyclyl-C₁-C₃Alkyl-, heteroaryl-C₁-C₃Alkyl-, N (R)³⁰)(R³¹) -heterocyclyl-C₁-C₃Alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents from (a); and

Y³¹selected from the group consisting of a bond, -O-, -N (R)³⁰)-、-C(O)-、-O-C(O)-、-C(O)-O-、-N(R³⁰)-C(O)-、-C(O)-N(R³⁰)-、-N(R³⁰)-C(S)-、-C(S)-N(R³⁰)-、-N(R³⁰)-C(O)-N(R³¹)-、-N(R³⁰)-C(NR³⁰)-N(R³¹)-、-N(R³⁰)-C(NR³¹)-、-C(NR³¹)-N(R³⁰)-、-N(R³⁰)-C(S)-N(R³¹)-、-N(R³⁰)-C(O)-O-、-O-C(O)-N(R³¹)-、-N(R³⁰)-C(S)-O-、-O-C(S)-N(R³¹)-、-S(O)_0-2-、-SO₂N(R³¹)-、-N(R³¹)-SO₂-and-N (R)³⁰)-SO₂N(R³¹)-。

The substituted moiety is one or more (e.g., 1 to 4, or 1 to 3 and either 1 or 2) a moiety wherein the hydrogen has been independently replaced with another chemical substituent. By way of non-limiting example, substituted phenyl groups include 2-fluorophenyl, 3, 4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyl groups include 2, 4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylene (-CH)₂-) is substituted with oxygen to form a carbonyl (-CO-).

When two optional substituents are bound to adjacent atoms of a ring structure such as phenyl, thienyl or pyridyl, these substituents together with the atoms to which they are attached optionally form a 5 or 6 membered cycloalkyl or heterocyclic ring having 1, 2 or 3 ring heteroatoms.

In some embodiments, the hydrocarbyl, heteroalkyl, heterocyclyl, and/or aryl groups are unsubstituted.

In some embodiments, the hydrocarbyl, heteroalkyl, heterocyclyl, and/or aryl groups are substituted with 1 to 3 independently selected substituents.

Examples of substituents on alkyl groups include, but are not limited to, hydroxy, halo (e.g., single halo substituent or multiple halo substituents; in the case of multiple halo substituents, is, for example, CF)₃Or with Cl₃Alkyl group of (a), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl, -OR ^a、-SR^a、-S(=O)R^e、-S(=O)₂R^e、-P(=O)₂R^e、-S(=O)₂OR^e、-P(=O)₂OR^e、-NR^bR^c、-NR^bS(=O)₂R^e、-NR^bP(=O)₂R^e、-S(=O)₂NR^bR^c、-P(=O)₂NR^bR^c、-C(=O)OR^e、-C(=O)R^a、-C(=O)NR^bR^c、-OC(=O)R^a、-OC(=O)NR^bR^c、-NR^bC(=O)OR^e、-NR^dC(=O)NR^bR^c、-NR^dS(=O)₂NR^bR^c、-NR^dP(=O)₂NR^bR^c、-NR^bC(=O)R^aor-NR^bP(=O)₂R^eWherein R is^aIs hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; r^b、R^eAnd R^dIndependently hydrogen, alkyl, cycloalkyl, heterocyclyl or aryl, or these R^bAnd R^eOptionally forming a heterocyclic ring together with the N to which it is attached; and R is^eIs alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl or aryl. Among the foregoing exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, and aryl may themselves be optionally substituted.

Examples of substituents on alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, and those cited as examples of alkyl substituents.

Examples of substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, and those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-linked or fused cyclic substituents, such as spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclyl (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl, and aryl substituents may themselves be optionally substituted.

Examples of substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, and those groups recited as examples of alkyl substituents. Other examples of substituents include, but are not limited to, spiro-linked or fused cyclic substituents, such as spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclyl (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl, and aryl substituents may themselves be optionally substituted.

Examples of substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, and those groups recited above as examples of alkyl substituents. Other examples of substituents include, but are not limited to, fused cyclic groups such as fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl, and aryl substituents may themselves be optionally substituted. Other examples of substituents on aryl (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those recited as examples of alkyl substituents.

Examples of substituents on the heterocyclyl include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., = O), cyano, alkyl, substituted alkyl, and those groups recited above as examples of alkyl substituents. Additional examples of substituents on a heterocyclyl include, but are not limited to, spiro-linked or fused cyclic substituents at any available point of attachment, such as spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocyclyl (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl, and aryl substituents may themselves be optionally substituted.

In some embodiments, the heterocyclyl is substituted at one or more positions on carbon, nitrogen, and/or sulfur. Examples of substituents on the nitrogen include, but are not limited to, alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfur include, but are not limited to, oxy and C_1-6An alkyl group. In some embodiments, the nitrogen and sulfur heteroatoms may independently be optionally oxidized, and the nitrogen heteroatoms may independently be optionally quaternized.

In some embodiments, substituents on the ring groups, such as aryl, heteroaryl, cycloalkyl, and heterocyclyl groups, include halogen, alkoxy, and/or alkyl.

In some embodiments, substituents on the alkyl group include halogen and/or hydroxyl.

"haloalkyl" as used herein is a hydrocarbyl moiety group in which from 1 to all hydrogens have been replaced with a halogen.

The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine or iodine. The term "acyl" as used herein refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group (i.e., R-CO-NH-) attached at a nitrogen atom. The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH)₂-CO-). The nitrogen atom of the amido or carbamoyl substituent is additionally optionally substituted. The term "sulfonamide group" refers to a sulfonamide substituent attached by a sulfur or nitrogen atom. The term "amino" is intended to include NH₂Alkylamino, dialkylamino (wherein each alkyl group may be the same or different), arylamino, and cyclic amino. The term "ureido" as used herein refers to a substituted or unsubstituted urea moiety.

The term "radical" as used herein refers to a chemical moiety that comprises one or more unpaired electrons.

Where the optional substituents are selected from "one or more" groups, it is understood that this definition includes combinations where all substituents are selected from one or all of the specified groups.

Additionally, substituents on the cyclic moiety (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-to 6-membered monocyclic moieties and 9-to 14-membered bicyclic moieties fused to the parent ring moiety to form bicyclic or tricyclic fused ring systems. Substituents on the cyclic moiety also include 5-to 6-membered monocyclic moieties and 9-to 14-membered bicyclic moieties linked to the parent ring moiety by a covalent bond to form a bicyclic or tricyclic bicyclic ring system. For example, optionally substituted phenyl includes (but is not limited to) the following

An "unsubstituted" moiety (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) refers to a moiety that does not have any optional substituents, as defined above.

A saturated, partially unsaturated, or unsaturated 3-to 8-membered carbocyclic ring is, for example, a 4-to 7-membered, or 5-or 6-membered, saturated or unsaturated carbocyclic ring. Examples of saturated or unsaturated 3-to 8-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Saturated or unsaturated carbocyclic and heterocyclic groups may be condensed with another saturated or heterocyclic group to form a bicyclic group, such as a saturated or unsaturated 9-to 12-membered bicyclic carbocyclic or heterocyclic group. Bicyclic groups include naphthyl, quinolyl, 1,2,3, 4-tetrahydroquinolyl, 1, 4-benzoxelohexyl, indanyl, indolyl and 1,2,3, 4-tetrahydronaphthyl.

When a carbocyclic or heterocyclic group is substituted by two C₁-C₆When substituted by alkyl groups, two alkyl groups may combine to form an alkylene chain, e.g. C₁-C₃An alkylene chain. The carbocyclic or heterocyclic group having such a crosslinked structure includes bicyclo [2.2.2]Octyl and norbornyl.

The terms "kinase inhibitor" and "inhibitor of kinase activity" and similar terms are used to identify compounds that are capable of interacting with a kinase and inhibiting its enzymatic activity.

The term "inhibiting the enzymatic activity of a kinase" and similar terms are used to refer to reducing the ability of a kinase to transfer a phosphate group from a donor molecule (e.g., ATP) to a particular target molecule (substrate). For example, kinase activity can be inhibited by at least about 10%. In some embodiments of the invention, the reduction in kinase activity is at least about 25%, or at least about 50%, or at least about 75% and or at least about 90%. In other embodiments, the kinase activity is reduced by at least 95% and alternatively at least 99%. IC (integrated circuit) ₅₀Kinase inhibition with a value of 50% reduction of kinase activity to uninhibited enzymeAgent concentration.

The term "inhibitor of VEGF receptor signaling" is used to identify compounds having a structure as defined herein, which are capable of interacting with a VEGF receptor and inhibiting the activity of the VEGF receptor. In some embodiments, the reduction in activity is at least about 50%, or at least about 75% and alternatively at least about 90%. In some embodiments, the activity is reduced by at least 95% and alternatively at least 99%.

The term "inhibitory effective amount" refers to a dose sufficient to cause inhibition of kinase activity. The amount of a compound of the present invention that constitutes an "inhibiting effective amount" will vary depending on the compound, kinase, and analog thereof. An amount effective for inhibition can generally be determined by one skilled in the art. The kinase may be in a cell, which in turn may be in a multicellular organism. The multicellular organism can be, for example, a plant, a fungus, or an animal, such as a mammal and, for example, a human. Fungi may infect a plant or mammal, such as a human, and thus may be located in and/or on the plant or mammal.

In an exemplary embodiment, the inhibition is specific, i.e., the concentration of the kinase inhibitor that reduces the ability of the kinase to transfer phosphate groups from a donor molecule (e.g., ATP) to a particular target molecule (substrate) is lower than the concentration required for the inhibitor to produce another unrelated biological effect. For example, the concentration of inhibitor required for kinase inhibitory activity is at least 1/2, or at least 1/5, or at least 1/10 and or at least 1/20 of the concentration required to produce an unrelated biological effect.

Accordingly, the present invention provides a method of inhibiting the enzymatic activity of a kinase, comprising contacting the kinase with an inhibitory effective amount of a compound or composition of the invention. In some embodiments, the kinase is in an organism. Accordingly, the present invention provides a method of inhibiting the enzymatic activity of a kinase in an organism, the method comprising administering to the organism an inhibitory effective amount of a compound or composition of the present invention. In some embodiments, the organism is a mammal, such as a domesticated mammal. In some embodiments, the organism is a human.

The term "therapeutically effective amount" as used herein is the amount of a compound of the present invention that, when administered to a patient, causes the desired therapeutic effect. The therapeutic effect depends on the disease to be treated and the desired outcome. Thus, the therapeutic effect may be the treatment of a disease state. In addition, the therapeutic effect may be inhibition of kinase activity. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. A therapeutically effective amount can generally be determined by one of ordinary skill in the art.

In some embodiments, the therapeutic effect is inhibition of angiogenesis. The phrase "inhibiting angiogenesis" is used to indicate the ability of a compound of the invention to retard vascular growth, e.g., retard vascular growth in contact with an inhibitor as compared to non-contacted blood vessels. In some embodiments, the angiogenesis is tumor angiogenesis. The phrase "tumor angiogenesis" refers to the proliferation of blood vessels that penetrate into or otherwise contact cancerous growths, such as tumors. In some embodiments, angiogenesis is abnormal angiogenesis in the eye.

In an exemplary embodiment, angiogenesis is delayed by at least 25%, or at least 50%, or at least 75%, or at least 90%, or at least 95% and or at least 99% compared to angiogenesis in the non-contacted blood vessel. Alternatively, angiogenesis is 100% inhibited (i.e., blood vessel size or number is not increased). In some embodiments, the phrase "inhibiting angiogenesis" includes a reduction in the number or size of blood vessels as compared to non-contacted blood vessels. Thus, compounds of the invention that inhibit angiogenesis may induce a delay in vascular growth, arrest of vascular growth or induce a decrease in vascular growth.

Accordingly, the present invention provides a method of inhibiting angiogenesis in an animal comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or composition of the present invention. In some embodiments, the animal is a mammal, such as a domesticated mammal. In some embodiments, the animal is a human.

In some embodiments, the therapeutic effect is the treatment of an ophthalmic disease, condition, or disorder. The phrase "treating an ophthalmic disease, condition, or disorder" means that the compounds of the present invention are capable of treating (a) a disease, condition, or disorder caused by choroidal angiogenesis, including, but not limited to, age-related macular degeneration; or (b) diabetic retinopathy or retinal edema. In some embodiments, the phrase "treating an ophthalmic disease, condition, or disorder" refers to a compound of the invention capable of treating an exudative and/or inflammatory ophthalmic disease, condition, or disorder, a condition associated with abnormal retinal vascular permeability and/or integrity, a condition associated with retinal microvascular rupture leading to focal bleeding, a posterior ocular disease, a retinopathy, or a pre-ocular disease, or other ophthalmic disease, condition, or disorder.

In some embodiments, the ophthalmic disease, condition, or disorder includes, but is not limited to, age-related macular degeneration (ARMD), exudative macular degeneration (also referred to as "wet" or neovascular age-related macular degeneration (wet AMD)), macular edema, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, acute macular optic neuroretinopathy, central serous chorioretinopathy, choroidal neovascularization, neovascular maculopathy, neovascular glaucoma, obstructive arterial and venous retinopathy (e.g., retinal vein occlusion or retinal artery occlusion), central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus change, ocular ischemic syndrome, Retinal artery microaneurysms, Coat's Disease, collateral foveal telangiectasia, hemilateral retinal vein occlusion, papillary phlebitis (Papilopohlebitis), central retinal artery occlusion, branch retinal artery occlusion, Carotid Artery Disease (CAD), frosty branch vasculitis (Frosted Branchangiitis), sickle cell retinopathy and other heme diseases, angioid streaks, macular edema (e.g., diabetic macular edema) due to, for example, the etiology of the Disease, eye injury or eye surgery, retinal ischemia or degeneration caused by, for example, injury, trauma or tumor, uveitis, iritis, retinal vasculitis, endophthalmitis, globulitis, metastatic ophthalmia, choroiditis, epiretinitis, conjunctivitis, cyclitis, episcleritis, neuritis, retrobulbar neuritis, and retinal vein thrombosis, Keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, shejogren's keratitis (Thygeson keratitis), progressive moronen's ulcer, ocular inflammatory disease caused by bacterial or viral infection or by ophthalmic surgery, ocular inflammatory disease caused by physical damage to the eye and symptoms caused by ocular inflammatory disease (including itch, flushing, edema, and ulceration), erythema multiforme, erythema nodosum, erythema annulare, scleroderma, dermatitis, angioedema, laryngeal edema, glottic edema, subglottic laryngitis, bronchitis, rhinitis, pharyngitis, sinusitis, laryngitis, or otitis.

In some embodiments, the ophthalmic disease, condition, or disorder is (a) a disease, condition, or disorder caused by choroidal angiogenesis, including but not limited to age-related macular degeneration, or (b) diabetic retinopathy or retinal edema.

In some embodiments, the ophthalmic disease, condition, or disorder includes, but is not limited to, age-related macular degeneration, diabetic retinopathy, retinal edema, retinal vein occlusion, neovascular glaucoma, retinopathy of prematurity, retinitis pigmentosa, uveitis, corneal neovascularization, or proliferative vitreoretinopathy.

In some embodiments, the ophthalmic disease, condition, or disorder is age-related macular degeneration, diabetic retinopathy, or retinal edema.

Accordingly, the present invention provides a method of treating an ophthalmic disease, condition or disorder in an animal comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or composition of the present invention. In some embodiments, the animal is a mammal, such as a domesticated mammal. In some embodiments, the animal is a human.

In some embodiments, the therapeutic effect is inhibition of retinal neovascularization. The phrase "inhibiting retinal neovascularization" means that the compounds of the invention delay the growth of blood vessels in the eye, e.g., new blood vessels originating in retinal veins, e.g., delay the growth of new blood vessels originating in retinal veins and extending along the inner (vitreous) surface of the retina.

In an exemplary embodiment, retinal neovascularization is delayed by at least 25%, or at least 50%, or at least 75%, or at least 90%, or at least 95% and or at least 99% as compared to retinal neovascularization that does not contact blood vessels. Alternatively, retinal neovascularization was 100% inhibited (i.e., no increase in blood vessel size or number). In some embodiments, the phrase "inhibiting retinal neovascularization" includes a reduction in the number or size of blood vessels as compared to non-contacted blood vessels. Thus, compounds of the invention that inhibit retinal neovascularization may induce a delay in vascular growth, stasis in vascular growth, or a decrease in vascular growth.

Accordingly, the present invention provides a method of inhibiting retinal neovascularization in an animal comprising administering to an animal in need thereof a therapeutically effective amount of a compound or composition of the invention. In some embodiments, the animal is a mammal, e.g., a domesticated mammal. In some embodiments, the animal is a human.

In some embodiments, the therapeutic effect is inhibition of cell proliferation. The phrase "inhibiting cell proliferation" is used to refer to the ability of a compound of the invention to delay the growth of cells contacted with an inhibitor as compared to cells not contacted. Cell proliferation assessment can be performed by counting the number of touching and non-contacting cells using a Coulter cell counter (Coulter, Miami, Fla.) or a hemocytometer. In the case of cells in a solid growth (e.g., a solid tumor or organ), this assessment of cell proliferation can be made by measuring the growth with a caliper or comparing the size of the growth contacted with cells to growth not contacted with cells.

In an exemplary embodiment, the growth of cells contacted with the inhibitor is delayed by at least 25%, or at least 50%, or at least 75%, or at least 90%, or at least 95% and or at least 99% compared to the growth of non-contacted cells. Alternatively, cell proliferation is inhibited by 100% (i.e., the number of contacted cells is not increased). In some embodiments, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of contacted cells as compared to non-contacted cells. Thus, a compound of the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo progressive cell death (i.e., apoptosis), or to undergo necrotic cell death.

In some embodiments, the contacted cell is a neoplastic cell. The term "neoplastic cell" is used to refer to a cell that exhibits abnormal cell growth. In some embodiments, the abnormal cell growth of the neoplastic cell is an increase in cell growth. The neoplastic cell can be a proliferating cell, a cell that exhibits contact inhibition of growth in vitro, a benign tumor cell that cannot metastasize in vivo, or a cancer cell that is capable of metastasizing in vivo and may relapse after attempted removal. The term "neoplasia" is used to mean the induction of proliferation of cells that result in the production of neoplastic growth.

In some embodiments, the contacted cell is in an animal. Accordingly, the present invention provides a method of treating a cell proliferative disease or condition in an animal comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound or composition of the present invention. In some embodiments, the animal is a mammal, such as a domesticated mammal. In some embodiments, the animal is a human.

The term "cell proliferative disease or condition" means any condition characterized by abnormal cell growth, e.g., an abnormal increase in cell proliferation. Examples of such cell proliferative diseases or conditions that may be inhibited and treated include, but are not limited to, cancer. Examples of specific types of cancer include, but are not limited to, breast, lung, colon, rectal, bladder, prostate, leukemia, and kidney cancer. In some embodiments, the invention provides a method of inhibiting the proliferation of a neoplastic cell in an animal, comprising administering to an animal in which at least one neoplastic cell is present a therapeutically effective amount of a compound of the invention or a composition thereof.

For the purposes of the present invention, the term "patient" as used herein includes humans and other animals, such as mammals and other organisms. Thus, the compounds, compositions and methods of the invention are useful in human therapy and veterinary applications. In some embodiments, the patient is a mammal, e.g., a human.

The term "treating" or similar terms as used herein encompasses treating a disease state of an organism and includes at least one of: (i) preventing the occurrence of a disease state, particularly where the animal is predisposed to the disease state but has not yet been diagnosed; (ii) inhibiting the disease state, i.e. partially or completely preventing its development; (iii) alleviating the disease state, i.e., reducing or ameliorating the symptoms of the disease state; and (iv) reversing or reducing the disease state, e.g. eliminating or curing the disease. In some embodiments of the invention, the organism is an animal, e.g., a mammal, e.g., a primate, e.g., a human. As known in the art, adjustments for systemic local delivery, age, body weight, general health, sex, diet, time of administration, drug interactions, severity of the condition, etc. may be necessary and can be determined by one of ordinary skill in the art with routine experimentation. In some embodiments, the term "treating" or similar terms thereof, as used herein, encompasses treating a disease state of an organism and includes at least one of (ii), (iii), and (iv) above.

Administration for a non-ophthalmic disease, condition or disorder can be by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In some embodiments, the compounds of the invention are administered intravenously in a hospital setting. In some embodiments, administration may be by the oral route.

Examples of routes of administration for ophthalmic diseases, conditions and disorders include, but are not limited to, systemic, periocular, retrobulbar, intratubular, intravitreal injection, topical (e.g., eye drops), subconjunctival injection, sub-tenon, transscleral, intracameral, subretinal, electroporation, and sustained release implants. Other routes of administration, other injection sites, or other forms of administration for ophthalmic conditions are known or contemplated by those skilled in the art and are within the scope of the present invention.

In some embodiments of the invention, routes of administration for ophthalmic diseases, conditions and disorders include topical, subconjunctival, intravitreal, or other ocular routes, systemic routes, or other methods known to those skilled in the art for post-ocular surgery patients.

In some other embodiments of the invention, routes of administration for ophthalmic diseases, conditions and disorders include topical, intravitreal, transscleral, periocular, conjunctival, sub-tenon, intracameral, sub-retinal, subconjunctival, retrobulbar, or intratubular administration.

In some embodiments of the invention, routes of administration for ophthalmic diseases, conditions and disorders include topical administration (e.g., eye drops), systemic administration (e.g., oral or intravenous administration), subconjunctival injection for local delivery, periocular injection, intravitreal injection, and surgical implants for local delivery.

In some embodiments of the invention, routes of administration for ophthalmic diseases, conditions and disorders include intravitreal injection for local delivery, periocular injection, and sustained release implants.

In some embodiments of the invention, the intra-ocular injection may be into the vitreous (intravitreal), sub-conjunctiva (subconjunctival), posterior to the eye (retrobulbar), in the sclera, under the Tenon's Capsule (sub-Tenon), or may be in depot form.

In some embodiments of the invention, administration is topical administration, including (but not limited to) topical, intravitreal, orbital, intraocular, and other topical administration to the eye, eye and/or periocular tissues and spaces, including (but not limited to) administration via a delivery device.

The compounds of the present invention form salts, which are also within the scope of the present invention.

The term "salt" as used herein denotes acid and/or base salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e. non-toxic (exhibiting minimal or no undue toxicological effects) and physiologically acceptable) salts are preferred, but other salts are also suitable, for example, for isolation or purification steps useful during preparation. Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount (e.g., equivalent amount) of an acid or base in, for example, a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

Compounds of the invention containing a basic moiety such as, but not limited to, an amine or a pyridine or imidazole ring can form salts with a variety of organic and inorganic acids. Examples of acid addition salts include acetates (e.g., those formed with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, peroxysulfates, phenylpropionates (e.g., 3-phenylpropionate), Phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and the like.

Compounds of the present invention containing an acidic moiety such as, but not limited to, carboxylic acids can form salts with a variety of organic and inorganic bases. Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as organic amines, for example benzathine (benzathine), dicyclohexylamine, hydrabamine (hydrabamine) (formed as N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-imidazolediamide, tert-butylamine; and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups can be quaternized with, for example: lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

The term "pharmaceutically acceptable salt" as used herein refers to a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undue toxicological effects. Examples of such salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and polygalacturonic acid. Other salts include the pharmaceutically acceptable quaternary salts known to those skilled in the art, including in particular quaternary ammonium salts of the formula-NR + Z-, wherein R is hydrogen, alkyl or benzyl and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, tosylate, methylsulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate and diphenylacetate).

Another aspect of the invention provides compositions comprising a compound of the invention. For example, in some embodiments of the invention, the composition comprises a compound of the invention or an N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug of a compound of the invention in at least about a 30% enantiomeric or diastereomeric excess. In some embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is in an enantiomeric or diastereomeric excess of at least about 50%, at least about 80%, or even at least about 90%. In some embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is in an enantiomeric or diastereomeric excess of at least about 95%, at least about 98%, and alternatively at least about 99%. In other embodiments of the invention, the compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug is in a substantially racemic mixture.

Some of the compounds of the present invention may have enantiomeric and/or geometric centers (E-isomers and Z-isomers), and it is understood that the present invention encompasses all such optical, enantiomeric, diastereomeric and geometric isomers. The present invention also encompasses all tautomeric forms of the compounds disclosed herein. Where the compounds of the invention include an enantiomeric center, the invention encompasses enantiomerically and/or diastereomerically pure isomers of these compounds, enantiomerically and/or diastereomerically enriched mixtures of these compounds, and racemic and non-racemic mixtures of these compounds. For example, the composition may comprise at least about 30% diastereomeric excess or enantiomeric excess of a mixture of enantiomers or diastereomers of the compound of formula (I). In some embodiments of the invention, the compound is in at least about 50% enantiomeric or diastereomeric excess, at least about 80% enantiomeric or diastereomeric excess, or even at least about 90% enantiomeric or diastereomeric excess. In some embodiments of the invention, the compound is in at least about 95%, alternatively at least about 98% enantiomeric or diastereomeric excess and alternatively at least about 99% enantiomeric or diastereomeric excess.

The enantiomeric centers of the present invention can have the S or R configuration. The racemic form can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by enantiomeric column chromatography. Individual optical isomers may be obtained by any suitable method, including but not limited to known methods, e.g. salt formation with an optically active acid followed by crystallization, starting from enantiomeric precursors/intermediates or starting from racemates.

The invention also includes prodrugs of the compounds of the invention. The term "prodrug" denotes a compound covalently bound to a carrier, which prodrug is capable of releasing an active ingredient upon administration of the prodrug to a mammalian subject. The release of the active ingredient takes place in vivo. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques typically alter the appropriate functional groups in a given compound. However, these modified functional groups reproduce the original functional groups by routine manipulation or in vivo. Prodrugs of the compounds of the present invention include compounds modified with hydroxy, amino, carboxy, or the like. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of the invention, amides (e.g., trifluoroacetamide, acetamide, and the like), and the like.

The compounds of the invention may be administered, for example, as such or as a prodrug, for example, in the form of an in vivo hydrolysable ester or an in vivo hydrolysable amide. Containing carboxyl or hydroxyl groupsThe in vivo hydrolysable esters of the compounds of the invention are, for example, pharmaceutically acceptable esters which hydrolyse in the human or animal body to produce the parent acid or alcohol. Pharmaceutically acceptable esters suitable for the carboxyl group include C₁-C₆Alkoxymethyl esters (e.g. methoxymethyl ester), C₁-C₆Alkanoyloxymethyl esters (e.g. pivaloyloxymethyl ester), phthalidyl esters, C₃-C₈cycloalkoxy-carbonyloxy-C₁-C₆Alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl); 1, 3-dioxolan-2-one methyl ester (e.g., 5-methyl-1, 3-dioxol-2-one methyl ester); and C₁-C₆Alkoxycarbonyloxyethyl groups (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any suitable carboxyl group in the compounds of the invention.

In vivo hydrolysable esters of compounds of the invention containing a hydroxy group include inorganic esters such as phosphate esters and α -acyloxyalkyl ethers and related compounds which decompose to give the parent hydroxy group as a result of in vivo hydrolysis of the ester. Examples of α -acyloxyalkyl ethers include acetoxymethoxy and 2, 2-dimethylpropionyloxy-methoxy. Alternative groups which may form in vivo hydrolysable esters with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl groups (to give alkyl carbonates), dialkylcarbamoyl and dialkylaminoethyl) -N-alkylcarbamoyl groups (to give carbamates), N-dialkylaminoacetyl groups and carboxyacetyl groups. Examples of substituents on benzoyl include N-morpholinyl and N-piperazinyl linked from the ring nitrogen via a methylene group to the 3 or 4 position of the benzoyl ring. Suitable embodiments of the in vivo hydrolysable amides of the compounds of the invention containing carboxyl groups are, for example, N-C ₁-C₆Alkyl or N, N-di-C₁-C₆Alkylamides, for example N-methyl, N-ethyl, N-propyl, N-dimethyl, N-ethyl-N-methyl or N, N-diethylamide.

When administered to a subject, the prodrug is chemically converted by metabolic or chemical processes to yield the compounds of the invention.

The present invention is also directed to solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound with a stoichiometric or non-stoichiometric amount of one or more solvent molecules. The molecular complexes of a compound or compound moiety and a solvent may be stabilized by non-covalent intramolecular forces, such as electrostatic forces, van der Waals forces, or hydrogen bonding those skilled in the art of organic chemistry understand that many organic compounds may form with solvents in which they are obtained, prepared, or synthesized, or precipitated or crystallized from. Wiley, Weinheim, Germany, 2006).

In some embodiments of this aspect, the solvent is an inorganic solvent (e.g., water). In some embodiments of this aspect, the solvent is an organic solvent such as, but not limited to, an alcohol such as, but not limited to, methanol, ethanol, isopropanol, and the like, acetic acid, a ketone, an ester, and the like. In certain embodiments, the solvent is one commonly used in pharmaceutical technology, which is known to be harmless to the recipient to whom the solvate is administered (e.g., water, ethanol, and the like), and in preferred embodiments, does not interfere with the biological activity of the solute.

Throughout the specification, embodiments of one or more chemical substituents have been identified. Combinations of the various embodiments are also contemplated. For example, the present disclosure describes some embodiments of D in the compound, and describes some embodiments of group G. Thus, for example, compounds in which embodiments of D are as described and embodiments of the group G are as described are also encompassed within the scope of the present invention.

Compound (I)

According to one aspect, the present invention relates to compounds having formula (I):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is selected from aryl, heteroaryl, cycloalkyl or heterocyclic systems, C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)⁶)-C(O)-、(R⁶)(R⁶) N-C (O) -O-heterocyclyl-C (O) -, PivO-heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -N (R)⁶) heterocyclyl-C (O) -, (C)₁-C₆Alkyl (Box) N-heterocyclyl-C (O) -, HO-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -O-heterocyclyl-C (O) -, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C (O) -and (R)⁶)(R⁶) N-heterocyclyl-C (O) -wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more independently selected R³⁸Substitution;

m is an optionally substituted fused heterocyclic moiety;

z is selected from-O-, -S (O)_0-2-and-NR⁵-, wherein R⁵Selected from H, optionally substituted C₁-C₅Alkyl, optionally substituted (C)₁-C₅) Acyl and C₁-C₆alkyl-O-C (O), wherein C₁-C₆Alkyl is optionally substituted;

ar is a group of the formula C,

wherein the content of the first and second substances,

A⁴、A⁵、A⁶and A⁷Independently selected from N and-CH-, with the proviso that A⁴、A⁵、A⁶And A⁷Up to two of which may be N, wherein Ar is optionally comparably substituted; and

g is a group B-L-T, wherein

B is selected from the group consisting of a covalent bond, -N (R)¹³)-、-N(SO₂R¹³)-、-O-、-S(O)_0-2and-C (= O) -;

l is selected from the group consisting of a covalent bond, -C (= S) N (R)¹³)-、-C(=NR¹⁴)N(R¹³)-、-SO₂N(R¹³)-、-SO₂-、-C(=O)N(R¹³)-、-N(R¹³)-、-C(=O)C_1-2alkyl-N (R)¹³)-、-N(R¹³)C_1-2alkyl-C (= O) -, -C (= O) C _0-1alkyl-C (= O) N (R)¹³)-、-C_0-4Alkylene, -C (= O) C_0-1alkyl-C (= O) OR³-、-C(=NR¹⁴)-C_0-1alkyl-C (= O) -, -C (= O) -C_0-1alkyl-C (= O) -and optionally substituted 4 to 6 membered heterocyclyl containing 1 to 3 ring heteroatoms including at least one nitrogen, wherein the alkyl and alkylene groups are optionally substituted; and

t is selected from-H, -R¹³、-C_0-4Alkyl, -C_0-4alkyl-Q, -O-C_0-4alkyl-Q, -C_0-4alkyl-O-Q, -N (R)¹³)C_0-4alkyl-Q, -SO₂C_0-4alkyl-Q, -C (= O) C_0-4alkyl-Q, -C_0-4alkyl-N (R)¹³) Q and-C (= O) N (R)¹³)-C_0-4alkyl-Q, wherein each C_0-4Alkyl is optionally substituted;

wherein

R³⁸Is selected from C₂-C₆Alkynyl-heterocyclyl, H (O) C-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_il-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_il-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocycle)Radical) -C₁-C₆Alkyl-, F-heterocyclyl-C₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-heterocyclyl-C ₁-C₆Alkyl-, R³⁷-C₁-C₆alkyl-O-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-O-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-O-aryl-N (R)⁶)-C₁-C₆Alkyl-, (by one or more C)₁-C₆Alkyl substituted heteroaryl) -N (R)⁶)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆alkyl-aryl-N (R)⁶)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆alkyl-C (O) -aryl-N (R)⁶)-C₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-O-aryl-N (R)⁶)-C₁-C₆Alkyl-, (R)⁶)₂N-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆Alkyl radical C (O) -O-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-S (O)₂-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, (optionally substituted by one or more C)₁-C₆Alkyl-substituted heterocyclyl) -C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -C₁-C₆Alkyl-, heterocyclyl-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -C₁-C₆alkyl-heteroaryl-N (R)⁶)-C(O)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-heterocyclyl-C (O) -C ₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-N (R)⁶)-C(O)-C₁-C₆Alkyl-, (Boc) (H) N-heterocyclyl-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, Boc-heterocyclyl-C (O) -C₁-C₆Alkyl-, Ac-O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, (Boc) (H) N-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, NH₂-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (H) N-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, NH₂-heterocyclyl-C (O) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-O-C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -N (R)⁶) -heterocyclyl-C (O) -, (R)⁶)(R⁶) N-heterocyclyl-C (O) -, (R)⁶)(R⁶) N-heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-O-C₁-C₆Alkyl-, C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C (O) -, (R)⁶)(R⁶) N-C (O) -heterocyclyl-O-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-O-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, halogen-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, halogen-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷-O-C(O)-C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (H) N-C (O) -heterocyclyl-N [ C ]₁-C₆alkyl-C (O) -OH]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -heterocyclyl-C ₁-C₆Alkyl-, HO-C (O) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -CO) -heterocyclyl-C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (C₁-C₆Alkyl) N-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O)-[(C₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) - [ (C)₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, R³⁷O-C₁-C₆Alkyl- [ (C)₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N (R)⁶)-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N [ C (O) -NH-C₁-C₆Alkyl radical]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N [ C (O) -NH-C₁-C₆Alkyl radical]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆Alkyl- [ C (O) -C₁-C₆alkyl-OH]-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, spiro-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -spiro-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₂-C₆alkenyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C₂-C₈alkenyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶)-C₁-C₆alkyl-C (O) -heterocyclyl-C ₁-C₆Alkyl-, heterocyclyl-C (O) -, (R)⁶)(R⁶) N-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷Alkyl radicals O-C (O) -C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) -O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶) N-C (O) -heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl- (heterocyclyl) -, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -N (R)⁶)-C₁-C₆Alkyl, -C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆alkyl-R³⁷O-(CH₂)_n[(CH₂)_iO]_xC₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, HO-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-cycloalkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-and R³⁷O-(CH₂)_n[(CH₂)_iO]_xC₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆An alkyl group, a carboxyl group,

a is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -, -C (= NR)³⁷) -H and-C₁-C₆alkyl-CF₃；

Each R is⁶Independently is H or C₁-C₆An alkyl group;

R³⁷selected from H, C₁-C₆Alkyl and C₃-C₁₀A cycloalkyl group;

R^37aselected from H, C₁-C₆Alkyl and C₃-C₁₀A cycloalkyl group;

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

il is 2 or 3;

jl is an integer from 0 to 4, or 1 or 2;

n is an integer of 0 to 4;

R³⁹Selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n2(C₆-C₁₀Aryl), - (CH)₂)_n2(C₅-C ₁₀Heteroaryl), (CH)₂)_n2(5-to 10-membered heterocyclic group), - (CH)₂)_n2O(CH₂)_i2OR³⁷And- (CH)₂)_n2OR³⁷Wherein R is as defined above³⁹Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

R⁹selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n3(C₆-C₁₀Aryl), - (CH)₂)_n3(C₅-C₁₀Heteroaryl), - (CH)₂)_n3(5-to 10-membered heterocyclic group), - (CH)₂)_n3O(CH₂)_i3OR³⁷And- (CH)₂)_n3OR³⁷Wherein R is as defined above⁹Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

R¹⁰selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n4(C₆-C₁₀Aryl), - (CH)₂)_n4(C₅-C₁₀Heteroaryl), - (CH)₂)_n4(5-to 10-membered heterocyclic group), - (CH)₂)_n4O(CH₂)_i4OR³⁷And- (CH)₂)_n4OR³⁷Wherein R is as defined above¹⁰Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

n2 is an integer from 0 to 6;

i2 is an integer from 2 to 6;

n3 is an integer from 0 to 6;

i3 is an integer from 2 to 6;

n4 is an integer from 0 to 6;

i4 is an integer from 2 to 6;

R²independently at each occurrence is selected from-H, halogen, trihalomethyl, -CN, -NO₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_nAryl, -O (CH)₂)_nHeteroaryl, - (CH)₂)_0-5(aryl), - (CH)₂)_0-5(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Wherein T is²Selected from-OH, -OMe, -OEt, -NH₂、-NHMe、-NMe₂-NHEt and-NEt ₂And wherein these aryl, heteroaryl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl is optionally substituted; and

q is an integer of 0 to 4;

R¹³selected from-H, -CN, -NO₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³、-C(O)SR³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_n5Aryl, -O (CH)₂)_n5Heteroaryl, - (CH)₂)_n5(aryl), - (CH)₂)_n5(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Optionally substituted C₁-C₄Alkylcarbonyl and a saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic radical, wherein T²Selected from-OH, -OMe, -OEt, -NH₂、-NHMe、-NMe₂-NHEt and-NEt₂And wherein these aryl, heteroaryl, C₁-C₆Alkyl radical、C₂-C₆Alkenyl and C₂-C₆Alkynyl is optionally substituted;

two R¹³Together with the atoms to which they are attached may be combined to form optionally substituted 1 to 4R⁶⁰Substituted heteroalicyclic wherein the heteroalicyclic can have up to 4 ring heteroatoms and the heteroalicyclic can be fused to an aryl or heteroaryl group, in which case the aryl or heteroaryl group is optionally further substituted with 1 to 4R⁶⁰Substitution;

n5 is an integer from 0 to 6;

R⁶⁰selected from-H, halogen, trihalomethyl, -CN, -NO₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-SO₂NR³R³、-CO₂R³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³Optionally substituted (C)₁-C₆) Alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl;

when attached to a non-aromatic carbon, two R⁶⁰May be oxo;

each R is³Independently selected from-H and R ⁴；

R⁴Is selected from (C)₁-C₆) Alkyl, aryl, lower arylalkyl, heterocyclyl and lower heterocyclyl-alkyl, each of which is optionally substituted, or

R³And R⁴Together with the common nitrogen to which they are attached form optionally substituted: a 5-7 membered heterocyclyl, said optionally substituted 5-7 membered heterocyclyl optionally containing at least one other ring heteroatom selected from N, O, S and P;

R¹⁴is selected from-H, -NO₂、-NH₂、-N(R³)R⁴、-CN、-OR³Optionally substituted (C)₁-C₆) Alkyl, optionally substituted heteroalicyclic-alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic,

q is a 3-to 10-membered ring system optionally substituted with zero, one or more R²⁰Substitution;

R²⁰selected from-H, halogen, trihalomethyl, -CN, -NO₂、-NH₂、-OR³、-OCF₃、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)C(O)OR³、-C(O)R³、-C(O)SR³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_n6Aryl, -O (CH)₂)_n6Heteroaryl, - (CH)₂)_n6(aryl), - (CH)₂)_n6(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Optionally substituted C₁-C₄Alkylcarbonyl group, C₁-C₄Alkoxy, optionally substituted by C₁-C₄Alkoxy-substituted C₁-C₄Alkyl-substituted amino, - (CH)₂)_n6P(=O)(C₁-C₆Alkyl radical)₂Saturated or unsaturated 3-to 7-membered cycloalkyl or heterocyclyl, -SiMe₃and-SbF₅(ii) a And

n6 is an integer from 0 to 6.

In some embodiments of the first aspect, the compounds have formula (I), wherein D is-aryl or-heteroaryl, each substituted with one or more R ³⁸And (4) substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein D is selected from

Wherein the members of the group are substituted by one or more R³⁸And (4) substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein D is selected from

Wherein the members of the group are substituted by one or more R³⁸And (4) substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein D is selected from the group consisting of³⁸Substituted phenyl, pyridine, imidazole, pyrazole and tetrahydropyridine, wherein when D is imidazole, the imidazole is further optionally substituted with one C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted phenyl or pyridine.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸A substituted pyridine.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH ₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Selected from: r³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and N (R)⁹)(R¹⁰)-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6N(A)-(CH₂)_1-4Or R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, and A is selected from the group consisting of-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6N(A)-(CH₂)_1-4Or R³⁷O-(CH₂)₂-N(A)-(CH₂) -or R³⁷O-(CH₂)₂-N(A)-(CH₂)-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6N(A)-(CH₂)_1-4And A is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is selected from the group consisting of-C (O) -C₁-C₆alkyl-N (R)³⁹) alkyl-C (O) -C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁽⁾) And (R)³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspectThe compounds have the formula (I) wherein D is substituted by one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -H.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R ³⁸Substituted pyridines in which R³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is NC-C₁-C₆alkyl-heterocyclyl-CH ₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridinesWherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (optionally substituted 8-to 10-membered fused heterocyclylalkyl) -C₁-C₆Alkyl-, wherein the optional substituents are selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH and-C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C ₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸And a C₁-C₆An alkyl substituted imidazole.

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compounds have formula I, wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R ³⁸A substituted phenyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O))-N(R³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸A substituted tetrahydropyridine.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -or R³⁷O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷O-C₁-C₆alkyl-O-C ₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸A substituted pyrazole.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-or R³⁷O-(CH)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-or R³⁷O-(CH)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH)₁-₆-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compounds have formula (I) wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (I), wherein R is ³⁸Is R³⁷O-(CH)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂Or MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-, or CH₃-S(O)₂-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-, or R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, or HO-C (O) - (CH)₂)₂-piperazine-CH₂-, EtO-C (O) -piperidine-CH₂-、EtO-C(O)-CH₂-piperidine-CH₂-、EtO-C(O)-CH₂-piperazine-CH₂-, HO-C (O) -piperidine-CH₂-、HO-C(O)-CH₂-piperidine-CH₂-、HO-C(O)-CH₂-piperazine-CH₂-,、(CH₃)₃C-O-C (O) -piperazine-CH₂-or HO-C (O) -pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹) -C (O) -, or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-C(O)-。

In some embodiments of the first aspect, the compound has formula (I), whereinR³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, or CH₃-CH₂-O-C(O)-(CH₂)₂-piperazine-C (O) -or HO-C (O) - (CH)₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is HOOC-C₁-C₆alkyl-N (A) -CH₂-, or HOOC- (CH)₂)₃-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (HOOC) (NR)⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-, or (HOOC) (NH)₂)CH-(CH₂)₄-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is ³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, or HO-C (O) - (CH)₂)₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, or C₃cycloalkyl-NH-C (O) -O- (CH)₂)₂-。

In the first aspectIn some embodiments, the compound has formula (I), wherein R is³⁸Is R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, or MeO- (CH)₂)₂-O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is NC-C₁-C₆alkyl-heterocyclyl-CH₂-, or NC- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-, or F₃C-CH₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-which isWherein

G is selected from CH₂O, NH, S, SO and SO₂，

G¹Is selected from CH₂O, NH, S, SO and SO₂;

G²Is CH or N;

G³is selected from CH₂O, NH, S, SO and SO₂，

G⁴Is selected from CH₂O, NH, S, SO and SO₂，

G⁵Is selected from CH₂O, NH, S, SO and SO₂，

G⁶Is CH or N;

G⁷is selected from CH₂O, NH, S, SO and SO₂；

R^sIs an optional substituent; and

R^s1is an optional substituent group, and the like,

with the proviso that the two O atoms are not adjacent to each other.

In some embodiments of the first aspect, the compound has formula (I), R thereof³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

Wherein G is selected from CH₂O, NH, S, SO and SO₂；G¹Is selected from CH₂O, NH, S, SO and SO₂(ii) a And R^sIs an optional substituent.

In some embodiments of the first aspect, the compound has formula (I), wherein R is^sSelected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein R is^s1Selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C ₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, wherein the optional substituents are selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein a is-C (o) -C ₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰) or-C (O) -CH₂-NH-C(O)-CH(NH₂)-CH(CH₃)₂、-C(O)-CH₂-NH-C(O)-CH₂-NH₂or-C (O) -CH [ CH (CH)₃)₂]-NH-C(O)-CH₂-NH₂)。

In some embodiments of the first aspect, the compound has formula (I), wherein a is-c (o) -N (R)³⁹)-C₁-C₆Alkyl, or-C (O) -NH-CH₂-CH₃、-C(O)-NH-CH₃、-C(O)-NH-CH(CH₃)₂、-C(O)-NH-CH(CH₃)₂or-C (O)-N(CH₃)₂。

In some embodiments of the first aspect, the compound has formula (I), wherein a is-C (= NR)³⁷)-C₁-C₆Alkyl, or-C (= NH) H.

In some embodiments of the first aspect, the compound has formula (I), wherein a is-c (o) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, or-C (O) -CH₂-S(O)₂-Me。

In some embodiments of the first aspect, the compound has formula (I), wherein a is-c (o) -N (R)³⁹) -cycloalkyl, or-C (O) -NH-cyclopentyl or-C (O) -NH-C₃A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (I), wherein a is-c (o) -N (R)⁹)(R¹⁰) or-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (I), wherein a is (R)³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -, or (HO)₂P(O)O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (I), wherein M is a structure selected from:

wherein

Denotes the position of the connection to D;

represents the position of attachment to Z;

A¹selected from the group consisting of CH, -O-, -S-, -N (H) -, -N (C)₁-C₆Alkyl) -, -N- (Y-aryl) -, -N-OMe, -NCH₂OMe and N-Bn;

Y is a bond or- (C (R)^x)(H))_t-, where t is an integer from 1 to 6; and

R^xeach occurrence is independently selected from H and C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is optionally substituted;

A²is selected from N and CR, wherein R is selected from-H, halogen, -CN, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -COOH and-C (O) Oalkyl, wherein C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl and-c (O) oalkyl optionally substituted;

each A³Independently selected from CH and N;

each R is⁸⁰Independently selected from H, halogen, NO₂Cyano, OR⁸³、N(R⁸³)₂、CO₂R⁸³、C(O)N(R⁸³)₂、SO₂R⁸³、SO₂N(R⁸³)₂、NR⁸³SO₂R⁸³、NR⁸³C(O)R⁸³、NR⁸³CO₂R⁸³、-CO(CH₂)₁R⁸³、-CONH(CH₂)₁R⁸³Alkylaminoalkyl, alkylaminoalkynyl, C₁-C₆Alkyl, substituted C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, substituted C₃-C₇Cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heterocycloalkyl, and substituted heterocycloalkyl; and

each R is⁸³Independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkylA group, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; or

Two R⁸³Together with the N atom, form a heterocyclic ring.

In some embodiments of the first aspect, the compound has formula (I), wherein M is a structure selected from:

Wherein

J is CR⁸⁰Or N;

R⁸²selected from H, C₁-C₆Alkyl or substituted C₁-C₆Alkyl, -Y- (aryl), -Y- (heteroaryl), -alkoxy and-CH₂OMe；

Wherein,、R⁸⁰And Y is as described above.

In some embodiments of the first aspect, the compound has formula (I), wherein M is a structure selected from:

wherein

As described above; and

R²²is selected from-H, -C₁-C₆Alkyl, -Y-aryl, alkoxy, -CH₂-O-Me and-Bn.

In some embodiments of the first aspect, the compound has formula (I), wherein M is

In some embodiments of the first aspect, the compound has formula (I), wherein Z is O.

In some embodiments of the first aspect, the compounds have formula (I), wherein Ar is selected from phenyl, pyrazine, pyridazine, pyrimidine and pyridine, wherein each of said phenyl, pyrazine, pyridazine, pyrimidine and pyridine is optionally substituted with 0 to 4R²And (4) substitution.

In some embodiments of the first aspect, the compounds have formula (I), wherein Ar is phenyl, optionally substituted with 0 to 4R²And (4) substitution.

In some embodiments of the first aspect, the compounds have formula (I), wherein Ar is phenyl, optionally substituted with 0 to 4 halogens.

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

Wherein R is¹³、R¹⁴、Q、R³And R⁴As described above;

w is S, O or NH;

any methylene group is independently optionally represented by R²⁵Is substituted in which

R²⁵Selected from halogen, trihalomethyl, -CN, -NO₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-SO₂NR³R³、-CO₂R³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³Optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl and optionally substituted (C)₁-C₆) An alkyl group, a carboxyl group,

two R²⁵Together with or attached to carbon to form a 3-to 7-membered alicyclic or heterocyclic ring, an

Two R on the same carbon²⁵Is oxo;

R⁹one or more hydrogens selected therefrom optionally substituted by-R²¹、-T¹-R¹⁵Substituted C_1-6Alkyl, or-NR¹⁶R¹⁷、-N(R¹⁸)(R¹⁹) Partially and saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic ring (optionally substituted by C)_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl) or a saturated or unsaturated 5-or 6-membered heterocyclyl group, wherein when the 3-to 8-membered carbocyclic or heterocyclic group is substituted by two C_1-6Alkyl groups, two alkyl groups may together form an olefinic chain, or a 3 to 8 membered carbocyclic or heterocyclic group may be bicyclic fused to another saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group,

wherein

T¹Selected from the group consisting of-O-, -S-, and-NH-;

R²¹represents a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group;

R¹⁵、R¹⁶And R¹⁷Which may be the same or different, represents C_1-6Alkyl or a saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group; wherein the 3-to 8-membered carbocyclic or heterocyclic group denotes R²¹、R¹⁵、R¹⁶And R¹⁷Optionally by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl substituted, or saturated or unsaturated 5 or 6 membered heterocyclyl; and wherein when a 3 to 8 membered carbocyclic or heterocyclic group is attached C_1-6Alkyl groups are substituted, and two alkyl groups can be connected to form an alkenyl chain; and wherein the 3 to 8 membered carbocyclic or heterocyclic group may be bicyclic fused to another saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group; and

R¹⁸and R¹⁹Which may be the same or different, represent (1) a hydrogen atom, (2) C_1-6Alkyl optionally substituted by C_1-6Alkoxy radical, C_1-6Alkylthio-substituted, or saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, wherein the 3-to 8-membered carbocyclic or heterocyclic group is optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl substituted, or saturated or unsaturated 5-or 6-membered heterocyclyl and, wherein, when the 3-to 8-membered carbocyclic or heterocyclic group is interrupted by two C _1-6Alkyl groups, two alkyl groups may together form an olefinic chain, or a 3 to 8 membered carbocyclic or heterocyclic group may be bicyclic fused to another saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group, or (3) a saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group, optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl substituted, or saturated or unsaturated 5-or 6-membered heterocyclyl and, wherein, when the 3-to 8-membered carbocyclic or heterocyclic group is interrupted by two C_1-6Alkyl groups, two alkyl groups may together form an alkenyl chain or a 3 to 8 membered carbocyclic ring, or the heterocyclic group may be bicyclic fused to another saturated or unsaturated 3 to 8 membered carbocyclic or heterocyclic group;

x and X¹Each independently selected from-H, halogen, cyano, nitro, C₁-C₆Alkyl, or

X and X¹Together with the atom to which they are attached form C₃-C₄A cycloalkyl group;

e is selected from-O-, -N (R)¹³)-、-CH₂-and-S (O)_0-2-；

M is selected from-O-, -N (R)¹³)-、-CH₂-and-C (= O) N (R)¹³)；

M¹represents-C (R)²⁶)(R²⁷) -, wherein

R²⁶And R²⁷Independently selected from hydrogen atom, C_1-4Alkyl radical, C_1-4Alkoxy and-N (R)¹²) Wherein

R¹²Is a hydrogen atom or C_1-4An alkyl group; and

each V is independently selected from = N-and = c (h) -.

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

In some embodiments of the first aspect, the compound has formula (I), wherein G is selected from

In some embodiments of the first aspect, the compound has formula (I), wherein G is

In some embodiments of the first aspect, the compound has formula (I), wherein G is

In some embodiments of the first aspect, the compound has formula (I), wherein G is

In some embodiments of the first aspect, the compound has formula (I), wherein G is

In some embodiments of the first aspect, the compound has formula (I), wherein G is

In some embodiments of the first aspect, the compound has formula (I), wherein Q is selected from

Wherein P is¹Is a 5-to 7-membered ring comprising P¹Two of the fused aromatic rings share a carbon atom, and wherein P¹Optionally containing 1 to 3 heteroatoms.

In some embodiments of the first aspect, the compound has formula (I), wherein Q is selected from phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indanyl, benzodioxolyl, benzofuran, phenazinyl, phenothiazinyl, thiophene Oxazinyl, tetrahydroisoquinolinyl, pyrrolyl, pyrazolyl, pyrazolidine, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,Azolyl group,An azolinyl group,Oxazolidinyl, triazolyl, isotriazolylOxazole, isoOxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, thiadiazolyl, thiabendazole, thiabendaAzolyl, furyl, thienyl, benzothienyl anda diazolyl group; each optionally substituted by 1 to 4R²⁰And (4) substitution.

In some embodiments of the first aspect, the compound has formula (I), wherein Q is phenyl or C₃A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (I), wherein Q is 1 or 2 independently selected R²⁰A substituted phenyl group.

In some embodiments of the first aspect, the compound has formula (I), wherein Q is 1R²⁰Substituted phenyl, wherein R²⁰Selected from-P (O) (Me)₂、-CH₃、F、-CF₃、-C(O)-NH₂、-S(O)₂CH₃、Cl、-OCF₃、-OMe、Br、-S(O)₂-NH₂、-COOCH₃、-C(O)NH(CH₃) and-C (O) N (CH)₃)(CH₃)。

In some embodiments of the first aspect, the compound has formula (I), wherein Q is C ₃A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (Ia),

wherein D, M, Z, Ar and G are as defined for formula (I), except that

R³⁸Is selected from (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, (optionally substituted 7-or 8-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered thickHeterocyclic radical) -C₁-C₆Alkyl-, (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted bridged bicyclic ring system) -C₁-C₆Alkyl-, (substituted piperazine) -C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, C₁-C₆alkyl-S (O)_0-2-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R³⁷S(O)_0-2aryl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R¹¹-C₁-C₆alkyl-C (O) -piperazine-C₁-C₆Alkyl-, C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C₁-C₆Alkyl-, (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R) ¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-S (O)_0-2- (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, (R)²³)(R²⁴)P(O)-C₁-C₆alkyl-C (O) -, (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-N (R)³⁷)-C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C(H)(R²⁸)-、R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-and (substituted piperidine) -C₁-C₆Alkyl-;

wherein

R¹Is H or C₁-C₆An alkyl group;

R¹¹is-OH, -O-C₁-C₆Alkyl, optionally substituted 5-to 10-membered heterocyclyl or-O- (amino acid);

R²³selected from H, -OH, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, aryl, -O-aryl, cycloalkyl, -O-cycloalkyl, heteroaryl, -O-heteroaryl, 5-to 10-membered heterocyclyl, -O- (5-to 10-membered heterocyclyl), -C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl, -O-C₁-C₆Alkyl-heteroaryl, -C₁-C₆Alkyl-cycloalkyl, -O-C₁-C₆Alkyl-cycloalkyl, -C₁-C₆Alkyl- (5 to 10-membered heterocyclyl) and-O-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl);

R²⁴selected from H, -OH, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, aryl, -O-aryl, cycloalkyl, -O-cycloalkyl, heteroaryl, -O-heteroaryl, 5-to 10-membered heterocyclyl, -O- (5-to 10-membered heterocyclyl), -C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl、-O-C₁-C₆Alkyl-heteroaryl, -C ₁-C₆Alkyl-cycloalkyl, -O-C₁-C₆Alkyl-cycloalkyl, -C₁-C₆Alkyl- (5 to 10-membered heterocyclyl) and-O-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl);

R²⁸selected from H, -CF₃、-CHF₂、-CH₂F. CN, optionally substituted C₁-C₆Alkyl and C₃-C₆A cycloalkyl group;

R²⁹selected from H, C₁-C₆Alkyl and cation; and

R^29aselected from H, C₁-C₆Alkyl groups and cations.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, wherein heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, wherein heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, dioxanyl, oxathienylhexyl, morpholinyl, dithiinyl, piperazinyl, azothienylhexyl, oxepinyl, thienylheptyl, azepinyl, dioxepinyl, oxathienylheptyl, oxazepinyl, dithienyl, thiazepinyl, and diazepanyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is ³⁸Is (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, wherein heterocyclyl is selected from piperidinyl, morpholinyl and piperazinyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 7-or 8-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 7-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 7-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl has 1 or two N atoms.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl has 1 or two N atoms.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C ₁-C₆Alkyl radical of whichWherein

G is selected from CH₂O, NH, S, SO and SO₂；

G¹Is selected from CH₂O, NH, S, SO and SO₂；

G²Is CH or N;

G³is selected from CH₂O, NH, S, SO and SO₂；

G⁴Is selected from CH₂O, NH, S, SO and SO₂；

G⁵Is selected from CH₂O, NH, S, SO and SO₂；

G⁶Is CH or N;

G⁷is selected from CH₂O, NH, S, SO and SO₂；

R^sIs an optional substituent; and

R^s1is an optional substituent group, and the like,

provided that the two O atoms are not adjacent to each other.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

Wherein G is selected from CH₂O, NH, S, SO and SO₂；G¹Is selected from CH₂O, NH, S, SO and SO₂(ii) a And R^sIs an optional substituent.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, wherein the optionally substituted spiro-heterocyclyl is selected from optionally substituted [4-4 ]Spiro-heterocyclyl, optionally substituted [4-5 ]]Spiro-heterocyclyl, optionally substituted [4-6 ]]Spiro-heterocyclyl, optionally substituted [5-4 ]]Spiro-heterocyclyl, optionally substituted [5-5 ]]Spiro-heterocyclyl, optionally substituted [5-6 ]]Spiro-heterocyclyl, optionally substituted [6-4 ]]Spiro-heterocyclyl, optionally substituted [6-5 ]]Spiro-heterocyclyl and optionally substituted [6-6]Spiro-heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, wherein the optionally substituted spiro-heterocyclyl is selected from optionally substituted [4-4]Spiro-heterocyclyl, optionally substituted [4-5 ]]Spiro-heterocyclyl, optionally substituted [4-6 ]]Spiro-heterocyclyl, optionally substituted [5-4 ]]Spiro-heterocyclyl, optionally substituted [5-5 ]]Spiro-heterocyclyl, optionally substituted [5-6 ]]Spiro-heterocyclyl, optionally substituted [6-4 ]]Spiro-heteroCyclic group, optionally substituted [6-5 ]]Spiro-heterocyclyl and optionally substituted [6-6]Spiro-heterocyclyl, and wherein the optional substituents are fused cycloalkyl, heterocyclyl, aryl or heteroaryl rings.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, wherein the spiro-heterocyclyl is optionally substituted with one or more substituents selected from: H. halogen, -N (R) ⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, wherein the optionally substituted spiro-heterocyclyl is selected from

Wherein R is^sAnd R^s1Is an optional substituent.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, wherein the optionally substituted spiro-heterocyclyl is selected from

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is^sSelected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O) _0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is^s1Selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted bridged bicyclic ring system) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted bridged bicyclic ring system) -C₁-C₆Alkyl-, wherein the bridged bicyclic ring system is selected from [1.1.0 ]、[2.2.0]、[2.2.1]、[2.2.2]、[3.2.0]、[3.2.1]、[3.2.2]、[3.3.0]、[3.3.1]、[3.3.2]、[4.2.0]、[4.2.1]、[4.3.0]、[4.3.1]、[4.3.2]、[4.4.0]、[4.4.1]、[4.4.2]Bridged bicyclic ring systems.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted bridged bicyclic ring system) -C₁-C₆Alkyl-, wherein the bridged bicyclic ring system is a bridged bicyclic amine.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (optionally substituted bridged bicyclic ring system) -C₁-C₆Alkyl-is selected from

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (substituted piperazine) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (substituted piperazine) -C₁-C₆Alkyl-is selected fromWherein R is^sIs an optional substituent.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C ₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is C₁-C₆alkyl-S (O)_0-2-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is C₁-C₆alkyl-S (O)_0-2-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is C₁-C₆alkyl-S (O)_0-2-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, which is.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl and each R³⁷And R^37aIs H.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is ³⁸Is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷S(O)_0-2aryl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷S(O)_0-2aryl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷S(O)_0-2aryl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-piperazine-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-in which D isExamples of the first aspectIn one embodiment, the compound has formula (Ia), wherein R³⁸Is R³⁷O-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-which isOr

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is ³⁸Is R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-in which D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-wherein the 5 to 10-membered heterocyclyl is a 6-membered heterocyclyl and wherein D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆Alkyl-(5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-in which D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, wherein R⁹And R¹⁰Independently is H or C₁-C₄An alkyl group.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, wherein R⁹And R ¹⁰Independently is H or C₁-C₄Alkyl, and D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, and D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the 5-to 10-membered heterocyclic group is a 6-membered heterocyclic group, and D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5 to 10-membered heterocycles)Radical) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R¹¹-C₁-C₆alkyl-C (O) -piperazine-C ₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R¹¹-C₁-C₆alkyl-C (O) -piperazine-C₁-C₆Alkyl-and D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R¹¹-C₁-C₆alkyl-C (O) -piperazine-C₁-C₆Alkyl-, wherein R¹¹is-O- (amino acid).

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R¹¹-C₁-C₆alkyl-C (O) -piperazine-C₁-C₆Alkyl-, wherein R¹¹is-O- (amino acid) and D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-in which D is

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C ₁-C₆Alkyl-, wherein the 5-10-membered optionally substituted heterocycle is a 6-membered heterocycle, optionally substituted by C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C₁-C₆Alkyl-, wherein the oxo-substituted 5-to 10-membered heterocyclic ring is a 5-membered heterocyclic ring, e.g.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C₁-C₆Alkyl-, wherein the 5-10-membered optionally substituted heterocycle is a 6-membered heterocycle, optionally substituted by C₁-C₆Alkyl-substituted, and oxo-substituted 5 to 10-membered heterocycles are 5-membered heterocycles, e.g.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-O- (oxo-substituted 5 to 10-membered heterocycle) -C₁-C₆Alkyl-, is selected from

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is ³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, wherein the 5-10-membered optionally substituted heterocycle is a 6-membered heterocycle, optionally substituted by C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, wherein the oxo-substituted 5-to 10-membered heterocyclic ring is a 5-membered heterocyclic ring, e.g.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, wherein the 5-10-membered optionally substituted heterocycle is a 6-membered heterocycle, optionally substituted by C₁-C₆Alkyl-substituted, and oxo-substituted 5 to 10-membered heterocycles are 5-membered heterocycles, e.g.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆Alkyl-, wherein the 5-10-membered optionally substituted heterocycle is a 6-membered heterocycle, optionally substituted by C₁-C₆Alkyl-substituted, and oxo-substituted 5-to 10-membered heterocycles are 5-membered heterocycles such asIs selected from

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (5-10-membered optionally substituted heterocycle) -C₁-C₆alkyl-S (O)_0-2- (oxo-substituted 5-to 10-membered heterocyclic) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)P(O)-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-N (R)³⁷)-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C(H)(R²⁸)-。

Some of the first aspectIn an embodiment, the compound has formula (Ia), where R³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, dioxanyl, oxathienylheptyl, morpholinyl, dithiinyl, piperazinyl, azothienylhexyl, oxepinyl, thienylheptyl, azepinyl, dioxepinyl, oxathienylheptyl, oxazepinyl, dithienyl, thiazepinyl, and diazepanyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is selected from piperidinyl, morpholinyl and piperazinyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, dioxanyl, oxathienylheptyl, morpholinyl, dithiinyl, piperazinylA group selected from the group consisting of phenyl, thienyl, oxacycloheptyl, thiacycloheptyl, azepanyl, dioxacycloheptyl, oxathiepinyl, oxazepinyl, dithepinyl, thiazepinyl, and diazepanyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is³⁸Is R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is selected from piperidinyl, morpholinyl and piperazinyl.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²³Selected from H, C₁-C₆Alkyl, aryl, cycloalkyl, heteroaryl, 5-to 10-membered heterocyclyl, -C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl, -C₁-C₆Alkyl-cycloalkyl and-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl).

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²³Is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl), -O-C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-heteroaryl, -O-C₁-C₆Alkyl-cycloalkyl and-O-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl).

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁴Selected from H, C₁-C₆Alkyl, aryl, cycloalkyl, heteroaryl, 5-to 10-membered heterocyclyl, -C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl, -C₁-C₆Alkyl-cycloalkyl and-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl).

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁴Is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl), -O-C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-heteroaryl, -O-C₁-C₆Alkyl-cycloalkyl and-O-C₁-C₆Alkyl- (5 to 10-membered heterocyclyl).

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁸Is selected from-CF₃、-CHF₂、-CH₂F. CN, optionally substituted C₁-C₆Alkyl and C₃-C₆A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁸Is selected from-CF₃、-CHF₂、-CH₂F and CN.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁹Is H or C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is^29aIs H or C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁹Is a cation, such as a pharmaceutically acceptable cation, such as a cation selected from the group consisting of: li⁺、Na⁺、K⁺、Mg²⁺2 and Ca²⁺/2。

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is²⁹Is Na⁺Or K⁺。

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is^29aIs a cation, such as a pharmaceutically acceptable cation, such as a cation selected from the group consisting of: li⁺、Na⁺、K⁺、Mg²⁺2 and Ca²⁺/2。

In some embodiments of the first aspect, the compound has formula (Ia), wherein R is^29aIs Na⁺Or K⁺。

In some embodiments of the first aspect, the compounds of the invention have formula (II) and formula (III):

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine, wherein pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine are substituted by 1R³⁸Substituted, or D is unsubstituted tetrahydropyridine;

R³⁸is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, (oxo-substituted heterocyclyl) -C₁-C₂Alkyl- (wherein the oxo-substituted heterocyclyl is further optionally substituted by a substituent selected from the group consisting of-N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac) and-OH), R³⁷O-(CH₂)_n-O-(CH₂)_n1C(O)-N(R⁴⁰)-CH₂-、C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, (heterocyclyl) -C (O) - (wherein heterocyclyl is C₁-C₆Alkyl optionally substituted), C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, HO-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -, (C)₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-、C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)³⁹)-C(O)-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷-O-C (O) -heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH ₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, C₁-C₆alkyl-SO₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, (HO-substituted C)₁-C₆alkyl-N (R)³⁹)-C(O)-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-, heterocyclyl radical-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-, C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, H (O) C-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-;

wherein when D is imidazole, the imidazole is further optionally substituted with C₁-C₆Alkyl substitution;

R³⁷is H, C₁-C₆An alkyl group;

R^37ais H, C₁-C₆An alkyl group;

a is H, Ac, -C (O) -CH₂-OMe、-C(O)-CH(NH₂)-C(CH₃)₃、-C(O)-C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (O) -H, -C (O) -C₁-C₆Alkyl, -C₁-C₆alkyl-O-C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -, C₁-C₆Alkyl and-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)-C(O)-OBn；

j is an integer from 0 to 4, alternatively from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, or 2 or 3;

i1 is 2 or 3;

j1 is an integer from 0 to 4, or 1 or 2;

n is an integer of 0 to 4;

n1 is an integer from 0 to 4;

R³⁹is H, C₁-C₆Alkyl, aryl, heteroaryl, and heteroaryl,

R⁴⁰Is C₁-C₆alkyl-OR⁴¹；

R⁴¹Is H, C₁-C₆An alkyl group;

R⁹is H, C₁-C₆An alkyl group;

R¹⁰is H, C₁-C₆An alkyl group;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

R²is H or F;

R^2ah, F, Cl;

g is selected from

R¹³Is H or C₁-C₆An alkyl group; and

each R is²⁰Independently selected from H, halogen, -PO (C)₁-C₆Alkyl radical)₂、-S(O)₂-C₁-C₆Alkyl) and-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (II).

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸A substituted pyridine.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C ₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-or R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, and A is selected from the group consisting of-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂) -, or R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is selected from the group consisting of-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH) ₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspectThe compounds have the formula (II) wherein D is substituted by one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is selected from the group consisting of-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -H.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (oxo-substituted heterocyclyl) -C₁-C₂Alkyl-; in some embodiments of the first aspect, the compound has formula (II), wherein R is³⁸-D-is

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R ³⁸Substituted pyridines in which R³⁸Is C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₀-C₆Alkyl- (7-membered heterocyclyl) -CH₂-. In some embodiments, C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3is-CH₃- (7-membered heterocyclyl) -CH₂-such as C₀-C₆Alkyl- (1, 4-diazepanyl) -CH₂-, such as CH₃- (1, 4-diazepanyl) -CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

in some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, are combinedThe compound has the formula (II) in which D is a substituted or unsubstituted R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is NC-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH ₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein the phenyl ring of the group G is substituted with one R²⁰Substituted, which is-PO (C)₁-C₆Alkyl radical)₂Said R is²⁰Ortho to the point of attachment of the nitro nitrogen atom to the phenyl ring.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines and in which the phenyl ring of the group G is substituted by an R²⁰Substituted, which is-PO (C)₁-C₆Alkyl radical)₂Said R is²⁰Ortho to the point of attachment of the nitro nitrogen atom to the phenyl ring.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and wherein the phenyl ring of the group G is substituted by one R²⁰Substituted, which is-PO (C)₁-C₆Alkyl radical)₂Said R is²⁰In the presence of a catalyst bonded to benzeneOrtho to the point of attachment of the nitro nitrogen atom on the ring.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R ³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, wherein the optional substituents are selected from: H. halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH and-C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C ₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸And a C₁-C₆Alkyl (e.g. -CH)₃) A substituted imidazole.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one or R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸And a C₁-C₆Alkyl substituted imidazoles, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl radical。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R ³⁸Substituted imidazoles, in which R is³⁸Is C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, such as piperazine- (CH)₂)₂-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (II), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which isOr

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-2-。

In the first aspectIn some embodiments, the compound has formula (II) wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R ³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, where heterocyclyl is 5-or 6-membered heterocyclyl, R³⁷Is H and- (CH)₂)_1-6Is- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸A substituted phenyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted phenyl, wherein R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -N (R)³⁹) -a cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (II),wherein D is substituted by one R³⁸A substituted tetrahydropyridine.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -or R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R ³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted tetrahydropyridines, wherein R³⁸Is R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸A substituted pyrazole.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-or R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-or R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the method comprisesThe compound has the formula (II) in which D is a substituted or unsubstituted R³⁸Substituted pyrazoles in which R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-。

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R) ³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II), wherein D is substituted with one R³⁸Substituted pyrazoles in which R is³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (III).

In some embodiments of the first aspect, the compound has formula (III), wherein D is substituted with one R³⁸A substituted pyridine.

In some embodiments of the first aspect, the compound has formula (III), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)-。

In some embodiments of the first aspect, the compound has formula (III), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (III), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein D is further selected from heterocycle-C ≡ C-, or morpholine-C ≡ C-.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、(C₁-C₆alkyl-S (O) ₂-(CH₂)₂-N(A)-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (oxo-substituted heterocyclyl) -C₁-C₂Alkyl-, wherein the oxo-substituted heterocyclyl is optionally substituted with: -N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac), and-OH. Or R³⁸Is composed of

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (oxo-substituted heterocyclyl) -C₁-C₂Alkyl-, wherein the oxo-substituted heterocyclyl is optionally substituted with: -N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac), and-OH. Or R³⁸Is composed of

Some of the first aspectIn an embodiment, the compound has formula (II) or formula (III), wherein R³⁸Is (oxo-substituted heterocyclyl) -C₁-C₂Alkyl-, wherein the oxo-substituted heterocyclyl is optionally substituted with: -N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R) ³⁷) (Ac), and-OH.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, or C₁-C₆alkyl-piperazine-CH₂-or CH₃-piperazine- (CH)₂)₂-)。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (heterocyclyl) -C (O) -, wherein heterocyclyl is optionally substituted by C₁-C₆Alkyl substitution. Or R³⁸Is composed of

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (heterocyclyl) -C (O) -, wherein heterocyclyl is optionally substituted by C₁-C₆Alkyl substitution. Or R³⁸Is composed of

In some embodiments of the first aspect, the compound has formula (II)Or formula (III) wherein R³⁸Is C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, or heterocyclyl- (CH)₂) -, piperazine-CH₂-、morpholine-CH₂-, morpholine- (CH)₂)₂-、CH₃-piperazine- (CH)₂)₂-, morpholine- (CH)₂)₃-or piperazine- (CH)₂)₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is HO-heterocyclyl-CH₂-, or HO-pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (R)⁹)(R¹⁰) N-heterocyclyl-CH₂-, or NH₂-pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is ³⁸Is (R)⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -, or N (CH)₃)₂-pyrrolidinyl-C (O) -or (CH)₃)₂)₂N-(CH₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (C)₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-, or CH₃-C (O) -piperazine-CH₂-)。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-heterocyclyl-CH₂-, or HO- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or HO- (CH)₂) -C (O) -piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)³⁹) -C (O) -, or morpholine- (CH)₂)₂-NH-C (O) -, morpholine- (CH)₂)₃-NH-C (O) -or CH₃-piperazine- (CH)₂)₂-NH-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷-O-C (O) -heterocyclyl-C (O) -, or EtO-C (O) -piperidine-C (O) -, BuO-C (O) -morpholino-C (O) -, HO-C (O) -piperidine-C (O) -, or HO-C (O) -morpholino-C (O) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is ³⁸Is C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, or C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-heterocyclyl-C (O) -, morpholine- (CH)₂)₂piperazine-C (O) -, CH₃-piperidine-CH₂-piperazine-C (O) -or CH₃-piperazine-piperidine-c (o) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is CH₃-piperazine-piperidine-c (o) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₁-C₆alkyl-SO₂-, or Me-S (O)₂-。

In the first aspectIn some embodiments, the compound has formula (II) or formula (III), wherein R³⁸Is R³⁷O-C ₁-C₆alkyl-heterocyclyl-CH₂-, or MeO- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (HO-substituted C)₁-C₆alkyl-N (R)³⁹) -C (O) -, or HO-CH₂-[CH(OH)]₄-CH₂-N(Me)-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is heterocyclyl-C₁-C₆alkyl-heterocyclyl-CH₂-, or morpholine- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, or Me-S (O)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is ³⁸Is heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-, imidazole- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C₁-C₆Alkyl-, or HO- (CH)₂)₄-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-or MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-, or CH₃-S(O)₂-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-, or R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, or HO-C (O) - (CH)₂)₂-piperazine-CH₂-, EtO-C (O) -piperidine-CH₂-、EtO-C(O)-CH₂-piperidine-CH₂-、EtO-C(O)-CH₂-piperazine-CH₂-, HO-C (O) -piperidine-CH₂-、HO-C(O)-CH₂-piperidine-CH₂-HO-C(O)-CH₂-piperazine-CH₂-、(CH₃)₃C-O-C (O) -piperazine-CH₂-or HO-C (O) -pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹) -C (O) -, or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is ³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, or CH₃-CH₂-O-C(O)-(CH₂)₂-piperazine-C (O) -or HO-C (O) - (CH)₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is HOOC-C₁-C₆alkyl-N (A) -CH₂-, or HOOC- (CH)₂)₃-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (HOOC) (NR)⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-, or (HOOC) (NH)₂)CH-(CH₂)₄-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, or HO-C (O) - (CH)₂)₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (II) or (II)Formula (III) wherein R³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, or C₃cycloalkyl-NH-C (O) -O- (CH)₂)₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, or MeO- (CH)₂)₂-O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, orOr

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is NC-C₁-C₆alkyl-heterocyclyl-CH₂-, or NC- (CH)₂)₂-piperazine-CH₂-。

In the first aspectIn some embodiments, the compound has formula (II) or formula (III), wherein R³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-, or F₃C-CH₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (optionally substituted 8-membered fused heterocyclyl) -C₁-C₆Alkyl radical of whichWherein

G is selected from CH₂O, NH, S, SO and SO₂；

G¹Is selected from CH₂O, NH, S, SO and SO₂；

G²Is CH or N;

G³is selected from CH₂O, NH, S, SO and SO₂；

G⁴Is selected from CH₂O, NH, S, SO and SO ₂；

G⁵Is selected from CH₂O, NH, S, SO and SO₂；

G⁶Is CH or N;

G⁷is selected from CH₂O, NH, S, SO and SO₂；

R^sIs an optional substituent; and

R^s1is an optional substituent group, and the like,

provided that the two O atoms are not adjacent.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl radical selected from

Wherein G is selected from CH₂O, NH, S, SO and SO₂；G¹Is selected fromCH₂O, NH, S, SO and SO₂(ii) a And R^sIs an optional substituent.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is^sSelected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C ₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is^s1Selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, wherein the optional substituents are: H. halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH and-C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted, e.g. by halogen or-C ₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-, wherein both fluorine substituents are substituents on the same carbon atom.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is C₀-C₆Alkyl- (5 or 6-membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, where heterocyclyl is 5-or 6-membered heterocyclyl, R³⁷Is H and- (CH)₂)_1-6Is- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is ³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is selected from-C (o) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl and-C (O) -N (R)⁹)(R¹⁰)、(R²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is H.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is not H.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is Ac.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) -CH₂-OMe。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) -CH (NH)₂)-C(CH₃)₃。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-C (o) -H, -C (o) -C₁-C₆Alkyl, or-C (O) -CH₃、-C(O)-CH₂-CH₃。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-C₁-C₆alkyl-O-C₁-C₆Alkyl, or- (CH) ₂)₂-OMe)。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-C (o) -C₁-C₆alkyl-OH.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-C (o) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C ₁-C₆alkyl-N (R)⁹)(R¹⁰) or-C (O) -CH₂-NH-C(O)-CH(NH₂)-CH(CH₃)₂、-C(O)-CH₂-NH-C(O)-CH₂-NH₂or-C (O) -CH [ CH (CH)₃)₂]-NH-C(O)-CH₂-NH₂)。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) -N (R)³⁹)-C₁-C₆Alkyl, or-C (O) -NH-CH₂-CH₃、-C(O)-NH-CH₃、-C(O)-NH-CH(CH₃)₂、-C(O)-NH-CH(CH₃)₂or-C (O) -N (CH)₃)₂。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-C (= NR)³⁷)-C₁-C₆Alkyl, or-C (= NH) H.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, or-C (O) -CH₂-S(O)₂-Me。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) -N (R)³⁹) -cycloalkyl, or-C (O) -NH-cyclopentyl or-C (O) -NH-C₃A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is-c (o) -N (R)⁹)(R¹⁰) or-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is (R) ²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -, or (HO)₂P(O)O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein a is not C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein R is¹³Is H.

In some embodiments of the first aspectThe compound has formula (II) or formula (III), wherein each R is²⁰Independently H or halogen (e.g. Br, Cl or F, or F).

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein G comprises one R²⁰And (4) a substituent.

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein G comprises one R²⁰A substituent selected from: -PO (C)₁-C₆Alkyl radical)₂(e.g., -PO (Me)₂)、-S(O)₂-C₁-C₆Alkyl) (e.g., -S (O)₂Me) and-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (II) or formula (III), wherein

R³⁸Is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、(C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R) ³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-; and

a is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (IV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from the group consisting of pyridine, phenyl, imidazole and heterocycle-C.ident.C- (such as morpholine-C.ident.C-), wherein each of the pyridine, phenyl and imidazole is substituted by an R³⁸Substitution;

R³⁸is selected from R³⁷O-(CH₂)₂-N(A)-CH₂- (e.g. R)³⁷O-(CH₂)₂-N(A)-CH₂-, (oxo-substituted heterocyclyl) -C₁-C₆Alkyl- (e.g. alkyl)) And (heterocyclyl) -C (O) - (e.g. C))，

Wherein when D is imidazole, said imidazole is further optionally substituted with C₁-C₆Alkyl (e.g. -CH)₃) And (4) substitution.

R³⁷Is H or C₁-C₆An alkyl group;

a is H or Ac;

R²is F;

R^2ais H; and

each R is²⁰Independently selected from H, -PO (C)₁-C₆Alkyl radical)₂(e.g., -PO (Me)₂)、-S(O)₂-C₁-C₆Alkyl) (e.g., -S (O) ₂Me) and-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (IV), wherein one R is²⁰Is H and the other R²⁰is-PO (C)₁-C₆Alkyl radical)₂the-PO (C)₁-C₆Alkyl radical)₂In the ortho position relative to the point of attachment of the nitrogen atom of the phenyl ring to the group G.

In some embodiments of the first aspect, the compound has formula (VI):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine, each substituted by one R³⁸Substituted, or D is unsubstituted tetrahydropyridine;

R³⁸is selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、R³⁷O-(CH₂)_n-O-(CH₂)_n1C(O)-N(R⁴⁰)-CH₂-、C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, (oxo-substituted heterocyclyl) -C₁-C₆Alkyl- (wherein the oxo-substituted heterocyclyl is further substituted with a substituent selected from the group consisting of-N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac), -OH and (heterocyclyl) -C (O) -, wherein said heterocyclyl is optionally substituted with C₁-C₆Alkyl substituted), C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, HO-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-CH₂-、(C₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)_1-6-、C₀-C₆alkyl-heterocyclyl-C ₁-C₆alkyl-N (R)³⁹)-C(O)-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-C (O) -, R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R₃₇-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷-O-C (O) -heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, C₁-C₆alkyl-SO₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, (HO-substituted C)₁-C₆Alkyl) -N (R)³⁹)-C(O)-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-, heterocyclyl radical-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆Alkyl-, N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-and (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-;

wherein when D is imidazole, the imidazole is further optionally substituted with C₁-C₆Alkyl substitution;

R³⁷is H, C₁-C₆An alkyl group;

R^37ais H, C₁-C₆An alkyl group;

a is H, Ac, -C (O) -CH₂-OMe、-C(O)-CH(NH₂)-C(CH₃)₃、-C(O)-(CH₂)_n-N(R³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (O) -H, -C (O) -C₁-C₆Alkyl, -C₁-C₆alkyl-O-C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, -C (O) -C₁-C₆alkyl-N (R) ³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(=NH)-H、-C(O)-(CH₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -and C₁-C₆An alkyl group, a carboxyl group,

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

il is 2 or 3;

jl is an integer from 0 to 4, or 1 or 2;

n is an integer of 0 to 4;

nl is an integer from 0 to 4;

R³⁹is H or C₁-C₆An alkyl group;

R⁴⁰is-C₁-C₆alkyl-OR⁴¹；

R⁴¹Is H or C₁-C₆An alkyl group;

R⁹is H or C₁-C₆An alkyl group;

R¹⁰is H or C₁-C₆An alkyl group;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

R²is H or F; and

R^2ah, F or Cl.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸A substituted pyridine.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸A substituted phenyl group.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazole, and further optionally substituted by C₁-C₆Alkyl (e.g. -CH)₃) And (4) substitution.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R ³⁸A substituted pyrazole.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted tetrahydropyridine, or D is unsubstituted tetrahydropyridine.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is selected from R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R₃₇-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-and N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-, e.g. MeO- (CH)₂)₂-N(A)-CH₂Or MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-(CH₂)_n-O-(CH₂)_n1C(O)-N(R⁴⁰)-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, such as C₁-C₆alkyl-piperazine-CH₂-or CH₃-piperazine- (CH)₂)₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R ³⁸Substituted pyridines in which R³⁸Is C₁-C₆Alkyl- (7-membered heterocyclyl) -CH₂-. In some embodiments, C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2is-CH₃- (7-membered heterocyclyl) -CH₂-, such as C₁-C₆Alkyl- (1, 4-diazepanyl) -CH₂-, such as CH₃- (1, 4-diazepanyl) -CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (optionally substituted 8-to 10-membered fused heterocyclylalkyl-, wherein the optional substituents are selected from H, halo, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH and-C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R ³⁸Substituted pyridines in which R³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-, wherein the two fluoro substituents are substituents on the same carbon atom.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (oxo-substituted heterocyclyl) -C₁-C₆Alkyl-, wherein the oxo-substituted heterocyclyl is further substituted with a substituent selected from the group consisting of: -N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac) and-OH. Such as R³⁸Is selected from

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is selected from

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (heterocyclyl) -C (O) -, wherein the heterocyclyl is optionally substituted by C₁-C₆Alkyl radicals substituted, e.g.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-S (O) ₂-(CH₂)₂-N(A)-CH₂-, such as CH₃-S(O)₂-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, such as heterocyclyl- (CH)₂) -, piperazine-CH₂-、morpholine-CH₂-, morpholine- (CH)₂)₂-、CH₃-piperazine- (CH)₂)₂-, morpholine- (CH)₂)₃-or piperazine- (CH)₂)₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is HO-heterocyclyl-CH₂-, such as HO-pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰) N-heterocyclyl-CH₂-, such as NH₂-pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (C)₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-, such as CH₃-C (O) -piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-heterocyclyl-CH₂-, such as HO- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO- (CH)₂) -C (O) -piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)³⁹) C (O) -, e.g. morpholine- (CH)₂)₂-NH-C (O) -, morpholine- (CH) ₂)₃-NH-C (O) -or CH₃-piperazine- (CH)₂)₂-NH-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, such as CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-, such as R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、HO-C(O)-(CH₂)₂-piperazineoxazine-CH₂-, EtO-C (O) -piperidine-CH₂-、EtO-C(O)-CH₂-piperidine-CH₂-、EtO-C(O)-CH₂-piperazine-CH₂-, HO-C (O) -piperidine-CH₂-、HO-C(O)-CH₂-piperidine-CH₂-、HO-C(O)-CH₂-piperazine-CH₂-、(CH₃)₃C-O-C (O) -piperazine-CH₂-, or HO-C (O) -pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰) N-heterocyclyl-C (O) -e.g. N (CH)₃)₂-pyrrolidine-C (O) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹) -C (O) -, such as CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -e.g. CH₃-CH₂-O-C(O)-(CH₂)₂-piperazine-C (O) -or HO-C (O) - (CH)₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is HOOC-C₁-C₆alkyl-N (A) -CH₂-, such as HOOC- (CH)₂)₃-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (HOOC) (NR)⁹R¹⁰)-C ₁-C₆alkyl-N (A) -CH₂-, e.g. (HOOC) (NH)₂)-CH-(CH₂)₄-N(A)-CH₂-。

In the first placeIn some embodiments of one aspect, the compound has formula (VI), wherein R ³⁸Is R³⁷-O-C (O) -heterocyclyl-C (O) -, such as EtO-C (O) -piperidine-C (O) -, BuO-C (O) -morpholino-C (O) -, HO-C (O) -piperidine-C (O) -or HO-C (O) -morpholino-C (O) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -e.g. N (CH)₃)₂pyrrolidine-C (O) -, (CH)₃)₂)₂N-(CH₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -e.g. C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-heterocyclyl-C (O) -, morpholine- (CH)₂)₂piperazine-C (O) -, CH₃-piperidine-CH₂-piperazine-C (O) -or CH₃-piperazine-piperidine-c (o) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, e.g. HO-C (O) - (CH)₂)₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, such as C₃cycloalkyl-NH-C (O) -O- (CH)₂)₂。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, e.g. MeO- (CH)₂)₂-O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is ³⁸Is C₁-C₆alkyl-SO₂-, such as Me-S (O)₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, such as

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-, such as

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, e.g. MeO- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (HO-substituted C)₁-C₆Alkyl) -N (R)³⁹) C (O) -, e.g. HO-CH₂-[CH(OH)]₄-CH₂-N(Me)-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is NC-C₁-C₆alkyl-heterocyclyl-CH₂-, such as NC- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is heterocyclyl-C₁-C₆alkyl-heterocyclyl-CH₂-, such as morpholine- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-, such as F₃C-CH₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, such as Me-S (O)₂-piperazine-CH ₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-, such as imidazole- (CH)₂)₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆Alkyl-, such as HO- (CH)₂)₄-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as

il in some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-which is

In some embodiments of the first aspect, the compound has formula (VI), wherein R is ³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (optionally substituted 8-membered fused heterocyclic group)-C₁-C₆Alkyl-which isWherein

G is selected from CH₂O, NH, S, SO and SO₂；

G¹Is selected from CH₂O, NH, S, SO and SO₂;

G²Is CH or N;

G³is selected from CH₂O, NH, S, SO and SO₂；

G⁴Is selected from CH₂O, NH, S, SO and SO₂；

G⁵Is selected from CH₂O, NH, S, SO and SO₂；

G⁶Is CH or N;

G⁷is selected from CH₂O, NH, S, SO and SO₂；

R^sIs an optional substituent; and

R^s1is an optional substituent group, and the like,

with the proviso that the two O atoms are not adjacent to each other.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is selected from (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl groups:and

in some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is selected from (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl groups:

wherein G is selected from CH₂O, NH, S, SO and SO₂；G¹Is selected from CH₂O, NH, S, SO and SO₂(ii) a And R^sIs an optional substituent.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is^sSelected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C ₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is^s1Selected from H, halogen, -N (R)⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH, -C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, wherein the optional substituents are selected from H, halogen, -N (R) ⁹)(R¹⁰) Nitro, -OH, oxo, C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, Ac, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (O)_0-2-C₁-C₆Alkyl, -S (O)_0-2-cycloalkyl, -S (O)_0-2-heterocyclyl, -S (O)_0-2-aryl, -S (O)_0-2-heteroaryl, -C (O) H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰)、-C₁-C₆alkyl-OH, -C₁-C₆alkyl-C (O) -OH and-C₁-C₆alkyl-C (O) -N (R)⁹)(R¹⁰) Wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are themselves optionally substituted by, for example, halogen or-C₁-C₆Alkyl substitution.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-, wherein the two fluoro substituents are substituents on the same carbon atom.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (VI), wherein R is ³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group.

In some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group, R³⁷Is H and- (CH)₂)_1-6Is- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is selected from-c (o) - (CH)₂)_n-N(R³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)-C(O)-N(R³⁹)-C₁-C₆alkyl-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)-C(=NH)-H、-C(O)-(CH₂)_n-S(O)₂-C₁-C₆alkyl-C (O) -N (R)³⁹) cycloalkyl-C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is H.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is not H.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is Ac.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -CH₂-OMe。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -CH (NH)₂)-C(CH₃)₃。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) - (CH)₂)_n-N(R³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰) Such as-C (O) -CH₂-NH-C(O)-CH(NH₂)-CH(CH₃)₂。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -N (R) ³⁹)-C₁-C₆Alkyl radicals, e.g. C (O) -NH-CH₂-CH₃、-C(O)-NH-CH₃、-C(O)-NH-CH(CH₃)₂or-C (O) -N (CH)₃)₂。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -H.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-C (o) -C₁-C₆Alkyl radicals, e.g. C (O) -CH₃or-C (O) -CH₂-CH₃。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-C₁-C₆alkyl-O-C₁-C₆Alkyl radicals, e.g. - (CH)₂)₂-OMe。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-C (o) -C₁-C₆alkyl-OH.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-C (o) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰) Such as-C (O) -CH₂-NH-C(O)-CH₂-NH₂or-C (O) -CH [ CH (CH)₃)₂]-NH-C(O)-CH₂-NH₂。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-C (= NH) -H.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl radicals, e.g. C (O) -CH₂-S(O)₂-Me。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -N (R)³⁹) Cycloalkyl radicals, e.g., -C (O) -NH-cyclopentyl or-C (O) -NH-C₃A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is-c (o) -N (R) ⁹)(R¹⁰) Such as-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (VI), wherein a is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -, e.g. (HO)₂P(O)O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (VI), whichWherein A is C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (VI), wherein a is not C₁-C₆An alkyl group.

In some embodiments of the first aspect, the invention relates to compounds having formula (VI) wherein D is substituted with R³⁸A substituted pyridine.

In some embodiments of the first aspect, the invention relates to compounds having formula (VI) wherein D is substituted with R³⁸Substituted pyridines, and R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-。

In some embodiments of the first aspect, the invention relates to compounds having formula (VI) wherein D is substituted with R³⁸Substituted pyridines, R³⁸Is R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-, and A is selected from-C (O) - (CH)₂)_n-N(R³⁹)-C(O)-C ₁-C₆alkyl-N (R)⁹)(R¹⁰)。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is (oxo-substituted heterocyclyl) -C₁-C₂Alkyl-; in some embodiments of the first aspect, the compound has formula (VI), wherein R is³⁸-D-is

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R ³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆An alkyl group-.

In some embodiments of the first aspect, are combinedThe compound has the formula (VI) wherein D is substituted by one R³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, wherein the heterocyclyl is a 6-membered heterocyclyl.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclylalkyl-which is

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, such as HO-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group.

In some embodiments of the first aspect, the compound has formula (VI), wherein D is substituted with one R³⁸Substituted imidazoles, in which R is³⁸Is R³⁷O-C₁-C₆alkyl-C (O) -heterocyclesRadical- (CH)₂)_1-6-, wherein the heterocyclic group is a 5-or 6-membered heterocyclic group, R³⁷Is H and- (CH)₂)_1-6Is- (CH)₂)_1-2-。

In some embodiments of the first aspect, the compound has formula (VII)

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is pyridine or imidazole, wherein the pyridine and imidazole are substituted by one R³⁸Substitution;

R³⁸selected from (oxo-substituted heterocyclyl) -C₁-C₆Alkyl-, (heterocyclyl) -C (O) -, C₁-C₆Alkyl radical, R³⁷O-(CH₂)₂-N(A)-CH₂-, heterocyclyl radical-C₁-C₆alkyl-N (R)³⁹) -C (O) -, heterocyclyl-CH₂-;

Wherein when D is imidazole, the imidazole is further optionally substituted with C₁-C₆Alkyl (e.g. -CH)₃) Substitution;

R³⁷is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -C₁-C₆An alkyl group;

R³⁹is H or C₁-C₆An alkyl group;

R²is F; and

R^2ais H.

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is (oxo-substituted heterocyclyl) -C₁-C₆Alkyl-, such as

In some embodiments of the first aspect, the compound has formula (VII), wherein R is ³⁸Is (heterocyclyl) -C (O) -, e.g.

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is other than C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is R³⁷O-(CH₂)₂-N(A)-CH₂-, e.g. MeO- (CH)₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is heterocyclyl-C₁-C₆alkyl-N (R)³⁹) C (O) -, e.g. morpholine- (CH)₂)₂-NH-C(O)-。

In some embodiments of the first aspect, the compound has formula (VII), wherein R is³⁸Is heterocyclyl-CH₂-, preferably for example morpholine-CH₂-。

In some embodiments of the first aspect, the compound has formula (VII), wherein a is-c (o) -N (R)³⁹)-C₁-C₆Alkyl radicals, e.g., -C (O) -NH-CH (CH)₃)₂or-C (O) -NH-CH₂-CH₃。

In some embodiments of the first aspect, the compound has formula (VII), wherein a is-C (o) -C₁-C₆Alkyl radicals, e.g. C (O) -CH₃。

In some embodiments of the first aspect, the compound has formula (VIII)

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-CH₂-, e.g. MeO- (CH)₂)₂-N(A)-CH₂-；

A is H or-C (O) -C₁-C₆Alkyl radicals, e.g. C (O) -CH₃；

R¹³Is H or C₁-C₆An alkyl group;

R³⁷is C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

R²⁰is H or F.

In some embodiments of the first aspect, the compound has formula (IX):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-CH₂-, e.g. MeO- (CH)₂)₂-N(A)-CH₂-；

A is H or-C (O) -C₁-C₆An alkyl group;

R³⁷is H or C₁-C₆An alkyl group; and

R²is F.

In some embodiments of the first aspect, the compound has formula (X):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、N(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C ₁-C₆alkyl-C (O) -heterocyclyl-CH₂-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-;

R³⁷is H or C₁-C₆An alkyl group;

a is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -;

n is an integer of 0 to 4;

R³⁹is H or C₁-C₆An alkyl group;

R⁹is H or C₁-C₆An alkyl group;

R¹⁰is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H or F;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

il is 2 or 3;

jl is an integer of 0 to 4, or 1 or 2, and

g is

In some embodiments of the compounds of formula (X), R³⁸Further comprises C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, or-C (O) -piperidine-piperazine-CH₃。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂Or MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-, or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is ³⁸Is R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-, or R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, or HO-C (O) - (CH)₂)₂-piperazine-CH₂-, EtO-C (O) -piperidine-CH₂-、EtO-C(O)-CH₂-piperidine-CH₂-、EtO-C(O)-CH₂-piperazine-CH₂-, HO-C (O) -piperidine-CH₂-、HO-C(O)-CH₂-piperidine-CH₂-、HO-C(O)-CH₂-piperazine-CH₂-、(CH₃)₃C-O-C (O) -piperazine-CH₂-or HO-C (O) -pyrrolidine-CH₂-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹) -C (O) -, or CH₃-O-[CH₂-CH₂-O]₃-(CH₂)₂-N(A)-C(O)-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, or CH₃-CH₂-O-C(O)-(CH₂)₂-piperazine-C (O) -or HO-C (O) - (CH)₂)₂-piperazine-C (O) -.

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-, or F₃C-CH₂-piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C ₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, or

In some embodiments of the first aspect, the compound has formula (X), wherein R is³⁸Is C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, such as

In some embodiments of the first aspect, the compound has formula (X), wherein a is-C (o) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰) or-C (O) -CH₂-NH-C(O)-CH(NH₂)-CH(CH₃)₂、-C(O)-CH₂-NH-C(O)-CH₂-NH₂or-C (O) -CH [ CH (CH)₃)₂]-NH-C(O)-CH₂-NH₂)。

In some embodiments of the first aspect, the compound has formula (X), wherein a is-c (o) -N (R)³⁹)-C₁-C₆Alkyl, or-C (O) -NH-CH₂-CH₃、-C(O)-NH-CH₃、-C(O)-NH-CH(CH₃)₂、-C(O)-NH-CH(CH₃)₂or-C (O) -N (CH)₃)₂。

In some embodiments of the first aspect, the compound has formula (X), wherein a is-C (= NR)³⁷)-C₁-C₆Alkyl, or-C (= NH) H.

In some embodiments of the first aspect, the compound has formula (X), wherein a is-c (o) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, or-C (O) -CH₂-S(O)₂-Me。

In some embodiments of the first aspect, the compound has formula (X), wherein a is-c (o) -N (R)⁹)(R¹⁰) or-C (O) -NH₂。

In some embodiments of the first aspect, the compound has formula (X), wherein a is (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -, or (HO)₂P(O)O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound is of formula (XI),

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is a group R³⁸Substituted and further substituted by C₁-C₆Alkyl substituted imidazoles;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais F;

and

g is

In some embodiments of the first aspect, the compound has formula (XI), wherein R is³⁸Selected from: r³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-and MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (XII):

wherein

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸Substituted phenyl;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -a cycloalkyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais F; and

g is

In some embodiments of the first aspect, the compound has formula (XII), wherein R is³⁸Is selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-and MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (XII), wherein a is selected from-c (o) -N (R)³⁹)-C_3-6Cycloalkyl, -C (O) -N (R)³⁹)-C₃Cycloalkyl, -C (O) -N (R)³⁹)-C₄Cycloalkyl, -C (O) -N (R)³⁹)-C₅Cycloalkyl and-C (O) -N (R)³⁹)-C₆A cycloalkyl group.

In some embodiments of the first aspect, the compound has formula (XIII):

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸Substituted and further substituted by C₁-C₆Alkyl substituted imidazoles;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

Some embodiments of the first aspectWherein the compound has the formula (XIII), wherein R³⁸Is selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-and MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (XIV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸Substituted tetrahydropyridines;

R³⁸is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -;

R³⁷is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

In some embodiments of the first aspect, the compound has formula (XIV), wherein R is³⁸Is HO-C (O) - (CH)₂)₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (XIV), wherein R is ³⁸Is R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, or MeO- (CH)₂)₂-O-CH₂-C(O)-。

In some embodiments of the first aspect, the compound has formula (XV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is R³⁸A substituted pyrazole;

R³⁸is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

In some embodiments of the first aspect, the compound has formula (XV), wherein R is³⁸Is cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, or C₃cycloalkyl-NH-C (O) -O- (CH)₂)₂-。

In some embodiments of the first aspect,the compound has the formula (XV), wherein R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, such as being selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-and MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (XVI):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-CH₂；

A is selected from H, -C (O) -C ₁-C₆Alkyl, -C (O) -N (R)³⁹)-C₁-C₆Alkyl, and-C (O) -C₁-C₆alkyl-OH;

R³⁷is H, C₁-C₆An alkyl group;

R³⁹is H, C₁-C₆An alkyl group; and

R²is H.

In some embodiments of the first aspect, the compound has formula (XVI), wherein R is³⁸Is MeO- (CH)₂)₂-N(A)-CH₂-。

In some embodiments of the first aspect, the compoundHas the formula (XVI), wherein A is-C (O) -C₁-C₆Alkyl radicals, e.g. C (O) -CH₃)。

In some embodiments of the first aspect, the compound has formula (XVI), wherein a is-c (o) -N (R)³⁹)-C₁-C₆Alkyl radicals, e.g. C (O) -NH-CH₂-CH₃。

In some embodiments of the first aspect, the compound has formula (XVI), wherein a is-C (o) -C₁-C₆alkyl-OH, e.g. -C (O) -CH₂-OH。

In some embodiments of the first aspect, the compound has formula (XVII):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-，

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is H; and

g is

In some embodiments of the first aspect, the compound has formula (XVII), wherein R is³⁸Is selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、MeO-(CH₂)₂-N(A)-CH₂-and MeO- (CH)₂)₂-N(A)-(CH₂)₂-。

In some embodiments of the first aspect, the compound has formula (XVIII):

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is pyridine or imidazole, each R³⁸And wherein the imidazole is further substituted by-C₁-C₆Alkyl radicals such as-CH₃Substitution;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-or R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, -C (O) -H,

R³⁹is H or C₁-C₆An alkyl group;

R²is H or F;

R^2ais H or F; and is

G is

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)-。

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -, and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -, A is-C (O) -N (R) ³⁹)-C₁-C₆Alkyl and G is

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-and A is-C (O) -H.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -and A is-C (O) -H.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -, A is-C (O) -H and G is

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted imidazoles and further substituted by one-CH₃Is substituted in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, or R³⁷O-(CH₂)₂-N(A)-(CH₂)-。

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted imidazoles and further substituted by-CH₃Is substituted in which R³⁸Is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted imidazoles and further substituted by-CH₃Is substituted in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -and A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group.

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R ³⁸Substituted imidazoles further substituted by-CH₃Is substituted in which R³⁸Is HO- (CH)₂)₂-N(A)-(CH₂) -, A is-C (O) -N (R)³⁹)-C₁-C₆Alkyl and G is

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-。

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-CH₂-C (O) -piperazine-CH₂-。

In some embodiments of the first aspect, the compound has formula (XVIII), wherein D is substituted with one R³⁸Substituted pyridines in which R³⁸Is HO-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, such as HO-CH₂-C (O) -piperazine-CH₂-, and G are

In some embodiments of the first aspect, the compound has formula (XIX):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-；

R³⁷Is C₁-C₆An alkyl group;

a is H or C₁-C₆An alkyl group, a carboxyl group,

R²is F;

R^2ais H; and

in some embodiments of the first aspect, the compound has formula (XIX), wherein a is H.

In some embodiments of the first aspect, the compound has formula (XIX), wherein R is³⁷is-CH₃。

In some embodiments of the first aspect, G is

In some embodiments of the first aspect,

in some embodiments of the first aspect, Ar isWherein Ar is optionally substituted.

In some embodiments of the first aspect, D is pyridyl, imidazolyl, or triazolyl, each of which is substituted with one R³⁸And (4) substitution.

In some embodiments of the first aspect, R³⁸Is selected from R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-and R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, wherein each of these alkyl and heterocyclic groups is optionally substituted.

In some embodiments of the first aspect, D is substituted with one R³⁸A substituted pyridyl group.

In some embodiments of the first aspect, when R³⁸From C₁-C₆When alkyl is attached to D, the C₁-C₆Alkyl is-CH₂-。

In some embodiments of the first aspect, D is selected from C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)⁶)-C(O)-、(R⁶)(R⁶) N-C (O) -O-heterocyclyl-C (O) -, PivO-heterocyclyl-C (O) -, C ₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -N (R)⁶) heterocyclyl-C (O) -, (C)₁-C₆Alkyl (Box) N-heterocyclyl-C (O) -, HO-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -O-heterocyclyl-C (O) -, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C (O) -and (R)⁶)(R⁶) N-heterocyclyl-C (O) -, wherein these alkyl and heterocyclyl radicalsEach of which is optionally substituted.

In some embodiments of the first aspect, R⁶Is H.

In some embodiments of the first aspect, the compound is selected from:

including the N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, as well as racemic and non-racemic mixtures, diastereomers and enantiomers thereof.

In one embodiment of the first aspect, the compound is

In one embodiment of the first aspect, the compound is

In one embodiment of the first aspect, the compound is

The compounds of the above formulae can generally be prepared according to the following schemes. Tautomers and solvates (e.g., hydrates) of the compounds of the above formulae are also within the scope of the invention. Solvation processes are generally known in the art. Thus, the compounds of the present invention may be in free, hydrate or salt form and may be obtained by the methods illustrated in the following schemes.

The following examples and preparations describe the manner and method of making and using the invention and are intended to be illustrative and not limiting. It should be understood that other embodiments are possible within the spirit and scope of the invention as defined by the claims.

The compounds of the present invention include, but are not limited to, those described in the following embodiments. Compounds are named using Chemdraw Ultra (version 10.0,10.0.4 or version 8.0.3), which are available via or are produced by Cambridge soft (www.Cambridgesoft.com,100 Cambridge Park Drive, Cambridge, MA 02140).

The data presented herein demonstrate the inhibitory effect of the kinase inhibitors of the present invention. These data suitably suggest that the compounds of the invention are not only useful for inhibiting kinase activity, protein tyrosine kinase activity or embodiments thereof, such as VEGF receptor signaling, but also for use as therapeutic agents in the treatment of proliferative diseases, including cancer and tumor growth, as well as ophthalmic diseases, conditions and disorders.

Synthetic protocol and Experimental procedures

The compounds of the present invention can be prepared by methods generally known to those skilled in the art according to the reaction schemes or examples shown below. These schemes serve to illustrate some of the procedures that may be used to prepare the compounds of the present invention. Those skilled in the art will recognize that other general synthetic procedures may be used. The compounds of the invention can be prepared from commercially available starting components. Any kind of substitution may be made on the starting components to obtain the compounds of the invention according to procedures well known to those skilled in the art.

All reagents and solvents were obtained from commercial sources and used as received. In thatRecording in the indicated solvents by Mercury Plus Varian 400MHz instrument¹H-NMR spectrum. Low Resolution Mass Spectra (LRMS) were obtained via an Agilent MSD instrument. Using a Zorbax 3 μm, XDB-C8, 2.1X50mm column via an Agilent 1100 instrument; analytical HPLC was performed with a gradient of 5 to 95% methanol in methanol/water (containing 0.1% formic acid) over 15 min. Used with Biotage SP1 or Biotage SP4 instrumentsSNAP、SiliaSep^TMOrThe column performs automatic column chromatography. Silica gel (SiliaFlash F60, 40 to 63pM, pore size 60A,) Flash column chromatography was performed. Preparative column chromatography was performed on a Gilson 215 instrument using a Phenomenex Luna 15 μm, C18(2)100A, 250x21mm column eluting with a methanol/water mixture (containing 0.05% formic acid) gradient of 0 to 95% methanol in up to 60 minutes.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Scheme 2

Example 2

N- [3- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) ] -N- (1-methyl) -N- [3- (2-methoxyethyl) ] urea

To a stirred solution of 1(150mg, 0.296mmol) in THF (9mL) at-78 ℃ under nitrogen was added dropwise a solution of triphosgene (50mg, 0.17mmol) in THF (1 mL). The reaction mixture was allowed to warm to-25 ℃ over 1 hour, and methylamine was slowly added to THF Solution (0.6mL, 2.0M). The reaction mixture was allowed to warm to room temperature for 1.5 hours and stirred at room temperature for 30 minutes. The reaction mixture was cooled to-20 ℃ and a solution of triphosgene (120mg, 0.40mmol) in THF (2mL) was added slowly. After stirring for 1 hour between-20 ℃ and-10 ℃, a solution of methylamine in THF (1mL, 2.0M) was added. The reaction mixture was allowed to warm to room temperature for 1.5 hours and stirred at room temperature overnight, then partitioned between ethyl acetate and water. The organic layer was collected and washed successively with 1N NaOH and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 10/90 followed by 5CV 10/90) to give the title compound 3(35mg, 0.06mmol, 25% yield) as a white loose solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.74(s,1H),8.52(d,J=5.3Hz,1H),8.48(d,J=1.6Hz,1H),8.31(s,1H),8.23(d,J=8.2Hz,1H),7.78-7.69(m,2H),7.38(t,J=9.1Hz,1H),7.23-7.17(m,1H),6.64(dd,J=5.4,0.9Hz,1H),6.62-6.58(m,1H),6.38(q,J=4.4Hz,1H),4.53(s,2H),3.44-3.36(m,4H),3.22(s,3H),2.60(d,J=4.3Hz,3H),2.58-2.52(m,1H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS(m/z):565.2(M+H)。

Scheme 3

Example 3

N- [3- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) ] -N- (1, 1-dimethyl) -N- [3- (2-methoxyethyl) ] urea

To a stirred suspension of 1(200mg, 0.394mmol) in THF (25mL) at-35 ℃ under nitrogen was added dropwise a solution of triphosgene (222mg, 0.75mmol) in THF (5 mL). The reaction mixture (suspension) was warmed to-10 ℃ over 1.5 hours, and a solution of dimethylamine in MeOH (1.87mL, 2.0M) was slowly added. The reaction mixture was allowed to warm to room temperature over 1.5 hours and DIPEA (300. mu.L, 1.72mmol) was added. The reaction mixture was stirred at room temperature For 3.5 days, then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was successively washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV0/100 to 10/90) to give the title compound 4(32mg, 0.055mmol, 14% yield) as an ivory solid.¹HNMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.54(d,J=1.4Hz,1H),8.52(d,J=5.3Hz,1H),8.32(s,1H),8.24(d,J=8.2Hz,1H),7.82(dd,J=8.2,2.2Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.1Hz,1H),7.20(bd,J=9.0Hz,1H),6.64(dd,J=5.4,0.9Hz,1H),6.58(bd,J=2.5Hz,1H),4.40(s,2H),3.49(t,J=5.7Hz,2H),3.25(t,J=5.7Hz,2H),3.23(s,3H),2.77(s,6H),2.59-2.51(m,1H),0.69-0.62(m,2H),0.46-0.40(m,2H)。MS(m/z):579.6(M+H)。

Scheme 4

Example 4

N- [3- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) ] -N- [3- (2-methoxyethyl) ] urea

To a stirred suspension of 1(200mg, 0.394mmol) and DIPEA (200. mu.L, 1.12mmol) in THF (28mL) at-35 ℃ under nitrogen was added dropwise a solution of triphosgene (133mg, 0.45mmol) in THF (2 mL). The reaction mixture was stirred at-35 ℃ to-15 ℃ over 30 minutes, and a solution of ammonia in isopropanol (1.87mL, 2.0M) was slowly added at-25 ℃. The reaction mixture was allowed to warm to room temperature for 1.5 hours and 28% aqueous ammonium hydroxide (3mL) was added. The reaction mixture was then stirred at room temperature overnight and partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV0/100 to 10/90 followed by 5CV 10/90) to give the title as an off white solid Compound 5(151mg, 0.27mmol, 73% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.52(d,J=5.5Hz,1H),8.49(d,J=1.6Hz,1H),8.31(s,1H),8.24(d,J=8.2Hz,1H),7.79-7.69(m,2H),7.38(t,J=9.0Hz,1H),7.20(dd,J=8.9,1.3Hz,1H),6.64(d,J=5.3Hz,1H),6.58(bd,J=2.5Hz,1H),6.02(s,2H),4.52(s,2H),3.45-3.36(m,4H),3.23(s,3H),2.59-2.52(m,1H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS(m/z):551.5(M+H)。

Scheme 6

Example 6

N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) carboxamidine

A suspension of 1(150mg, 0.296mmol) and ethyl azomethine hydrochloride (130mg, 1.18mmol) in MeCN/EtOH (10mL/5mL) was heated to reflux overnight. Ethylimidyl chloride hydrochloride (130mg, 1.18mmol), MeCN (20mL) and EtOH (10mL) were added and the reaction mixture was heated to reflux overnight, then cooled to room temperature. Finally, the reaction mixture was concentrated and partitioned between ethyl acetate and water. The aqueous layer was concentrated (the desired compound was water soluble at a pH of about 4 to 5). The residue was purified from Gilson (Phenomenex, Luna,15 μ, C18(2)100A,250 × 50.00mm,15 μm, MeOH/water with 0.05% formic acid: 60 min 20/80 to 95/5, flow =30mL/min) to give the title compound 7(30mg, 0.056mmol, 23% yield) as a mustard yellow solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): a mixture of isomers and/or rotamers, 9.62-9.48(m, ~0.5H),8.70-8.56(m, ~0.5H),8.53(d, J =5.5Hz,1H),8.45-8.25(m,4H),8.15-7.80(m, ~2H),7.75(dd, J =13.7,2.3Hz,1H),7.36(t, J =9.1Hz,1H),7.36-7.30(m, ~1H),7.24(bd, J =10.2Hz,1H),6.67(d, J =5.3Hz,1H),4H masked by a water peak, 3.24(s,3H),2.60-2.50(m,1H),0.66-0.58(m,2H),0.44-0.38(m, 2H). MS (M/z) 535.6(M + H).

Scheme 7

Example 7

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (((2-methoxyethyl) (2,2, 2-trifluoroethyl) amino) -methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea

A solution of 1(150mg, 0.296mmol), DIPEA (0.3mL, 1.72mmol) and 2-iodo-1, 1, 1-trifluoroethane (2mL, 20.29mmol) in DMSO (4mL) was stirred at 110 ℃ overnight, followed by cooling to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified 3 times by Biotage (SNAP 12g column; MeOH/DCM: from 20CV 00/100 to 10/90 followed by 5CV10/90) followed by Gilson (Phenomenex, Luna 15. mu.C 18(2)100A,250X50.00mm, 15. mu.m, MeOH/water containing 0.05% formic acid: from 60 minutes 60/40 to 95/5, flow =30mL/min) to give the title compound 8 as a colorless, viscous film (2.6mg, 0.004mmol, 2% yield).¹H NMR(400MHz,MeCN-d₃)δ(ppm)：8.55(d,J=1.4Hz,1H),8.48(d,J=5.5Hz,1H),8.06(s,1H),8.02(d,J=8.2Hz,1H),7.87(dd,J=8.2,2.2Hz,1H),7.72(dd,J=13.6,2.3Hz,1H),7.51(bs,1H),7.26(t,J=8.5Hz,1H),7.21(dd,J=9.1,2.3Hz,1H),6.62(dd,J=5.4,0.9Hz,1H),5.51(bs,1H),3.93(s,2H),3.48(t,J=5.6Hz,2H),3.36(q,J=9.8Hz,2H),3.27(s,3H),2.85(t,J=5.5Hz,2H),1.79-1.75(m,1H),0.77-0.69(m,2H),0.56-0.49(m,2H)。MS(m/z):590.6(M+H)。

Scheme 8

Example 8

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-hydroxyethylamino) methyl) pyridin-2-yl) -thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea

To a solution of 1(400mg, 0.788mmol) in anhydrous DCM under nitrogen at-50 ℃ BBr was slowly added ₃Solution in DCM (6.3mL, 1.0M). The reaction mixture was allowed to warm to room temperature over 5 hours. The reaction mixture was then quenched by the addition of methanol and concentrated. The residue was dissolved in a mixture of methanol/1 NHCl/DMSO and purified twice by Gilson (Phenomenex, Luna,15 μ,18 (2)) 100A,250 × 50.00mm,15 μm, MeOH/water with 0.05% formic acid over 60 minutes 20/80 to 95/5, flow =30mL/min), followed by (Phenomenex, Luna,15 μ, C18 (2)100A,250 × 50.00mm,15 μm, MeOH/water with 0.05% formic acid over 60 minutes 20/80 to 70/30, flow =30mL/min) to give the title compound 9(53mg, 0.107mmol, yield 15%, formate salt as an off-white solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.12(s,1H),8.60(d, J =1.4Hz,1H),8.52(d, J =5.5Hz,1H),8.32(s,1H),8.30-8.21(m,2H),7.92(dd, J =8.1,2.1Hz,1H),7.74(dd, J =13.6,2.4Hz,1H),7.37(t, J =9.1Hz,1H),7.22(dd, J =9.1,1.5Hz,1H),6.94(bd, J =2.9Hz,1H),6.64(d, J =5.5Hz,1H),3.83(s,2H),3.50(t, J =5.7Hz,2H),2.62(t, J =5.7, 2H),2.59, 0.51H), 0.51H, 0.5H, and one deletion. MS (M/z) 494.6(M + H).

In analogy to compound 9 (example 8, scheme 8) was prepared from N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3, 2-b) ]Pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) acetamide and BBr₃The reagents were reacted to prepare compound 10 (example 9) in one step.

TABLE 1 characterization of Compound 10 (example 9)

Scheme 9

Example 10

2-cyclopropyl-N- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) -thieno [3,2-b ] pyridin-7-yloxy) phenyl) acetamide

Step 1: tert-butyl (6- (7- (4- (2-cyclopropylacetamido) -2-fluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (12)

To a stirred solution of tert-butyl (6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (11, 500mg, 0.95mmol), cyclopropylacetic acid (115mg, 1.149mmol), and triethylamine (400 μ L,2.86mmol) in DMF (10mL) was added HOBT hydrate (161mg, 1.05mmol) and EDC hydrochloride (457mg, 2.38mmol) reagent under nitrogen and the reaction mixture was stirred at room temperature overnight. Cyclopropylacetic acid (115mg, 1.149mmol) and EDC hydrochloride (500mg, 2.61mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched by addition of water and extracted with ethyl acetate. The organic layer was washed successively with water (× 2), saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (Siliaflash 40g column; MeOH/DCM: 20CV 0/100 to 10/90; and Siliaflash 40 g; MeOH/DCM: 20CV 0/100 to 5/95, followed by 10CV 5/95 to 10/90) to give title compound 12 as a light yellow viscous solid. The material was used in the next step without any further purification. MS (M/z) 607.7(M + H).

Step 2: 2-cyclopropyl-N- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) -thieno [3,2-b ] pyridin-7-yloxy) phenyl) acetamide (13)

A solution of 12(0.94mmol) and TFA (10mL) in DCM (50mL) was stirred at room temperature for 3 h. TFA was removed by co-evaporation with DCM and MeOH, diluted with waterThe residue and the pH was adjusted to 12 to 13 with 4n naoh. The resulting suspension was sonicated for 10 minutes. The solid was collected by filtration, washed with water, and air dried and purified by Biotage (SiliaSep 25g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 1/99 to 10/90 followed by 10CV 10/90 to 20/80) to give a material which was triturated with methanol to give the title compound 13 as a white loose solid (245mg,0.48mmol, 50% over 2 steps).¹H NMR(400MHz,DMSO-d₆)δ(ppm)：10.20(s,1H),8.57(bd,J=1.6Hz,1H),8.52(d,J=5.3Hz,1H),8.32(s,1H),8.23(d,J=8.0Hz,1H),7.94-7.86(m,2H),7.47(t,J=8.7Hz,1H),7.42(dd,J=9.1,2.2Hz,1H),6.67(d,J=5.3Hz,1H),3.78(s,2H),3.41(t,J=5.7Hz,2H),3.24(s,3H),2.65(t,J=5.7Hz,2H),2.37-2.28(m,1H),2.25(d,J=7.0Hz,2H),1.14-1.02(m,1H),0.57-0.43(m,2H),0.28-0.15(m,2H)。MS(m/z):507.5(M+H)。

Scheme 10

Example 11

4,4, 4-trifluoro-3- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenylamino) -N-phenylbutanamide (19)

Step 1: n- (1-ethoxy-2, 2, 2-trifluoroethyl) -3-fluoro-4- (2- (5- ((2-methoxyethylamino) -methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) aniline (14)

A solution of 11(2g, 3.62mmol), PTSA monohydrate (0.76g, 3.98mmol) and trifluoroacetaldehyde hemi-ethanol (2.38mL, 18.11mmol) in EtOH (50mL) was heated to reflux overnight. Further trifluoroacetic aldehyde hemi-ethanol (1.2mL,9.13mmol) was added and the reaction mixture was heated to reflux overnight. Trifluoroacetic aldehyde hemi-ethanol (2mL,15.22mmol) was again added and the reaction mixture was heated to reflux overnight. Finally, another portion of trifluoroacetaldehyde hemi-ethanol (2mL,15.22mmol) PTSA monohydrate (0.76g, 3.98mmol) was added and the reaction heated The mixture was maintained at reflux for 5 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purify the residue by Biotage (SNAP 100g column; MeOH/DCM: 20CV 0/100 to 10/90) to give title compound 14 as a light orange viscous solid (1.519g, 2.76mmol, 76% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.56(d, J =1.4Hz,1H),8.50(d, J =5.5Hz,1H),8.30(s,1H),8.22(d, J =8.0Hz,1H),7.89(dd, J =8.0,2.2Hz,1H),7.31(t, J =9.1Hz,1H),7.11-7.02(m,2H),6.87(dd, J =9.0,1.8Hz,1H),6.62(dd, J =5.3,0.8Hz,1H),5.73-5.64(m,1H),3.78(s,2H),3.77-3.59(m,2H),3.41(t, J =5.7Hz,2H),3.24(s,3H),2.65(t, J =5.7, 2H), 3.15H, NH, 0H, one proton. MS (M/z) 551.6(M + H).

Step 2: (6- (7- (4- (1-ethoxy-2, 2, 2-trifluoroethylamino) -2-fluorophenoxy) -thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamic acid tert-butyl ester (15)

To a solution of 14(1.354g, 2.46mmol) and DMAP (10mmol%) in DCM (45mL) was added Boc₂A solution of O (0.751g,3.44mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 50g, HP-Sil; MeOH/DCM: 20CV 0/100 to 10/90). The desired fractions were collected, concentrated and dried under high vacuum to give the title compound 15 as a colorless viscous foam (1.484g, 2.28mmol, 93% yield). MS (M/z) 651.7(M + H).

And step 3: 2- (1- (4- (2- (5- ((tert-butoxycarbonyl (2-methoxyethyl) amino) methyl) -pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenylamino) -2,2, 2-trifluoroethyl) -malonic acid diethyl ester (16)

To a solution of 15(1.484g,2.28mmol) and diethyl malonate (0.415mL, 2.74mmol) in anhydrous THF (25mL) under nitrogen was added NaH (274mg, 6.84mmol, 60% dispersion in mineral oil) and the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride (× 2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 50g column, MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 16(1.794g, 2.346mmol, 103% yield, crude product) as a pale yellow viscous oil. MS (M/z) 765.6(M + H).

And 4, step 4: 2- (1- (4- (2- (5- ((tert-butoxycarbonyl (2-methoxyethyl) amino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenylamino) -2,2, 2-trifluoroethyl) malonic acid (17)

A solution of 16(1.794g, 2.346mmol) in a mixture of EtOH/1N NaOH (25mL/11.7mL) was stirred at room temperature overnight. The reaction mixture was then concentrated, diluted with water, and the pH adjusted to 3 to 4 by the addition of 1N HCl. The resulting suspension was stirred for 30 minutes and the solid was collected by filtration, washed with water, air dried and dried under high vacuum to give the title compound 17(1.217 g; mixed with acid 18) as a pale yellow loose solid. MS (M/z) 665.5 and 709.5(M + H).

And 5: 3- (4- (2- (5- ((tert-butoxycarbonyl (2-methoxyethyl) amino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenylamino) -4,4, 4-trifluorobutanoic acid (18)

A solution of 17(1.21g, mixture of 17 and 18) in toluene (50mL) was heated to reflux for 1 hour, then cooled to room temperature. The reaction mixture was then concentrated, redissolved in MeOH, and re-concentrated. The residue was triturated with a mixture of ethyl acetate/hexane. The resulting suspension (gel) was collected by filtration, washed with hexanes, air dried and dried under high vacuum to give the title compound 18 as an off-white solid (1.157g, 1.74mmol, quantitative yield). MS (M/z) 665.6(M + H).

Step 6: 4,4, 4-trifluoro-3- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenylamino) -N-phenylbutanamide (19)

Under nitrogen 18(200mg, 0.30mmol), aniline (42mg, 0.45mmol) and DIPEA (0.90mmol) in DMF (4mL) was added HATU reagent (229mg, 0.60 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was successively washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 19 as a colorless viscous oil. MS (M/z) 740.8(M + H).

A solution of this material (0.3mmol) and TFA (5mL) in DCM (25mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted with a minimum amount of MeOH, and co-precipitated by the addition of water. The pH was adjusted to 11 to 12 with 1N NaOH and the suspension was stirred for 30 minutes. The solid was collected by filtration, washed with water, air dried and dried under high vacuum to give the title compound 19 as an ivory solid (161mg, 0.25mmol, 84% yield over 2 steps).¹H NMR(400MHz,DMSO-d₆)δ(ppm)：10.13(s,1H),8.56(d,J=1.4Hz,1H),8.48(d,J=5.3Hz,1H),8.30(s,1H),8.22(d,J=8.0Hz,1H),7.89(dd,J=8.2,2.2Hz,1H),7.57(bd,J=7.4Hz,2H),7.34-7.27(m,2H),7.24(t,J=9.1Hz,1H),7.05(bt,J=7.4Hz,1H),6.87(dd,J=13.5,2.7Hz,1H),6.69(dd,J=8.6,2.2Hz,1H),6.60(d,J=9.4Hz,1H),6.55(d,J=4.7Hz,1H),4.86-4.75(m,1H),3.78(s,2H),3.41(t,J=5.7Hz,2H),3.24(s,3H),2.92(dd,J=15.3,3.7Hz,1H),2.77(dd,J=15.4,9.5Hz,1H),2.65(t,J=5.7Hz,2H),2.34-2.22(m,1H)。MS(m/z):640.5(M+H)。

In analogy to compound 19 (example 11, scheme 10), compounds 20 to 21 (examples 12 to 13) were prepared in two steps from acid 18 and the corresponding amine.

TABLE 2 characterization of Compounds 20 and 21 (examples 12 and 13)

Scheme 11

Example 14

1-cyclopropyl-3- (2, 3-difluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (25)

Step 1: (6- (7- (4-amino-2, 3-difluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamic acid tert-butyl ester (23)

To a stirred solution of 4-amino-2, 3-difluorophenol (1.471g, 10.14mmol) in DMSO (11.5mL) was added potassium tert-butoxide (1.345g, 11.98mmol) at room temperature under nitrogen. After 30 minutes, tert-butyl (6- (7-chlorothieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (22,4.0g,9.22mmol) was added and the reaction mixture was heated at 100 ℃ for 2.5 hours, followed by cooling to room temperature. The reaction mixture was poured into water (90mL) and stirred for 30 minutes. Saturated aqueous sodium chloride solution was added and the mixture was stirred at room temperature for 3 days. The solid was collected by filtration, rinsed with water, air dried and dried under high vacuum. Purification of the crude material by Biotage (40+ M column; ethyl acetate/hexanes: 3CV 50/50, 6CV50/50 to 100% ethyl acetate followed by 8CV 100% ethyl acetate) gave a material which, when triturated with ether, gave the title compound 23 as an off-white solid (1.94g, 3.58mmol, 38% yield). MS (M/z) 543.3(M + H).

Step 2: tert-butyl (6- (7- (4- (3-cyclopropylureido) -2, 3-difluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (24)

To a stirred solution of aniline 23(500mg, 0.92mmol) and DIPEA (0.8mL, 4.61mmol) in THF (18mL) at-25 ℃ under nitrogen was added dropwise a solution of triphosgene (273mg, 0.920mmol) in THF (2 mL). The reaction mixture was stirred at-25 ℃ and cyclopropylamine (0.32mL, 4.61mmol) was added slowly. The reaction mixture was allowed to warm to room temperature for 1.5 hours and stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous ammonium chloride, 1N NaOH and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound 24 as an off-white solid. The crude material was used in the next step without any further purification. MS (M/z) 626.6(M + H).

And step 3: 1-cyclopropyl-3- (2, 3-difluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (25)

A solution of intermediate 24(0.92mmol) and TFA (10mL) in DCM (50mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted with minimal MeOH, and water was added. The pH was adjusted to about pH 12 with 4N NaOH. The fine suspension was sonicated for 15 minutes, collected by filtration, rinsed with water and dried under high vacuum to give the title compound 25 as a pale ivory solid (578mg, 0.9mmol, 98% yield, TFA salt. ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.78-8.61(m,1H),8.57(d,J=1.6Hz,1H),8.53(d,J=5.5Hz,1H),8.33(s,1H),8.23(d,J=8.2Hz,1H),8.02(t,J=7.8Hz,1H),7.90(dd,J=8.1,2.1Hz,1H),7.28(td,J=9.0,2.1Hz,1H),7.16-7.01(m,1H),6.75(d,J=5.3Hz,1H),3.78(d,J=6.1Hz,2H),3.41(t,J=5.7Hz,2H),3.24(s,3H),2.65(q,J=6.0Hz,2H),2.61-2.53(m,1H),2.30-2.21(m,1H),0.72-0.58(m,2H),0.49-0.36(m,2H)。MS(m/z):526.6(M+H)。

Scheme 12

Example 16

1-cyclopropyl-3- (5- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] -pyridin-7-yloxy) pyridin-2-yl) urea (29)

Step 1: tert-butyl (6- (7- (6-aminopyridin-3-yloxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (27)

A stirred suspension of 22(1.0g,2.3mmol), 2-amino-5-hydroxypyridine hydrochloride (405mg, 2.77mmol) and potassium tert-butoxide (817mg, 6.91mmol) in DMSO (20mL) was heated under nitrogen to 95 ℃ for 1 hour, then cooled to room temperature. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was washed successively with water, 0.1N NaOH, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice from Biotage (SNAP50g column; MeOH/DCM: 20CV 0/100 to 10/90; and Siliafilsh 80 g; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 27(634mg, 1.249mmol, 54% yield) as a pale yellow viscous oil. MS (M/z):508.6(M + H).

Step 2: tert-butyl (6- (7- (6- (3-cyclopropylureido) pyridin-3-yloxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (28)

To a stirred solution of aniline 27(634mg,1.249mmol) and pyridine (303. mu.L, 3.746mmol) in DMF (15mL) at 0 ℃ under nitrogen was added phenyl chloroformate (415. mu.L, 3.308mmol) dropwise. The reaction mixture was stirred at 0 ℃ for 2 h, and cyclopropylamine (433 μ L,6.250mmol) was added slowly. The reaction mixture was allowed to warm to room temperature over 30 minutes and heated at 55 ℃ for 5 hours, followed by cooling to room temperature. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated aqueous sodium bicarbonate, 1N NaOH, saturated aqueous ammonium chloride and brine, dried over anhydrous sulfuric acid, filtered and concentrated. The residue was purified by Biotage (Siliaflash 40g column; MeOH/DCM: 20CV 0/100 to 10/90). The desired fractions were collected, concentrated and dried under high vacuum to give the title compound 28 as a light yellow viscous oil (754mg, 1.27mmol, quantitative yield). MS (M/z):591.6(M + H).

And step 3: 1-cyclopropyl-3- (5- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] -pyridin-7-yloxy) pyridin-2-yl) urea (29)

A solution of 28(754mmol, 1.27mmol) and TFA (5mL) in DCM (25mL) was stirred at room temperature for 5.5 h. TFA was removed by co-evaporation with DCM, dissolved in a minimum amount of methanol, diluted with water and adjusted to pH about 13 with 1N NaOH. The resulting viscous suspension was extracted with DCM in the presence of traces of methanol. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue by Biotage (SiliaSep 40g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 1/99 to 10/90) gave a material which, when triturated with MeOH, gave the title compound 29 as a white, loose solid (360mg,0.734mmol, 67% over 2 steps).

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.23(bs,1H),8.56(d, J =1.6Hz,1H),8.51(d, J =5.5Hz,1H),8.31(s,1H),8.27-8.20(m,2H),7.89(dd, J =8.2,2.2Hz,1H),7.79-7.72(m,2H),7.66(bd, J =9.0Hz,1H),6.69(d, J =5.5Hz,1H),3.78(s,2H),3.41(t, J =5.9Hz,2H),3.24(s,3H),2.68-2.57(m,3H),0.74-0.60(m,2H),0.52-0.39(m,2H), one NH being absent. MS (M/z) 491.6(M + H).

Scheme 13

Example 17

N- ((6- (7- (6- (3-cyclopropylureido) pyridin-3-yloxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -2-hydroxy-N- (2-methoxyethyl) acetamide (31)

Step 1: ethyl 2- (((6- (7- (6- (3-cyclopropylureido) pyridin-3-yloxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (2-methoxyethyl) amino) -2-oxoethylacetate (30)

To a stirred solution of compound 29(108mg,0.22mmol), acetoxyacetic acid (73mg, 0.62mmol) and triethylamine (114 μ L,0.82mmol) in DMF (3mL) under nitrogen was added EDC hydrochloride (118mg, 0.62mmol) and HOBT monohydrate (39mg, 0.25mmol) reagents and the reaction mixture was stirred at rt overnight. The reaction was then quenched by addition of water and extracted with ethyl acetate. The organic phase was washed successively with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product 30 was used in the next step without any further purification. MS (M/z) 591.7(M + H).

Step 2: n- ((6- (7- (6- (3-cyclopropylureido) pyridin-3-yloxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -2-hydroxy-N- (2-methoxyethyl) acetamide (31)

To a stirred solution of 30 (from previous step) in MeOH/THF (15/5mL) was added 1N NaOH (2.6 mL). The reaction mixture was stirred at room temperature overnight, concentrated and diluted with water. The resulting suspension was shaken for 15 minutes. The solid was collected by filtration, rinsed with water and air dried. Purification of the residue by Biotage (SiliaSep 25g column; MeOH/DCM: 20CV 0/100 to 10/90) gave a material which, when triturated with methanol, gave the title compound 31(79mg, 0.144mmol, 72% over 2 steps) as a white, loose solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm) mixture of rotamers, 9.23(bs,1H),8.56-8.49(m,2H),8.38-8.20(m,3H),7.84-7.70(m,3H),7.66(bd, J =9.0Hz,1H),6.73-6.67(m,1H),4.82-4.57(m,3H),4.23 and 4.13(2d, J =6.0Hz,2H),3.52-3.39(m,4H),3.23-3.21(2s,3H),2.65-2.57(m,1H),0.74-0.60(m,2H),0.53-0.37(m, 2H). MS (M/z) 549.6(M + H).

Scheme 14

Example 18

2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl phosphate (34)

Step 1: di-tert-butyl phosphate 2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl (33)

To a stirred suspension of compound 32(200mg, 0.35mmol) and tetrazole (74mg, 1.06mmol) in DMF (3mL) under argon was added (t-BuO) in three portions over 5 hours₂PNEt₂(750. mu.L, 2.70 mmol)). The reaction mixture was stirred at room temperature for 2 days, cooled to-25 ℃, and hydrogen peroxide (0.217mL, 3.54mmol, 50% aqueous solution) was slowly added. The reaction mixture was allowed to warm to room temperature for 1 hour and stirred at room temperature for 45 minutes. The reaction mixture was then cooled to-20 ℃ and an aqueous solution of sodium metabisulfite (1.5g in 10mL of water) was slowly added. The reaction mixture was allowed to warm to room temperature for 1 hour and partitioned between water and ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SiliaSep 25g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 33 as a viscous oil, which was used in the next step without any further purification. MS (M/z) 646.5,702.5,758.7(M + H).

Step 2: 2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl phosphate (34)

To a stirred solution of 33 from the previous step in DCM (15mL) was added 4M HCl in 1, 4-bisAlkane (0.44mL,1.75 mmol). Stirring at room temperatureThe reaction mixture (suspension) was stirred for 1 hour. The solid was collected by filtration, washed with DCM and dried under high vacuum. The residue was suspended in MeOH, concentrated and triturated with a minimum of methanol/water to give the title compound 34 as an off-white loose solid (136mg, 0.21mmol, over 3 steps 60%).¹H NMR(400MHz,DMSO-d₆) δ (ppm) mixture of rotamers, 8.71(s,1H),8.58-8.48(m,2H),8.37 and 8.33(2s,1H),8.29 and 8.24(2d, J =8.2Hz,1H),7.86-7.77(m,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.1Hz,1H),7.20(bd, J =9.0Hz,1H),6.64(d, J =5.3Hz,1H),6.57(d, J =2.5Hz,1H),4.74-4.50(m,4H),3.47(bs,4H),3.24 and 3.21(2s,3H),2.59-2.51(m,1H), 0.73-0.58H, 0.36H), 0.36H (m, 0H). MS (M/z) 646.7(M + H).

Compounds 35 to 38 (examples 19 to 22) were prepared in one step by reacting the corresponding secondary amine precursors 25 (scheme 11), 179 (scheme 43), 29 (scheme 12) and 288 (scheme 64) with ethyl isocyanate.

TABLE 3 characterization of Compounds 35 to 38 (examples 19 to 22)

Compounds 39 through example 44 (examples 23 through 28) were prepared in one step by reacting the corresponding amine precursors 20 (table 2), 29 (scheme 12), 288 (scheme 64), 13 (scheme 9), 98 (scheme 25), and 108 (scheme 28) with acetic anhydride.

TABLE 4 characterization of Compounds 39 to 44 (examples 23 to 28)

In analogy to compound 31 (example 17, scheme 13), compounds 45 to 46 (examples 29 to 30) were prepared in two steps from the corresponding secondary amine precursors 179 (scheme 43) and 288 (scheme 64) and acetoxyacetic acid.

TABLE 5 characterization of Compounds 45 to 46 (examples 29 to 30)

Scheme 15

Examples 31 and 32

4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (48) and 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (piperazin-1-ylmethyl) pyridin-2-yl) thieno [3,2-b ] -pyridin-7-yloxy) phenyl) urea (49)

Step 1: 4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (48)

Sonication of 1-cyclopropyl-3- (3-fluoro-4- (2- (5-formylpyridin-2-yl) thieno [3, 2-b) in nitrogen at room temperature ]Pyridin-7-yloxy) phenyl) urea (47,3g,5.90mmol, acetate), L-boc-piperazine (1.65g, 8.85mmol) and a suspension of acetic acid (675. mu.L, 11.80mmol) in NMP (50mL) for 3 hours to obtain a solution, followed by the addition of NaBH (OAc)₃(3.95g, 17.70 mmol). The reaction was stirred at room temperatureThe mixture was quenched by addition of water for 3 days. The pH was adjusted to 12 to 13 with 4N NaOH, and the suspension was stirred and sonicated for 1 hour. The solid was collected by filtration, rinsed with water and air dried. The residue was purified twice by Biotage (SNAP 50g KP-Sil column; MeOH/DCM: 20CV 1/99 to 10/90). The desired fractions were collected, concentrated and co-precipitated with ethyl acetate with traces of methanol/hexanes to give the title compound 48 as a white, loose solid (1.511g, 2.44mmol, 41% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.71(s,1H),8.56(bd, J =2.0Hz,1H),8.52(d, J =5.5Hz,1H),8.33(s,1H),8.25(d, J =8.2Hz,1H),7.87(dd, J =8.1,2.1Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.1Hz,1H),7.20(bdd, J =8.8,1.2Hz,1H),6.65(d, J =5.3Hz,1H),6.57(bd, J =2.5Hz,1H),3.57(s,2H),4H is hidden by the water peak, 2.59-2.51(m,1H),2.42-2.27(m,4H), 1H (m, 0.58H), 0.36H, 0.58-0.36H), 0.58-0.36H (m, 0.36H). MS (M/z) 619.4(M + H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (piperazin-1-ylmethyl) pyridin-2-yl) thieno [3,2-b ] -pyridin-7-yloxy) phenyl) urea (49)

A solution of 48(1.456g, 2.35mmol) and TFA (15mL) in DCM (50mL) was stirred at room temperature for 5 h. TFA was removed by co-evaporation with DCM, the residue was diluted with water, and the pH was adjusted to about 12 to 13 with 1N NaOH. The resulting suspension was sonicated for 15 minutes. The solid was collected by filtration, washed with water and dried under high vacuum to give the title compound 49(1.227g, trace TFA) as an off-white, loose solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.76(bs,1H),8.54(d, J =1.4Hz,1H),8.52(d, J =5.5Hz,1H),8.32(s,1H),8.24(d, J =8.2Hz,1H),7.85(dd, J =8.1,2.1Hz,1H),7.73(dd, J =13.5,2.3Hz,1H),7.38(t, J =9.1Hz,1H),7.20(bd, J =10.2Hz,1H),6.64(d, J =5.5Hz,1H),6.62(bs,1H),3.58-3.48(m,2H),2.73-2.64(m,4H),2.59-2.52(m,1H),2.38-2.25(m, 69H), 0.62-0.40H), 0.46-0.40H, 0.46H, one deletion. MS (M/z) 519.6(M + H).

In analogy to compound 48 (example 31, scheme 15), compounds 50 to 60 (examples 33 to 43) were prepared in one step by reductive amination of compound 47 with the appropriate amine.

TABLE 6 characterization of Compounds 50 to 60 (examples 33 to 43)

Scheme 16

Example 44

2- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) acetic acid (61)

To a stirred solution of ester 60(85mg, 0.14mmol) in a mixture of MeOH/THF (5/5mL) was added 1N NaOH (2 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated, diluted with a minimal amount of water, quenched with 1N HCl to neutral pH, and concentrated. From Biotage (SNAP 10g column; containingPurification of the residue with 20CV 5/95 to 30/70 followed by 10CV100% MeOH in 2% ammonium hydroxide in MeOH/DCM gave the title compound 44(72mg,0.118mmol, 84% yield) as an ivory solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.95(s,1H),8.55(bd, J =1.8Hz,1H),8.52(d, J =5.5Hz,1H),8.33(s,1H),8.25(d, J =8.0Hz,1H),7.86(dd, J =8.1,2.0Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.1Hz,1H),7.40-7.00(m,1H),7.20(bd, J =9.0Hz,1H),6.72(bd, J =2.7Hz,1H),6.64(d, J =5.3Hz,1H),3.57(s,2H),2.69(bs,4H),2.59-2.51(m,1H),2.48(bs, 0.48H), 0.58H), hidden water peaks are present. MS (M/z) 577.6(M + H).

Compounds 62 to 63 (examples 45 to 46) were prepared in one step in analogy to compound 61 (example 44, scheme 16) by hydrolysis of esters 58 and 59 with sodium hydroxide, final purification by preparative HPLC.

TABLE 7 characterization of Compounds 62 and 63 (examples 45 and 46)

Scheme 17

Example 47

1- (4- (2- (5- ((4-acetylpiperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (66)

Step 1: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (hydroxymethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (64)

To a suspension of 47(5.60g, 12.49mmol) in a mixture of DCM (200mL)/MeOH (20mL) in a 1L round-bottom flask was added sodium triacetoxyborohydride (5.29g, 24.97 mmol). The reaction mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (5.29g, 24.97mmol) was added and the mixture was stirred at room temperature for 16 h. Followed by the addition of NaBH₄(2g, 52.9mmol) to the reaction mixture and stirred at room temperature for 24 h. Finally, NaBH is added again₄(2g, 52.9mmol), and the reaction mixture was heated to reflux for 5 hours, then cooled to room temperature, concentrated, quenched with 10% HCl (100mL), and saturated NaHCO₃The aqueous solution (200mL) was slowly neutralized to give a gray precipitate. The suspension was shaken for 15 min and the solid was collected by filtration, washed with water (2 × 25mL), and dried under high vacuum to give the title compound 64 as a light grey solid (5.34g, 11.85mmol, 94% yield). MS (M/z) 451.5(M + H). This material was used in the next step without additional purification.

Step 2: 1- (4- (2- (5- (chloromethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (65)

To a 500mL round bottom flask containing 64(5.34g, 11.85mmol) was slowly added SOCl₂(30mL, 411 mmol). The yellow solution was stirred at room temperature for 2 hours and cooled to 0 ℃. The reaction mixture was quenched by the addition of ice (150g) and water (100mL) and the yellow suspension was shaken at room temperature for 1 hour. The solid was collected by filtration, rinsed with water and dried under high vacuum. Trituration of the crude material with ethyl acetate afforded the title compound 65(5.55g, about 40% purity by HPLC, contaminated with the nor-cyclopropyl by-product) as a yellow solid. MS (M/z) 469.1(M + H). This material was used in the next step without additional purification.

And step 3: 1- (4- (2- (5- ((4-acetylpiperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (66)

Stirred 65(1g, 2.13mmol, 40% fromPrevious step), a solution of 1-acetyl-piperazine (328mg,2.56mmol) and DIPEA (1.12mL, 6.40mmol) in DMSO (20mL) overnight, followed by a return to room temperature. The reaction mixture was then quenched by the addition of water and 1N NaOH. The resulting suspension was collected by filtration, rinsed with water and air dried. Purification of the crude material twice by Biotage (SNAP 50g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV0/100 to 10/90 followed by 10CV10/90 to 15/8; silia flash 120g column, MeOH/DCM containing 2% ammonium hydroxide: via 20CV0/100 to 10/90 followed by 10CV10/90 to 20/80) yielded a material which when triturated with MeOH gave the title compound 66 as an off-white solid (79mg, 0.14mmol, 6% yield). ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.71(s,1H),8.57(d,J=1.8Hz,1H),8.52(d,J=5.5Hz,1H),8.34(s,1H),8.25(d,J=8.0Hz,1H),7.88(dd,J=8.1,2.1Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.0Hz,1H),7.20(bd,J=9.0Hz,1H),6.65(d,J=5.5Hz,1H),6.57(bd,J=2.3Hz,1H),3.59(s,2H),3.48-3.40(m,4H),2.59-2.51(m,1H),2.44-2.31(m,4H),1.98(s,3H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS(m/z):561.5(M+H)。

Compounds 67 to 69 (examples 48 to 50) were prepared in one step in analogy to compound 66 (example 47, scheme 17) by reacting the appropriate amine with chloride 65.

TABLE 8 characterization of Compounds 67 to 69 (examples 48 to 50)

Scheme 18

Example 51

3- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) propionic acid (70)

To a stirred solution of 68(100mg, 0.16mmol) in a mixture of MeOH/THF (5/5mL) was added 1N NaOH (2.42 mL). The reaction mixture was heated at 60 ℃ for 40 minutes, then returned to room temperature. The reaction mixture was concentrated, diluted with water, neutralized with 1N HCl until a precipitate-gel (pH about 4 to 5) was formed and sonicated for 1 hour. The solid was collected by filtration, rinsed with water and air dried. The crude solid was ground and sonicated in a minimal amount of methanol. The solid was collected by filtration, rinsed with methanol and dried under high vacuum to give the desired product as an off-white solid (66mg, 0.11mmol, 69% yield).¹HNMR(400MHz,DMSO-d₆) δ (ppm) one carboxylic acid OH,8.72(s,1H),8.54(bd, J =1.4Hz,1H),8.52(d, J =5.5Hz,1H),8.33(s,1H),8.24(d, J =8.0Hz,1H),7.85(dd, J =8.2,2.2Hz,1H),7.73(dd, J =13.5,2.5Hz,1H),7.38(t, J =9.0Hz,1H),7.20(dd, J =9.0,1.2Hz,1H),6.64(dd, J =5.5,0.8Hz,1H),6.58(bd, J =2.5Hz,1H),3.58(s,2H),2.65-2.30(m,13H),0.72-0.58(m, 0.58H), 0.36H (m-36H). MS (M/z) 591.5(M + H).

Scheme 19

Example 52

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-oxopiperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (72)

Step 1: 4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -3-oxopiperazine-1-carboxylic acid tert-butyl ester (71)

To a stirred suspension of NaH (426mg, 60% dispersion in mineral oil, 10.66mmol) in DMF (15mL) under nitrogen at 0 ℃ was added a solution of tert-butyl 3-oxopiperazine-1-carboxylate (512mg,2.56mmol) in DMF (5 mL). After 15 min, a solution of chloride 65(1g, 2.13mmol, 40%, scheme 17) in DMF (5mL) was added. The reaction mixture was stirred at 0 ℃ for 1.5 h and quenched by addition of 1N HCl and water. The resulting suspension was filtered and the solid material was washed with water and air dried. The crude product was suspended in MeOH and the suspension was stirred for 1 hour, filtered and the filter cake was rinsed with MeOH. The mother liquor and washings were collected, concentrated and the residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 71 as an off-white viscous solid (60mg, 0.095mmol, 4% yield). MS (M/z) 633.6(M + H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-oxopiperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (72)

A solution of 71(60mmol, 0.095mmol) and TFA (5mL) in DCM (20mL) was stirred at room temperature for 5 h. TFA was removed by co-evaporation with DCM and MeOH, diluted with water, and adjusted to pH about 12 with 1N NaOH. The resulting gel was extracted with DCM containing trace MeOH. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 10g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 0/100 to 10/90, 10CV 10/90 to 20/80, followed by 5CV 20/80) to give the title compound 72(35mg, 0.066mmol, 69% yield, trace TFA) as a white viscous solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.72(s,1H),8.55(d, J =1.8Hz,1H),8.52(d, J =5.3Hz,1H),8.35(s,1H),8.26(d, J =8.0Hz,1H),7.83(dd, J =8.2,2.2Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.1Hz,1H),7.20(dd, J =8.9,1.5Hz,1H),6.65(dd, J =5.3,0.6Hz,1H),6.58(bd, J =2.7Hz,1H),4.59(s,2H),3.37(s,2H),3.28(t, J =5.5, 2H), 2H = 95(t = 2.95, 0.5H), 2.5H, 1H, 0.59 (t, 2H), 2H-50H, 0.5H, 5H, 1H, 0.5H, 1H, 5H, 1H, 0.5H, 1H, 5H, 1H, 5H, 1H, 0.5H, 1H, 0.5. MS (M/z) 533.4(M + H).

Compound 73 (example 53) was prepared in one step in analogy to compound 72 (example 52, scheme 19) by subjecting compound 69 (example 50) to removal of the Boc protecting group.

TABLE 9 characterization of Compound 73 (example 53)

Scheme 20

Example 55

(S) -1- (4- (2- (5- ((4- (2-amino-3-methylbutyryl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (76)

Step 1: (S) -1- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) -3-methyl-1-oxobut-2-ylcarbamic acid tert-butyl ester (75)

To a stirred solution of compound 49(150mg, 0.289mmol, scheme 15), Boc-L-valine (94mg,0.43mmol) and triethylamine (120. mu.L, 0.87mmol) in DMF (5mL) under nitrogen was added HOBT monohydrate (49mg, 0.32mmol) and EDC hydrochloride (139mg, 0.72mmol) reagent and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was successively washed with a saturated aqueous ammonium chloride solution, a saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (Snap 25 g; MeOH/DCM: 20CV 1/99 to 10/90) to give the title compound 75(171mg, 0.238mmol, 82% yield) as a colorless viscous film. MS (M/z) 718.4(M + H).

Step 2: (S) -1- (4- (2- (5- ((4- (2-amino-3-methylbutyryl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (76)

A solution of 75(171mmol, 0.238mmol) and TFA (2mL) in DCM (10mL) was stirred at room temperature for 2 h. TFA was removed by co-evaporation with DCM, using minimal waterDiluted and the pH adjusted to about 10 with saturated aqueous sodium bicarbonate and finally a few drops of 1N NaOH. The resulting suspension was sonicated for 15 minutes. The solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was then purified by Biotage (SiliaFlash 12g column; MeOH/DCM containing 2% ammonium hydroxide; 20CV 5/95 to 15/85 followed by 10CV 15/85 to 20/80) to give the title compound 76(110mg, 0.178mmol, 74% yield) as a white viscous solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.75(s,1H),8.57(d, J =1.6Hz,1H),8.52(d, J =5.3Hz,1H),8.34(s,1H),8.25(d, J =8.2Hz,1H),7.88(dd, J =8.1,2.1Hz,1H),7.73(dd, J =13.5,2.5Hz,1H),7.38(t, J =9.0Hz,1H),7.21(bd, J =8.8Hz,1H),6.65(d, J =5.3Hz,1H),6.61(bd, J =2.5Hz,1H),3.59(s,2H),3.54-3.42(m,5H),2.59-2.51(m,1H), 2.48-2.28H (m = 28.4H), 2.59 (s,2H),3.54-3.42(m,5H),2.59-2.51(m,1H), 2.48-2.8H), 0.78 (m = 0.78H), 0.7.7.7.78H, 0.8H, 1H). MS (M/z) 519.6 and 618.7(M + H).

Compound 77 (example 56) was prepared in two steps in analogy to compound 76 (example 55, scheme 20) starting from piperazine 49.

TABLE 10 characterization of Compound 77 (example 56)

Scheme 21

Example 57

(S) -2-amino-3-methylbutyric acid 2- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethyl ester (79)

Step 1: (S) -2- (tert-Butoxycarbonylamino) -3-methylbutyric acid 2- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethyl ester (78)

To a stirred solution of compound 55 (example 38, table 6) (100mg,0.178mmol), Boc-L-Val-OH (58mg,0.27mmol) and DMAP (4.4mg,0.036mmol) in DMF (4mL) was added DCC reagent (73mg,0.35mmol) under nitrogen and the reaction mixture was stirred at room temperature overnight. Boc-L-Val-OH (60mg,0.28mmol), DCC (95mg,0.46mmol) and DMF (2mL) were added, respectively. The reaction mixture was stirred overnight. Boc-L-Val-OH (60mg,0.28mmol), DCC (95mg,0.46mmol) and DMF (1mL) were added again. The reaction mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was then dried over saturated aqueous sodium bicarbonate, water, and brine, anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM:1/99 to 10/90 over 20CV) to give the title compound 77(115mg,0.15mmol,85% yield) as a white sticky solid. MS (M/z) 762.4(M + H).

Step 2: (S) -2- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) ethyl 2-amino-3-methylbutyrate (79)

A solution of 78(115mg.0.15mmol) and TFA (2mL) in DCM (10mL) was stirred at room temperature for 3 h. TFA was removed by co-evaporation with DCM, washed with a small amount of water, and the pH was adjusted to about 9 with saturated aqueous sodium bicarbonate (and finally a few drops of 1N NaOH). The aqueous solution was extracted with DCM containing traces of methanol. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 10g column; 2% ammonium hydroxide in MeOH/DCM: 5/95-20/80 by 20CV) to give compound 79 as a white paste (36mg,0.05mmol,36% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.54(d,J=1.4Hz,1H),8.52(d,J=5.3Hz,1H),8.32(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.4,2.4Hz,1H),7.38(t,J=9.1Hz,1H),7.20(bd,J=10.4Hz,1H),6.64(d,J=5.3Hz,1H),6.58(bd,J=2.2Hz,1H),4.26-4.18(m,1H),4.11-4.03(m,1H),3.54(s,2H),3.10(d,J=5.3Hz,1H),2.59-2.30(m,11H),1.88-1.78(m,1H),0.87(d,J=6.8Hz,3H),0.83(d,J=6.7Hz,3H),0.69-0.62(m,2H),0.46-0.40(m,2H), absence of NH₂)。MS(m/z):662.7(M+H)。

Scheme 22

Example 59

3- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) -N-methylpropanamide (81)

A stirred suspension of compound 49(100mg,0.19mmol, scheme 15) and N-methacrylamide (1.5mL) in acetonitrile (20mL) was heated to 110 ℃ overnight in a sealed flask. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified twice by Biotage (SNAP 25g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV 5/95 to 15/85; and silia flash 12g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV 5/95 to 15/85, followed by 5CV 15/85) to give the title compound 81(50mg, 0.08mmol, 43% yield) as a white viscous solid. ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.54(bd,J=1.4Hz,1H),8.52(d,J=5.5Hz,1H),8.33(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.1,2.1Hz,1H),7.85-7.77(m,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.1Hz,1H),7.20(bd,J=8.9Hz,1H),6.64(bd,J=5.4Hz,1H),6.57(bd,J=2.5Hz,1H),3.54(s,2H),2.59-2.51(m,6H),2.47-2.11(m,10H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS 604.4(m/z):(M+H)。

Compounds 82-83 (examples 60-61) are prepared in one step in analogy to compound 81 (example 59, scheme 22) by reacting compound 49 (example 32) with the appropriate Michael Acceptor (Michael Acceptor).

TABLE 12 characterization of Compounds 82 to 83 (examples 60 to 61)

Example 62

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2,2, 2-trifluoroethyl) piperazin-1-yl) methyl) -pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (84)

A solution of 49(200mg, 0.39mmol), 2,2, 2-trifluoroethyl triflate (134mg, 0.58mmol) and DIPEA (0.2mL, 1.16mmol) in THF (15mL) was stirred in a sealed flask and heated at 85 ℃ for 4 h, then returned to room temperature (scheme 22). The reaction mixture was concentrated and diluted with a minimum amount of aqueous methanol. The pH was adjusted to 10 to 11 with saturated aqueous sodium bicarbonate solution and finally with a few drops of 1N NaOH. The suspension was shaken for 15 minutes and the solid was collected by filtration, rinsed with water and dried under high vacuum. Purify the crude by Biotage (SiliaFlash 25g column; MeOH/DCM containing 2% ammonium hydroxide; 20CV 1/99 to 10/90) to give the title compound 84(26mg, 0.043mmol, 11% yield) as an off-white solid. ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.54(bd,J=1.4Hz,1H),8.52(d,J=5.5Hz,1H),8.33(s,1H),8.24(d,J=8.2Hz,1H),7.85(dd,J=8.1,2.1Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.0Hz,1H),7.20(dd,J=9.0,1.4Hz,1H),6.64(dd,J=5.5,0.8Hz,1H),6.58(bd,J=2.5Hz,1H),3.55(s,2H),3.15(q,J=10.2Hz,2H),2.69-2.51(m,5H),2.48-2.35(m,4H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS 601.6(m/z):(M+H)。

Scheme 23

Example 63

N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -2-methoxy-N- (2-methoxyethyl) acetamide (85)

Under nitrogenNext, DIPEA (110. mu.l, 0.632mmol) was added to a solution of 1(107mg, 0.211mmol, scheme 1) and methoxyacetyl chloride (38.5. mu.l, 0.422mmol) in THF (4.2mL) and the mixture was stirred at room temperature overnight. Methanol was added and the reaction mixture was concentrated. The residue was purified by Biotage (SNAP 50g column; MeOH/DCM: 20CV 0/100 to 20/80) to give the desired product as an off-white solid (39mg, 0.067mmol, 31% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) mixture of rotamers, 8.71(s,1H),8.54-8.49(m,2H),8.36 and 8.33(2s,1H),8.29 and 8.24(2d, J =8.4Hz,1H),7.82-7.69(m,2H),7.38(t, J =8.8Hz,1H),7.20(d, J =8.0Hz,1H),6.67-6.62(m,1H),6.59-6.55(m,1H),4.66 and 4.61(2s,2H),4.24 and 4.14(2s,2H),3.50-3.18(m,10H),2.60-2.50(m,1H),0.69-0.62(m,2H),0.46-0.40(m, 2H). MS (M/z) 580.6(M + H).

Compound 86 (example 64) was prepared in one step in analogy to compound 85 (example 63, scheme 23) by reacting 1 with the corresponding formyl chloride reagent.

TABLE 12a characterization of Compound 86 (example 64)

Example 65

(S) -2-amino-N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) -3, 3-dimethylbutanamide (88)

Step 1: (S) -1- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (2-methoxyethyl) amino) -3, 3-dimethyl-1-oxobutan-2-ylcarbamic acid tert-butyl ester (87)

To a stirred solution of 1(100mg, 0.197mmol, scheme 1) and Boc-L-TLE-OH (51mg, 0.22mmol) in DMF (10mL) at room temperature under nitrogen was added DIPEA (0.120mL, 0.69mmol) followed by HATU (225mg, 0.59 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added, washed with water, saturated ammonium chloride and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (Snap 25 g; MeOH/DCM: 20CV 0/100 to 20/80) to afford the title compound 87 which was used directly in the next step. The yield was assumed to be quantitative.

Step 2: (S) -2-amino-N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) -3, 3-dimethylbutanamide (88)

To a solution of 87(142mg,0.197mmol) in DCM (10mL) was added TFA (3mL, 38.9mmol) and water (0.2 mL). The reaction mixture was stirred at room temperature overnight, concentrated, diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate, 1N NaOH and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purify the crude by Biotage (SNAP 50g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 0/100 to 40/60) to give the title compound 88 as an off-white solid (39mg, 0.064mmol, 32% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) mixture of rotamers, 8.75(s,1H),8.59-8.50(m,2H),8.37 and 8.32(2s,1H),8.28 and 8.24(2d, J =8.0Hz,1H),7.85 and 7.80(2dd, J =8.0 and 2.0Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.2Hz,1H),7.20(d, J =8.8Hz,1H),6.66-6.57(m,2H),5.18-4.40(m,2H),3.88-2.95(m,8H),2.59-2.51(m,1H),0.93 and 0.91(2s,9H),0.68-0.62(m,2H), 0.45-2H), primary amine deletion. MS (M/z) 621.7(M + H).

In analogy to compound 88 (example 65, scheme 23), compounds 89 to 91 (examples 66 to 68) were prepared in one step by coupling 1 with the appropriate formic acid. Compounds 92 (example 69) and 92-a (example 69-a) were prepared in two steps in analogy to compound 88 (example 65, scheme 23) starting from 2-amino-N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) acetamide.

TABLE 13 Compounds 89 to 92 (examples 66 to 69)

Scheme 24

Example 70

(S) -2- (2-Aminoacetamido) -N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) -thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2-methoxyethyl) -3-methylbutanamide (93)

To a solution of 91(270mg, 0.338mmol, table 13) in MeOH (20mL) was added palladium black (180mg, 1.692mmol) and the solution was degassed by bubbling nitrogen for 10 min. The mixture was placed under hydrogen (balloon), stirred overnight under hydrogen, then nitrogen and pyridine were placed under bubbling nitrogen into the solution. The reaction mixture was filtered through a pad of celite, rinsed with methanol and concentrated. The residue was purified from Gilson (Phenomenex, Luna,15 μ, C18(2)100A,250 × 50.00mm,15 μm, MeOH/water with 0.05% formic acid: 20/80 to 95/5 over 60 minutes, flow rate =30mL/min), followed by (Phenomenex, Luna,15 μ, C18(2)100A,250 × 50.00mm,15 μm, MeOH/water with 0.05% formic acid (30 mL/min): 20/80 to 95/05 over 60 minutes) to give the title compound 93(24mg, 0.037mmol, 10% yield, hydrated formate salt) as a beige solid.¹HNMR(400MHz,DMSO-d₆) δ (ppm) mixture of rotamers, 9.10-8.97(m,1H),8.60-8.47(m,2H),8.38-8.05(m,4H),7.88-7.70(m,2H),7.37(d, J =9.2Hz,1H),7.21(d, J =8.8Hz,1H),6.92-6.81(m,1H),6.67-6.62(m,1H),5.06-4.50(m,3H),3.90-2.80(m,9H),2.59-2.50(m,1H),2.29-2.19(m,2H),2.10-1.95(m,1H),0.94-0.78(m,6H),0.67-0.61(m,2H), 0.45-0.45 .39(m,2H)。MS(m/z):664.8(M+H)。

Scheme 26

Example 72

1- (3-fluoro-4- (2- (5- ((2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3- (3- (methylsulfonyl) phenyl) urea (105)

Step 1: (6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methanol (101)

To a stirred suspension of 94(3g, 7.59mmol) in DCM (50mL) at room temperature under nitrogen was added NaBH (OAc) in one portion₃(3.39g, 15.99 mmol). The reaction mixture was stirred at room temperature overnight and quenched by addition of 10% HCl and suspended in a mixture of water and DCM. The solid was collected by filtration, washed with water, DCM and dried under high vacuum to give the title compound 101(2.26g, 5.69mmol, 75% yield) as a yellow mustard solid which was used in the next step without further purification. MS (M/z):398.1(M + H).

Step 2: 2- (5- (chloromethyl) pyridin-2-yl) -7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] -pyridine (102)

A solution of 101(2.23g, 5.61mmol) in thionyl chloride (8.14mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was cooled to 0 ℃ and ice was added. The resulting suspension was stirred for 1 hour, the solid was collected by filtration, washed with water and dried under high vacuum to give the title compound 102(2.06g, 4.96mmol, 88% yield) as a yellow loose solid, which was used in the next step without any further purification. MS (M/z) 416.4 and 418.4(M + H).

And step 3: 1- ((6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -pyrrolidin-2-one (103)

A mixture of 102(500mg, 1.202mmol), ethyl 4-aminobutyrate (403mg, 2.405mmol) and DIPEA (0.630mL, 3.61mmol) in acetonitrile (12mL) was heated under nitrogen to reflux for 3 days, followed by cooling to room temperature. The reaction mixture was then concentrated. The crude product was purified by Biotage (25M column; MeOH/DCM; 20CV 0/100 to 20/80). The desired fractions were collected, concentrated and dried under high vacuum to give the title compound 103(270mg, 0.58mmol, 48% yield). MS (M/z) 465.5(M + H).

And 4, step 4: 1- ((6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) pyrrolidin-2-one (104)

A suspension of 103(270mg, 0.581mmol), iron (649mg, 11.63mmol) and ammonium chloride (187mg, 3.49mmol) in MeOH (10mL) and water (1mL) was heated to reflux for 3 hours, then cooled to room temperature. The mixture was then filtered through celite, and the filter cake was rinsed with methanol. The mother liquor was concentrated and partitioned with saturated NaHCO₃Between aqueous solution and ethyl acetate. The aqueous phase was extracted 3 times with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, redissolved in ethyl acetate, washed with 1N NaOH, dried over anhydrous sodium sulfate, filtered and concentrated. Purify the crude by Biotage (SNAP 50g column; MeOH/DCM: 20CV 0/100 to 20/80) to give the title compound 104 as a beige solid (220mg, 0.50mmol, 87% yield). MS (M/z):435.5(M + H).

And 5: 1- (3-fluoro-4- (2- (5- ((2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3- (3- (methylsulfonyl) phenyl) urea (105)

To a solution of 104(50mg, 0.115mmol) in THF (2.3mL) at-78 ℃ under nitrogen was added DIPEA (201. mu.L, 1.151mmol) followed by 4-nitrophenyl chloroformate (116mg, 0.575 mmol). The reaction mixture was held at-78 ℃ for 1 hour. 3- (Methanesulfonyl) aniline hydrochloride (143mg, 0.690mmol) was added at-78 ℃ and the reaction mixture was slowly warmed to room temperature. The reaction mixture was then quenched by addition of methanol, concentrated, dissolved in ethyl acetate, and successively with NH₄Cl and NaHCO₃Washed, dried over anhydrous sodium sulfate, filtered and concentrated. Purify the crude by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 20/80) to give the title compound 105 as a beige solid (14.8mg, 0.023mmol, 20% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.28(s,1H),9.21(s,1H),8.54(d, J =5.6Hz,1H),8.53(d, J =2.4Hz,1H),8.36(s,1H),8.27(d, J =8.4Hz,1H),8.18(t, J =2.0Hz,1H),7.82-7.74(m,2H),7.70(dt, J =8.0,1.6Hz,1H),7.59(t, J =8.0Hz,1H),7.55(dt, J =8.0,1.6Hz,1H),7.47(t, J =8.8Hz,1H),7.31(d, J =8.8Hz,1H),6.69(d, J =5.2Hz,1H),4.46(s,2H), 3.40H, 3.31H), 3.95 (t, 3.8H, 3.95H), 3.95 (t, 3.0H), 3.95H, 3.6H, 3H, five peaks. MS (M/z) 632.5(M + H).

Scheme 27

Example 73

3- (3- (3-fluoro-4- (2- (5- ((2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) ureido) benzamide (106)

To a solution of 104(83mg, 0.191mmol, scheme 26) in THF (19mL) at-10 ℃ was added DIPEA (334. mu.l, 1.910mmol) and triphosgene (56.7mg, 0.191 mmol). The reaction mixture was stirred at-10 ℃ for 90 minutes, followed by the addition of 3-aminobenzoic acid amine (104mg, 0.764 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 3 hours, quenched with MeOH and concentrated. The residue was suspended in 2mL MeOH, and saturated aqueous ammonium chloride was added, stirred for 30 minutes, collected by filtration and dried. Purification of the crude material by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 30/70) afforded a material which was further purified by Gilson (Phenomenex, Luna, 15. mu.g, C18(2)100A,250X50.00mm, 15. mu.m, 0.05% formic acid in MeOH/water (30mL/min): 30/70 to 95/5) over 60 min as a solid to afford the title compound 106(8.7mg, 0.015mmol, 7% yield, formate salt) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.34(s,1H),11.06(s,1H),8.55-8.50(m,2H),8.41(s,4H),8.35(s,1H),8.26(d, J =8.0Hz,1H),8.05(t, J =2.0Hz,1H),7.90-7.77(m,3H),7.71-7.67(m,1H),7.44-7.38(m,3H),7.34-7.27(m,2H),6.68(dd, J =5.2,0.8Hz,1H),4.46(s,2H),3.31(t, J =7.2Hz,2H),2.31(t, J =8.0Hz,2H),1.95 (quintuple peak, J =8.0Hz, 2H). MS (M/z) 597.5(M + H).

Scheme 28

Example 74

(S) -1- (4- (2- (5- ((3-amino-2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (108)

Step 1: (S) -1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] -pyridin-2-yl) pyridin-3-yl) methyl) -2-oxopyrrolidin-3-ylcarbamic acid tert-butyl ester (107)

To a suspension of 47(230mg, 0.51mmol, scheme 15) in DCM (5.1mL) was added (S) -4-amino-2- (tert-butoxycarbonylamino) butyric acid (224mg,1.03mmol) and acetic acid (59. mu.l, 1.03 mmol). After stirring at room temperature for 20 minutes, NaBH (OAc) was added₃(326mg, 1.54 mmol). The reaction mixture was stirred for 16 hours, quenched by addition of 1N NaOH, and concentrated. The solid was collected by filtration and purified by Biotage (SNAP 50g column; MeOH/DCM: 20CV 0/100 to 20/80) to give the title compound 107(120mg, 0.19mmol, 37% yield). MS (M/z) 633.7(M + H).

Step 2: (S) -1- (4- (2- (5- ((3-amino-2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea

To a solution of 107(120mg, 0.19mmol) in DCM (20mL) was added water (0.5mL) and TFA (4mL, 51.9 mmol). The reaction mixture was stirred at room temperature for 6 hours, concentrated, diluted with ethyl acetate and washed with 1N NaOH. Collecting organic matter The phases were extracted and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were concentrated (a large amount of insoluble material remained on the separatory funnel wall, which could be dissolved in MeOH and combined with the organic layer). Adding 1N NaOH solution; the suspension was stirred for 30 minutes and the solid was collected by filtration. Purify the crude by Biotage (SNAP 50g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV0/100 to 40/60) to give the title compound 108 as an off white solid (77mg,0.14mmol, 76% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.77(s,1H),8.55-8.51(m,2H),8.36(s,1H),8.27(d,J=8.0Hz,1H),7.81(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.2Hz,1H),7.20(d,J=8.8Hz,1H),6.65(d,J=5.6Hz,1H),6.60(d,J=2.4Hz,1H),4.52(d,J=15.2Hz,1H),4.45(d,J=15.2Hz,1H),4.15-3.65(m,2H),3.58(t,J=8.8Hz,1H),3.30-3.14(m,2H),2.59-2.52(m,1H),2.34-2.23(m,1H),1.77-1.65(m,1H),0.68-0.62(m,2H),0.45-0.37(m,2H)。MS(m/z):533.6(M+H)。

In analogy to compound 108 (example 74, scheme 28), compounds 109 to 111 (examples 75 to 77) were prepared in two steps from reductive amination 47 with an appropriately substituted γ -amino acid.

TABLE 14 characterization of Compounds 109 to 111 (examples 75 to 77)

Scheme 29

Example 78:

1-cyclopropyl-3- (3-fluoro-4- (2- (4- ((2-methoxyethylamino) methyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (113)

Step 1 tert-butyl 4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl (2-methoxyethyl) carbamate (112)

To a solution of 111-A (760mg, 1.451mmol) in THF (15mL) was added THF (5mL) containing TEA (0.607mL,4.35mmol) and triphosgene (431mg, 1.451mmol), and the mixture was stirred at room temperature for 1 hour. Cyclopropylamine (166mg, 2.90mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then partitioned between DCM and saturated NaHCO ₃Between the solutions. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate) to give the title compound 112(560mg, 64% yield) as a white solid. MS (M/z) =607.2(M + H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (4- ((2-methoxyethylamino) methyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (113)

To a solution of 112(560mg, 0.923mmol) in DCM (10mL) was added 4.0M HCl bisAlkane solution (0.923mL, 3.69mmol), and the reaction mixture is stirred at room temperature for 2 hours. With saturated NaHCO₃The solution dilutes the mixture and the layers are separated. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. With Et₂The resulting solid was triturated to give the title compound 113 as a yellow solid (350mg, 75% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.48(d,J=5.48Hz,1H),8.00(s,1H),7.82(d,J=8.41Hz,1H),7.70(m,1H),7.44(d,J=8.22Hz,1H),7.36(t,J=9.19Hz,1H),7.19(m,1H),6.56(m,2H),3.75(s,2H),3.39(t,J=5.67Hz,2H),3.22(s,3H),2.64(t,J=5.67Hz,2H),2.53(m,1H),0.63(m,2H),0.41(m,2H)。MS(m/z)=507.5(M+H)。

Example 79

N- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl) -N- (2-methoxyethyl) acetamide (114)

To a suspension of 113(100mg, 0.197mmol) in pyridine (3mL) was added acetic anhydride (30.2mg, 0.296mmol) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, then redissolved in ethyl acetate and washed with saturated CuSO₄The solution was then washed with water. Collecting organic phase, passing through anhydrous Na ₂SO₄Dried, filtered and concentrated. With Et₂The resulting solid was triturated to give the title compound 114 as a white solid (97mg, 90% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.68(s,1H),8.48(m,1H),8.03(s,1H, rotamer), 7.83(m,2H, rotamer), 7.70(m,1H),7.36(m,3H),7.18(m,1H),6.56(m,2H),4.57(s,2H, rotamer) 3.43(s,3H),3.29(s,2H),3.20(s,2H, rotamer), 2.49(m,1H),2.06(s,3H, rotamer), 0.63(m,2H),0.41(m, 2H). MS (M/z) =549.57(M + H).

Example 80

N- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl) -2- (2-methoxyethoxy) -N- (2-methoxyethyl) acetamide (115)

To a suspension of 113(120mg, 0.237mmol) in THF (3mL) was added 2- (2-methoxyethoxy) acetyl chloride (54.2mg, 0.355mmol) and TEA (71.9mg, 0.711mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, followed by washing with saturated ammonium chloride solution. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. With Et₂The resulting solid was triturated to give the title compound 115(113mg, 77% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.72(s,1H),8.50(d, J =5.48,1H),8.05(s,1H, rotamer), 7.90(m,2H, rotamer), 7.75(m,1H),7.20(m,3H),7.19(m,1H),6.59(m,2H),4.61(s,1H, rotamer), 4.31(s,2H, rotamer), 3.61(m,2H),3.49(m,6H),3.23(m,7H),2.55(m,1H),0.64(m,2H),0.43 (m,7H) (m,2H)。MS(m/z)=623.66(M+H)。

Example 80-A

N- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl) -2-hydroxy-N- (2-methoxyethyl) acetamide (115-A)

To a solution of 113(168mg, 0.332mmol) in DMF (8mL) at room temperature was added DIPEA (0.203mL,1.161mmol) followed by HATU reagent (378mg, 0.995 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added, and the reaction mixture was washed with water, saturated ammonium chloride solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. Purify the residue via Biotage (0 to 50% MeOH/ethyl acetate; SNAP 50g column) to give an off-white solid which when triturated with ether/acetone gave the title compound 115-A as a white solid (20mg, 11% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): contains two rotamers 8.74(s,1H),8.54(d,1H, J =5.5Hz),8.10,8.07(2s,1H),7.94,7.89(2d,2H, J =8.2Hz),7.78(dd,1H, J1=2.4Hz, J2=13.5Hz),7.44-7.38(m,3H),7.25-7.22(m,1H),6.63-6.61(m,2H),4.73-4.61(m,3H),4.28,4.14(2d,2H, J =5.5Hz),3.51-3.40(m,4H),3.27(s,3H),2.60-2.56(m,1H),0.71-0.67(m,2H),0.48-0.44(m, 2H). MS:565.5(M + H).

In analogy to compound 114 (example 79, scheme 29), compounds 116 to 117 (examples 81 to 82) were prepared by reacting the corresponding NH precursor described in WO 2009/109035a1 with acetic anhydride.

TABLE 15 characterization of Compounds 116 to 117-A (examples 81 to 82-A)

Scheme 30

Example 83

1- (2, 4-difluorophenyl) -3- (3-fluoro-4- (2- (3-morpholinoprop-1-ynyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (119)

To a solution of 118(150mg, 0.391mmol) in DCM (7mL) was added 2, 4-difluorophenyl isocyanate (121mg, 0.782mmol) and the reaction mixture was stirred at rt overnight. The resulting solid was collected by filtration, dissolved in DCM, and purified by column chromatography (ethyl acetate to 10% MeOH in ethyl acetate) to give the title compound 119(71mg, 34% yield) as a white solid.¹HNMR(400MHz,DMSO-d₆)δ(ppm):9.36(s,1H),8.61(s,1H),8.54(d,J=5.28,1H),8.03(m,1H),7.78(s,1H),7.73(m,1H),7.43(t,J=8.99Hz,1H),7.34(m,1H),7.23(m,1H),7.05(m,1H),6.71(d,J=5.48Hz,1H),3.63(s,2H),3.59(m,4H),2.52(m,4H)。MS(m/z)=539.62(M+H)。

Example 84

1- (3-fluoro-4- (2- (3-morpholinoprop-1-ynyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-phenylurea (120)

To a solution of 118(150mg, 0.391mmol) in DCM (7mL) was added phenyl isocyanate (93mg, 0.782mmol) and the reaction mixture was stirred at rt overnight. The resulting solid was collected by filtration, followed by column chromatography (ethyl acetate +1% NH₄OH to 10% MeOH in ethyl acetate +1% NH₄OH) to yield the title compound 120 as a white solid (37mg, 19% yield).¹HNMR(400MHz,DMSO-d₆)δ(ppm):9.06(s,1H),8.81(s,1H),8.54(d,J=5.48Hz,1H),7.79(s,1H),7.73(m,1H),7.44(m,3H),7.27(m,3H),6.98(t,J=7.24Hz,1H),6.70(d,J=5.48Hz,1H),3.63(s,2H),3.60(m,4H),2.48(m,4H)。MS(m/z)=503.62(M+H)。

Scheme 31

Example 85

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((3-oxomorpholine) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (123)

Step 1: 4- ((6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) morpholin-3-one (121)

To a solution of 102(350mg, 0.842mmol, scheme 26) in THF (10mL) was added the anion prepared from morpholin-3-one (340mg, 4 equiv., 3.37mmol) and NaH (81mg, 4 equiv., 3.37mmol)]A solution in THF (5mL) and the mixture was heated to reflux for 8 hours. With saturated NH₄The mixture was quenched with Cl solution and extracted with DCM. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The resulting solid was triturated with acetone to give the title compound 121(135mg, 33% yield), which was used in the next step without further purification. MS (M/z) =481.2(M + H).

Step 2: 4- ((6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) morpholin-3-one (122)

To a suspension of 121(135mg, 0.281) in methanol (10mL) was added zinc powder (184mg, 2.81mmol) and NH₄Cl (60.1mg, 1.124mmol) in water (1mL), and the reaction mixture was stirred at reflux for 5 hours, followed by stirring at room temperature for 2 days. The mixture was filtered, concentrated, dissolved in DCM and MeOH, and the resulting solution was washed with water. Collecting organic phase, passing through anhydrous Na ₂SO₄Dried, filtered and concentrated. The resulting solid 122(65mg, 51% yield) was used in the next step without further purification. MS (M/z) =451.49(M + H).

And step 3: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((3-oxomorpholine) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (123)

To a solution of 122(65mg,0.144mmol) in THF (7mL) was added THF containing TEA (0.06mL, 0.433mmol) and triphosgene (42.8mg, 0.144mmol)(2mL), and the mixture was stirred at room temperature for 1 hour. Cyclopropylamine (16.48mg, 0.289mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and saturated NH₄And (5) washing with a Cl solution. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The resulting solid was triturated with acetone to give the title compound 123(18mg, 23% yield) as an olive solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.55(s,1H),8.51(d,J=5.48Hz,1H),8.34(s,1H),8.25(d,J=8.22Hz,1H),7.82(m,1H),7.71(m,1H),7.36(t,J=8.99Hz,1H),7.19(m,1H),6.63(d,J=5.48Hz,1H),6.55(s,1H),4.60(s,2H),4.12(s,2H),3.83(m,2H),3.36(m,2H),2.49(m,1H),0.64(m,2H),0.42(m,2H)。MS(m/z)=534.51(M+H)

Scheme 32

Example 86

1- (2, 4-difluorophenyl) -3- (3-fluoro-4- (2- (4- (pyrrolidine-1-carbonyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (127)

Step 1: (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) phenyl) (pyrrolidin-1-yl) methanone (125)

To a solution of 124(1.685g, 4.57mmol) in DME (30mL) was added a solution containing 4- (pyrrolidine-1-carbonyl) phenylboronic acid (1g, 4.57mmol), Pd (PPh) ₃)Cl₂(0.32g，0.457mmol)、CsF(2.080g，13.70mmol)、Na₂CO₃(1.452g, 13.70mmol) of water (5mL) and with N₂The reaction mixture was degassed for 5 minutes, then heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the organic layer was collected over anhydrous Na₂SO₄Dried, filtered and concentrated. With Et₂The resulting black solid was triturated to give the title compound 125(1.5g, 71% yield) as a dark brown solid,it was used in the next step without further purification. MS (M/z) =464.48(M + H).

Step 2 (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) phenyl) (pyrrolidin-1-yl) methanone (126)

To a suspension of 125(1.5g, 3.24mmol) in MeOH (60mL) was added zinc powder (1.693g, 25.9mmol) and NH₄Cl (0.346g, 6.47mmol) and the reaction mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was dissolved in DCM and washed with water. Collecting organic phase, passing through anhydrous Na₂SO₄Drying, filtration and concentration gave the title compound 126 as a brown oil (1.3g, 93% yield) which turned into a fluffy solid after removal of the remaining solvent under high vacuum. MS (M/z) =434.50(M + H).

And step 3: 1- (2, 4-difluorophenyl) -3- (3-fluoro-4- (2- (4- (pyrrolidine-1-carbonyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (127)

To a solution of 126(125mg, 0.288mmol) in DCM (6mL) was added 2, 4-difluorophenyl isocyanate (134mg, 0.865mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated, and the resulting solid was triturated with acetone, and collected by filtration to give the title compound 127(100mg, 59% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.37(s,1H),8.61(s,1H),8.51(d,J=5.48Hz,1H),8.14(s,1H),8.04(m,1H),7.94(m,2H),7.76(m,1H),7.64(m,2H),7.45(t,J=8.99Hz,1H),7.35(m,1H),7.22(m,1H),7.06(m,1H),6.63(d,J=5.48Hz,1H),3.48-3.37(m,4H),1.85(m,4H)。MS(m/z)=589.546(M+H)。

Example 87

1- (3-fluoro-4- (2- (4- (pyrrolidine-1-carbonyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (128)

To a solution of 126(150mg, 0.346mmol) in DCM (7mL) was added isopropyl isocyanate (265mg, 3.11mmol) and the reaction mixture was heated to reflux for 8 hours. Cooling the mixture to room temperatureAnd concentrated. Purification by column chromatography (ethyl acetate) gave the title compound 128(90mg, 50% yield) as a white solid, which was further purified with Et₂And O grinding.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.50(d,J=5.28Hz,1H),8.49(s,1H),7.93(d,J=8.41Hz,2H),7.70(m,1H),7.63(d,J=8.41Hz,2H),7.35(t,J=9.19Hz,1H),7.11(m,1H),6.60(d,J=5.48Hz,1H),6.15(d,J=7.63Hz,1H),3.74(m,1H),3.59-3.40(m,4H),1.88-1.79(m,4H),1.09(d,J=6.46Hz,6H)。MS(m/z)=519.65(M+H)

Example 88

1-cyclopropyl-3- (3-fluoro-4- (2- (4- (pyrrolidine-1-carbonyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (129)

To a solution of 126(150mg, 0.346mmol) in DCM (7mL) was added TEA (105mg, 1.038mmol) and triphosgene (103mg, 0.346mmol) and the reaction mixture was stirred for 30 min. Cyclopropylamine (39.5mg, 0.692mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated and redissolved in ethyl acetate, then saturated NH ₄And (5) washing with a Cl solution. Through anhydrous Na₂SO₄The organic phase was dried, filtered and concentrated. Purification by column chromatography (10% MeOH in ethyl acetate) gave the title compound 129 as a white solid (40mg, 22% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.71(s,1H),8.51(m,1H),8.13(s,1H),7.93(d,J=7.82Hz,2H),7.73(m,1H),7.63(d,J=7.82Hz,2H),7.37(t,J=8.61Hz,1H),7.18(m,1H),6.61(m,1H),6.56(s,1H),3.47-3.42(m,4H),1.86-1.81(m,4H),2.53(m,1H),0.64(m,2H),0.411(m,2H)。MS(m/z)=517.533(M+H)。

Example 89

1- (3-fluoro-4- (2- (4- (pyrrolidine-1-carbonyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3- (3- (methylsulfonyl) phenyl) urea (130)

To a solution of 126(150mg, 0.346mmol) in THF (6mL) was added THF (1mL) containing TEA (175mg, 1.730mmol) and triphosgene (103mg, 0.346mmol), and the mixture was stirred for 30 min. 3- (methylsulfonyl) anilinium chloride (144mg, 0.692mmol) was added, and the mixture was stirred at room temperatureThe mixture was allowed to stand overnight. The mixture was then concentrated and the resulting solid was triturated with acetone, DCM and MeOH before being recrystallized from hot DMF. Trituration with acetone gave 130 as a grey powder (25mg, 11% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.32(s,1H),9.24(s,1H),8.52(d,J=5.48Hz,1H),8.16(s,1H),8.13(s,1H),7.94(d,J=8.41Hz,2H),7.75(m,1H),7.66-7.62(m,3H),7.56-7.53(m,2H),7.45(m,1H),7.31(m,1H),6.64(d,J=5.48Hz,1H),3.48-3.37(m,4H),3.19(s,3H),1.86-1.81(m,4H)。MS(m/z)=631.437(M+H)。

Scheme 33

Example 90

1-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- ((2-oxopyrrolidin-1-yl) methyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (137)

Step 1: tert-butyl 4- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methylamino) butanoate (132)

To a suspension of aldehyde 131(200mg,0.502mmol) in DCM (10mL) was added tert-butyl 5-amino-2-oxopentanoate (282mg, 1.506mmol) and AcOH (0.029mL, 1 equiv., 0.502mmol), and the reaction mixture was stirred for 30 min. Addition of NaB (OAc) ₃H (266mg, 1.255mmol), and the reaction mixture was stirred for an additional 24 hours. The reaction mixture was then diluted with excess DCM and washed with water. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated to give the title compound 132(272mg, 100% yield, crude product) as an oil, which was used in the next step without further purification. MS (M/z) =541.59(M + H).

Step 2: 4- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methylamino) butanoic acid (133)

To a solution of 132(272mg, 0.502mmol) in DCM (10mL) was added HCl (4 MEt)₂O solution) (0.502mg, 2.009mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated to give the title compound 133(244mg, yield 100%, crude product) as a yellow solid, which was used in the next step without further purification. MS (M/z) =486.1(M + H).

And step 3: methyl 4- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methylamino) butanoate (134)

A solution of 133(242mg, 0.498mmol) in anhydrous MeOH (10mL) was heated in the presence of PTSA (95mg, 0.498mmol) for 1 h. The reaction mixture was cooled to room temperature and then neutralized with solid sodium bicarbonate. The mixture was then concentrated and partitioned between water and DCM. Collecting organic phase, passing through anhydrous Na ₂SO₄Dried, filtered and concentrated to give the title compound 134(249mg, 100% yield, crude product), which was used directly in the next step without additional purification. MS (M/z) =500.1(M + H).

And 4, step 4: 1- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) pyrrolidin-2-one (135)

A solution of 134(249mg, 0.498mmol) in toluene (9mL) and DME (1mL) was heated to reflux for 24 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (10% MeOH in ethyl acetate) to give the title compound 135(125mg, 54% yield) as a yellow solid. MS (M/z)467.41(M + H).

And 5: 1- ((2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) pyrrolidin-2-one (136)

To a solution of 135(125mg, 0.267mmol) in MeOH (10mL) was added zinc powder (140mg, 2.14mmol) and ammonium chloride (42.9mg, 0.80mmol) in water (1mL) and the reaction mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature, filtered and concentrated. The residue was partitioned between water and DCM/MeOH, and collectedOrganic phase over anhydrous Na₂SO₄Drying, filtration and concentration gave the title compound 136(77mg, 66% yield) which was used as crude product in the next step without additional purification. MS (M/z) =438.50(M + H).

Step 6-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- ((2-oxopyrrolidin-1-yl) methyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (137)

To a solution of 136(77mg, 0.176mmol) in THF (10mL) was added THF (5mL) containing TEA (0.074mL, 0.528mmol) and triphosgene (52.2mg, 1.451mmol), and the mixture was stirred at room temperature for 1 hour. Cyclopropylamine (10.5mg, 0.176mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and partitioned between DCM and saturated NaHCO₃Between the solutions. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography (10% MeOH in ethyl acetate) to give the title compound 137(47mg, 51% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.50(d,J=5.48Hz,1H),7.89(s,1H),7.70(m,1H),7.35(t,J=8.99Hz,1H),7.17(m,1H),7.05(s,1H),6.65(d,J=5.48Hz,1H),6.55(m,1H),4.46(s,2H),3.82(s,3H),3.22(t,J=6.84Hz,2H),2.52(m,1H),2.27(t,J=7.82Hz,2H),1.90(m,2H),0.63(m,2H),0.40(m,2H)。MS(m/z)=521.638(M+H)

Scheme 34

Example 91

1-cyclopropyl-3- (4- (2- (5- ((2, 5-dioxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (140)

Step 1: 1- ((6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) pyrrolidine-2, 5-dione (138)

To a solution of 102(200mg, 0.481mmol, scheme 26) in DMF (5mL) was added Cs₂CO₃(313mg, 0.962mmol) and succinimide (95mg, 0.962mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Collecting organic phase, passing through anhydrous Na ₂SO₄Drying, filtration and concentration gave the title compound 138(100mg, 43% yield) as a residue in Et₂O was triturated and used without additional purification. MS (M/z) =479.50(M + H).

Step 2: 1- ((6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) pyrrolidine-2, 5-dione (139)

To a suspension of 138(100mg, 0.209mmol) in methanol (10mL) was added zinc (109mg, 1.672mmol) and NH₄Cl (44.7mg, 0.836mmol) in water (1mL) and the reaction mixture was heated to reflux for 4 hours, cooled to room temperature and concentrated. The crude product was dissolved in MeOH/DCM and washed with water. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated to give the title compound 139(80mg, 85% yield), which was used without additional purification. MS (M/z) =448.47(M + H).

And step 3: 1-cyclopropyl-3- (4- (2- (5- ((2, 5-dioxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (140)

To a solution of 139(101mg, 0.225mmol) in THF (6mL) at-35 ℃ was added TEA (0.094mL, 1.126mmol) and triphosgene (80mg, 0.270mmol) in THF (1mL) and the mixture was warmed to-10 ℃ for 1 hour. Cyclopropylamine (64.3mg, 1.126mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with ethyl acetate, followed by saturated NH ₄And (5) washing with a Cl solution. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. Purification by column chromatography (10% MeOH in ethyl acetate) gave the title compound 140 as a white solid (20mg, 17% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.53(s,1H),8.50(d,J=5.48Hz,1H),8.32(s,1H),8.22(d,J=8.021,1H),7.81(m,1H),7.70(m,1H),7.36(t,J=9.19Hz,1H),7.18(m,1H),6.62(d,J=4.89Hz,1H),6.55(s,1H),4.62(s,2H),2.68(s,4H),2.53(m,1H),0.63(m,2H),0.41(m,2H)。M(m/z)=532.543(M+H)。

Scheme 35

Example 92

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((3-methyl-2-oxoimidazolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (141)

To a solution of 1-methylimidazolidin-2-one (192mg, 1.919mmol) in DMF (10mL) was added NaH (79mg, 6.2 equiv., 0.1.983mmol) and the mixture was stirred for 15 min. A solution of 65(150mg, 0.320mmol, scheme 17) in DMF (5mL) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was then poured into water and extracted thoroughly with ethyl acetate. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. Purification by column chromatography (10% MeOH in ethyl acetate) gave the title compound 141 as a yellow solid (17mg, 10% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.71(s,1H),8.54(s,1H),8.51(d, J =5.48Hz,1H),8.33(s,1H),8.26(d, J =8.02Hz,1H),7.80(m,1H),7.72(m,1H),7.38(t, J =8.99Hz,1H),7.20(m,1H),6.65(m,1H),6,56(s,1H),4,35(s,2H),7.33(m,4H, part of H, is replaced by H₂O peak mask), 2.69(s,3H),2.55(m,1H),0.65(m,2H),0.43(m, 2H). MS (M/z) =533.49(M + H).

Example 93

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2, 2-dioxo-2-thiopyrrolidin-1-ylmethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (142)

To a solution of 1, 3-propanesultam (155mg, 1.280mmol) in DMF (10mL) was added NaH (53.7mg, 4.2 equiv., 1)343mmol) and the mixture was stirred for 15 minutes. A solution of 65(150mg, 0.320mmol, scheme 17) in DMF (5mL) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. Purification by column chromatography (10% MeOH in ethyl acetate) gave the title compound 142 as a yellow solid (17mg, 9% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.83(s,1H),8.58-8.55(m,2H),8.36(s,1H),8.28(d,1H,J=8.2Hz),8.19(s,1H),7.89(dd,1H,J1=1.9Hz,J2=8.2Hz),7.77(dd,1H,J1=2.3Hz,J2=13.5Hz),7.41(t,1H,J=9.0Hz),7.25-7.22(m,1H),6.69-6.67(m,1H),3.59-3.57(m,6H),2,62-2.57(m,1H),2.54-2.42(m,16H),0.71-0.66(m,2H),0.48-0.44(m,2H)。MS(m/z)=554.518(M+H)。

Example 94

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-oxoimidazolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (143)

To a solution of imidazolidin-2-one (165mg, 6 eq, 1.919mmol) in DMF (10mL) was added NaH (79mg, 0.1983mmol) and the mixture was stirred for 15 min. A solution of 65(150mg, 0.320mmol, scheme 17) in DMF (5mL) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. Collecting organic phase, passing through anhydrous Na ₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography (20% MeOH in DCM) to give the title compound 143 as a yellow solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.74(s,1H),8.58(m,1H),8.56(d,1H, J =5.3Hz),8.38(s,1H),8.31(d,1H, J =8.0Hz),7.85(dd,1H, J =2.1Hz and 8.2Hz),7.77(dd,1H, J =2.5 and 13.7Hz),7.42(t,1H, j9.2Hz),7.25-7.23(m,1H),6.69(d,1H, J =5.3Hz),6.60(m,1H),6.57(s,1H),4.36(s,2H),3.34-3.30(m,4H),2.60-2.58(m,1H),0.70-0.67(m,2H), 0.48-2H (m, 46H). MS (M/z) =519.5(M + H).

Scheme 37

Example 96

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (154)

Step 1: 2- (1- ((1, 3-dioxolan-2-yl) methyl) -1H-pyrazol-4-yl) -7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridine (145)

To a suspension of 144(3.57g, 8.57mmol) in DME (50mL) and water (5mL) was added 1- ((1, 3-dioxolan-2-yl) methyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2g,7.14mmol), CsF (3.25g, 21.42mmol), NaHCO₃(1.799g, 36mmol) and Pd (PPh)₃)₄(0.825g, 0.714mmol) and the reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. Collecting organic phase, passing through anhydrous Na ₂SO₄Dried, filtered and concentrated. With Et₂The resulting solid was triturated to give the title compound 145(3g, 95% yield) as a beige solid. MS (M/z) =443.51(M + H).

Step 2: 2- (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) acetaldehyde (146)

To a solution of 145(900mg, 2.034mmol) in THF (20mL) was added 3M HCl (30mL) and the reaction mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature and concentrated. The remaining aqueous solution was treated with solid sodium bicarbonate, followed by extraction with DCM. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The crude aldehyde 146(810mg, 100% yield) was used in the next step without further purification. MS (M/z) =399.3(M + H).

And step 3: 7- (2-fluoro-4-nitrophenoxy) -2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridine (152)

To a solution of 146(450mg, 1.13mmol, scheme 36) in NMP (10mL) was added acetic acid (0.129mL, 2.259mmol) and 1-methylpiperazine (113mg, 2.259mmol) and the reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (718mg, 6.10mmol) was added and the mixture was stirred at room temperature overnight. Followed by saturated NaHCO ₃The mixture was diluted with solution, followed by addition of solid NaHCO₃To neutralize the acid. The mixture was extracted with DCM and over anhydrous Na₂SO₄The extract was dried, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate with 10% MeOH to 50% MeOH) to give the title compound 152(250mg, yield 27%) as a brown oil. MS (M/z) =483.53(M + H).

And 4, step 4: 3-fluoro-4- (2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) aniline (153)

To a solution of 152(150mg, 0.311mmol) in MeOH (20mL) was added ammonium chloride (33.3mg, 0.622mmol) in water (5mL) and zinc powder (81mg, 3.01mmol), and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated to give the title compound 153(132mg, 92% yield), which was used directly in the next step without additional purification. MS (M/z) =453.2(M + H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (154)

To a stirred solution of 153(203mg, 0.449mmol) and pyridine (0.109mL,1.346mmol) in DMF (10mL) under nitrogen at 0 ℃ was added phenyl chloroformate (1.76mg, 1.121mmol) and the reaction mixture was stirred at 0 ℃ for 2 hours. Cyclopropylamine (128mg, 2.243mmol) was added and the reaction mixture was heated at 55 ℃ for 5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, followed by washing with saturated ammonium chloride solution and brine, and then with anhydrous sulfuric acidSodium was dried, filtered and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate to ethyl acetate with 30% MeOH) to give the title compound 154(30mg, 12% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.43(s,J=5.48Hz,1H),8.33(s,1H),7.99(s,1H),7.74(m,1H),7.67(s,1H),7.60(bs,1H),7.32(t,J=8.99Hz,1H),7.22(m,1H),6.63(d,J=5.48Hz,1H),4.25(t,J=6.46Hz,2H),2.73(t,J=6.46Hz,2H),2.55(m,1H),2.45(m,4H),2.28(m,4H),2.12(s,3H),0.61(m,2H),0.40(m,4H)。MS(m/z)=536.54(M+H)。

Example 97

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (155)

The title compound 155 was obtained in analogy to compound 154 (example 96, scheme 37) using morpholine instead of 1-methylpiperazine in the reductive amination step.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.67(s,1H),8.41(m,1H),8.33(s,1H),7.98(s,1H),7.70(d,J=13.69,1H),7.67(s,1H),7.34(t,J=8.80Hz,1H),7.17(d,J=8.61Hz,1H),6.54(bs,1H),6.51(d,J=5.48Hz,1H),4.26(m,2H),3.53(t,J=4.11Hz,4H),2.72(t,J=6.45Hz,2H),2.52(m,1H),2.41(BS,4H),0.63(m,2H),0.40(m,2H)。MS(m/z)=523.57.

Scheme 38

Example 98

Cyclopropylcarbamic acid 2- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl ester (157)

Step 1: 2- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethanol (156)

To a solution of 146(3g, 7.53mmol) in DCM (100mL) and methanol (100mL) was added NaBH₄(0.57g, 15.06mmol), and the reaction mixture was stirred at 0 ℃ for 20 minutes. With saturated NH₄The mixture was quenched with Cl solution and then extracted with DCM. Collecting the extract over anhydrous Na₂SO₄Drying, filtration, concentration and purification of the residue by column chromatography (eluent: 10% MeOH in ethyl acetate) gave the title compound 156 as a white solid (1g, 36% yield). MS (M/z) =371.40(M + H).

Step 2: cyclopropylcarbamic acid 2- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl ester (157)

To a stirred solution of 156(900mg, 2.430mmol) and pyridine (0.59mL, 7.29mmol) in DMF (10mL) under nitrogen at 0 ℃ was added phenyl chloroformate (951mg, 6.07mmol) and the reaction mixture was stirred at 0 ℃ for 2 hours. Cyclopropylamine (694mg, 12.15mmol) was added and the reaction mixture was heated at 55 ℃ for 5 hours. The reaction mixture was then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was collected, then washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate to ethyl acetate with 30% MeOH) to give the title compound 157(300mg, yield 23%) as a white solid. ¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.43(d,J=5.47Hz,1H),8.33(s,1H),8.03(s,1H),7.72(m,1H),7.70(m,1H),7.41(m,1H),7.35(t,J=9.19Hz,1H),7.19(m,1H),6.54(m,2H),4.34(m,4H),2.53(m,1H),2.49(m,1H),0.65(m,2H),0.54(m,2H),0.43(m,2H),0.36(m,2H)。MS(m/z)=537.58(M+H)。

Scheme 39

Example 99

1- ((2- (7- (2-fluoro-4-cyclopropylaminocarbonylaminophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-cyclopropyl-1- (2-methoxyethyl) urea (161)

Step 1: 3-cyclopropyl-1- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -1- (2-methoxyethyl) urea (159)

To a solution of 158(150mg,0.294mmol) in THF (5mL) was added THF (1mL) containing TEA (0.123mL, 0.881mmol) and triphosgene (43.6mg, 0.147mmol), and the mixture was stirred at room temperature for 1 hour. Cyclopropylamine (84mg, 1.469mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and then partitioned between DCM and saturated NaHCO₃Between the solutions. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash chromatography (eluent: ethyl acetate with 10% MeOH) to give the title compound 159 as an oil (40mg, 25% yield). MS (M/z) =541.54(M + H).

Step 2: 1- ((2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-cyclopropyl-1- (2-methoxyethyl) urea (160)

To a solution of 159(300mg, 0.555mmol) in MeOH (10mL) was added zinc powder (145mg, 2.22mmol) and ammonium chloride (59.4mg, 1.11mmol), and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and filtered. The solvent was evaporated and the residue was extracted with DCM. Through anhydrous Na ₂SO₄The extract was dried, filtered and concentrated. The crude title compound 160(283mg, 100% yield) was used in the next step without additional purification. MS (M/z) =511.2(M + H).

And step 3: 1- ((2- (7- (2-fluoro-4-cyclopropylaminocarbonylaminophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-cyclopropyl-1- (2-methoxyethyl) urea (161)

To a stirred 160(283mg, 0.554mmol) and pyridine (0.134mL, 1.663mmol) in DMF (10mL) under nitrogen was added phenyl chloroformate (158mg, 1.386mmol) at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 2 hours. Cyclopropylamine (0.195mL, 2.77mmol) was added and the reaction mixture was heated at 55 ℃ for 5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purify the crude by flash column chromatography (eluent: ethyl acetate to ethyl acetate with 20% MeOH) to give the title compound 161 as a white solid (100mg, 30% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.70(s,1H),8.50(d,J=5.48Hz,1H),7.89(s,1H),7.70(m,1H),7.35(t,J=9.19Hz,1H),7.19(m,1H),6.93(s,1H),6.64(d,J=5.48hz,1H),6.56(s,1H),6.51(m,1H),4.54(s,2H),3.82(s,3H),3.27(m,2H),3.25(m,2H),3.19(s,3H),2.54(m,2H),0.63(m,2H),0.55(m,2H),0.41(m,2H),0.37(m,2H)。MS(m/z)=594.61(M+H)。

Example 99-A

1- ((2- (7- (4-isopropylaminocarbonylamino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-ethyl-1- (2-methoxyethyl) urea (161-A)

161-A: example 99-A

The title compound 161-a (example 99-a) was obtained in analogy to compound 161 (example 99, scheme 39) starting from compound 158 and using ethyl isocyanate in the first step and isopropyl isocyanate in the third step.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.73(s,1H),8.55(d,1H,J=5.5Hz),7.93(s,1H),7.73(dd,1H,J1=2.5Hz,J2=13.5Hz),7.40(t,1H,J=9.0Hz),7.17-7.15(m,1H),6.99(s,1H),6.69(d,1H,J=5.3Hz),6.46(t,1H,J=5.5Hz),6.18(d,1H,J=7.8Hz),4.61(s,2H),3.88(s,3H),3.86-3.78(m,1H),3.40-3.38(m,2H),3.35-3.34(m,2H),3.26(s,3H),3.16-3.08(m,2H),1.15(s,3H),1.13(s,3H),1.05(t,3H,J=7.2Hz)。MS:584.6(M+H)。

Example 99-B

1- ((2- (7- (4-cyclopropylaminocarbonylamino-2-fluorophenoxy) thieno [3,2-B ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-ethyl-1- (2-methoxyethyl) urea (161-B)

The title compound 161-B (example 99-B) was obtained in analogy to compound 161 (example 99, scheme 39) starting from compound 158 and using ethyl isocyanate in the first step.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.75(s,1H),8.55(d,1H,J=5.4Hz),7.93(s,1H),7.75(dd,1H,J1=2.3Hz,J2=13.5Hz),7.41(t,1H,J=9.0Hz),7.24-7.39(m,1H),6.99(s,1H),6.70(d,1H,J=5.3Hz),6.60(m,1H),6.46(t,1H,J=5.7Hz),4.61(s,2H),3.88(s,3H),3.54-3.51(m,2H),3.38-3.33(m,2H),3.26(s,3H),3.13-3.09(m,2H),2.70-2.56(m,1H),1.06(t,3H,J=7.2Hz),0.71-0.67(m,2H),0.48-0.44(m,2H)。MS:582.6(M+H)。

Scheme 40

Example 100

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-oxopyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (166)

Step 1: 1- (2- (4-bromo-1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (162)

To the reaction mixture were added 3-bromopyrazole (5g, 34mmol), 1- (2-hydroxyethyl) pyrrolidin-2-one (5.75g,51mmol), PPh₃(13.38g,51mmol) in THF (100mL) was added DEAD (8.89g, 51mmol) and the reaction mixture was stirred at room temperature overnight. Concentrate the mixture with Et₂Co-evaporation of O followed by dissolution in Et₂In O and cooled in a refrigerator for 3 hours, whereupon Ph precipitates ₃P = O. The mixture was then filtered and concentrated to give the title compound 162(8.78g, 100% yield), which was used in the next step without additional purification. MS (M/z) =259.12/261.12(M + H).

Step 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (163)

To a solution of 162(8.78g, 34mmol) in toluene (150mL) was added bis (pinacolyl) diboron (12.96g, 51mmol), KOAc (8.35g, 85mmol) and Pd (PPh)₃)₄(1.96g, 1.701mmol) and the reaction mixture was heated to reflux for 4 hours. The mixture was concentrated and the residue was purified by flash column chromatography (eluent: ethyl acetate to 25% MeOH/ethyl acetate) to give the title compound 163(6.3g, 60% yield) as a yellow oil. MS (M/z) =306.4(M + H).

And step 3: 1- (2- (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (164)

To a solution of iodide 144(2.1g, 5.05mmol, scheme 36) in DME (60mL) at room temperature was added borate 163(2.31g, 7.57mmol), containing NaHCO₃(1.272g, 15.14mmol) of H₂O (5mL), CsF (2.3g, 15.14mmol) and Pd (PPh)₃)₄(0.583g, 0.505mmol) and with N₂The reaction mixture was degassed for 10 minutes, then heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and H ₂And O is between. The organic phase is separated and reused with H₂Washed with O, then dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude product was triturated with ether to give the title compound 164 as a brown solid (2g, 85% yield). MS (M/z) =468.48(M + H).

And 4, step 4: 1- (2- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (165)

To a suspension of 164(0.5g,1.07mmol) in MeOH (20mL) was added zinc (0.28g, 4.28mmol) and ammonium chloride (0.114g, 2.139mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the resulting oil was partitioned between water and DCM. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. With Et₂The resulting solid was triturated to give the title compound 165(0.468mg, 100% yield, crude product) as a black solid. MS (M/z) =438.4(M + H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-oxopyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (166)

To a stirred solution of 165(400mg, 0.914mmol) and pyridine (0.222mL, 2.74mmol) in DMF (10mL) under nitrogen was added phenyl chloroformate (0.287mg, 2.286mmol) at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 2 hours. Cyclopropylamine (0.322mL, 4.57mmol) was added and the reaction mixture was heated at 55 ℃ for 5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate to ethyl acetate with 20% MeOH) to give the title compound 166 as a white solid (250mg, 53% yield). ¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.44(d,J=5.48Hz,1H),8.35(s,1H),8.035(s,1H),7.74(m,1H),7.70(s,1H),7.35(t,J=8.99Hz,1H),7.19(d,J=8.99Hz,1H),6.55(m,2H),4.28(t,J=5.87Hz,2H),3.59(t,J=5.86Hz,2H),3.17(t,J=6.84Hz,2H),2.55(m,1H),2.15(t,J=7.83Hz,2H),1.86(m,2H),0.64(m,2H),0.42(m,2H)。MS(m/z)=521.38(M+H)

Scheme 41

Example 101

4- ((6- (7- (4- (3-cyclopropylureido) -2, 3-difluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methylamino) butanoic acid (168)

Aldehyde 167(0.075g, 0.16mmol, scheme 67), O-tert-butyl-4-aminobutyric acid (0.077g, 0.48mmol) and acetic acid (0.03mL, 0.5mmol) were dissolved in a 2:1 mixture of dichloromethane/NMP (75mL) to give a colorless solution. This solution was stirred at room temperature for 20 minutes, followed by addition of sodium triacetoxyborohydride (0.136g, 0.64mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and water, resulting in a white precipitate, which was isolated by suction filtration. The isolated solid was dissolved in a 1: 1 mixture of methanol/dichloromethane, followed by concentration. The residue was purified by flash column chromatography (eluent: 5% to 15% methanol/chloroform) to give a colorless solid. The material was suspended in acetic acid (15mL) and HCl bis-was addedAlkane solution (4M, 1.05mL) formed a gummy precipitate. The mixture was stirred for 3 hours, and then the supernatant was decanted. The residue was triturated with ethyl acetate and subsequently chromatographed on silica gel (eluent: 60%/35%/5% chloroform/methanol/NH)₄OH) to yield the title compound 168 as a colorless solid (29mg, 31% yield). ¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.60(d, J =1.8,1H), 8.54(d, J =5.5,1H), 8.53(s,1H), 8.36(s,1H), 8.27(d, J =8.0,1H), 8.07-8.01(m,1H), 7.94(dd, J =8.0,2.0,1H), 7.31-7.25(m,1H), 6.96(d, J =2.9,1H), 6.76(d, J =5.3,1H), 3.85(s,2H), 2.62(t, J =6.6,2H), 2.56(m,1H), 2.29(t, J =7.2,2H), 1.69 (quintuple, J =6.9,2H), 0.69-0.63(m,2H), 0.44 (m, 2H). LRMS (M + H):554.6

Example 102

1-cyclopropyl-3- (2, 3-difluoro-4- (2- (5- ((2-oxopyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (169)

To a solution of aldehyde 167(200mg, 0.429mmol) in DMF (10mL) was added 4-aminobutyric acid (133mg, 1.286mmol) and acetic acid (0.049mL, 0.858 mmol). After stirring at room temperature for 20 minutes, sodium triacetoxyborohydride (454mg, 2.144mmol) was added. Stirring was continued for a further 18 hours. Water was added to form a precipitate, which was collected by filtration, washed with water and passed through a Biotage [ linear gradient 0 to 20% (methanol +2% NH ]₄OH)/dichloromethane; SiliaFlash 25g column]Purification followed by trituration with methanol. The title compound 169 was obtained as an off-white solid (131.8mg, 57.4% yield).¹H NMR(400MHz,MeOH-d₆)δ(ppm)：8.54(d,J=5.2Hz,1H),8.53(d,J=2.0Hz,1H),8.47(s,1H),8.37(s,1H),8.27(d,J=8.4Hz,1H),8.04(t,J=9.2Hz,1H),7.80(dd,J=8.4,2.4Hz,1H),7.29(td,J=8.8,2.0Hz,1H),6.87(d,J=2.8Hz,1H),6.77(d,J=5.2Hz,1H),4.46(s,2H),3.39-3.27(m,2H),2.60-2.53(m,1H),2.31(t,J=8.0Hz,2H),1.96(q,J=7.6Hz,2H),0.69-0.63(m,2H),0.45-0.40(m,2H)。MS(m/z):536.6(M+H)。

Example 103

2-amino-6- ((6- (7- (4- (3-cyclopropylureido) -2, 3-difluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methylamino) hexanoic acid (170)

Aldehyde 167(0.110g, 0.236mmol), N-Boc-lysine (0.105g, 0.424mmol) and acetic acid (0.05mL, 0.9mmol) were dissolved in a 2:1 mixture of dichloromethane/NMP (75mL) to give a colorless solution. This solution was stirred at room temperature for 20 minutes, followed by addition of sodium triacetoxyborohydride (0.150g, 0.71mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between dichloromethane and water, resulting in a white precipitate, separated by suction filtration, dissolved in a 1:1 mixture of methanol/dichloromethane, then concentrated and purified by flash column chromatography (eluent 70/25/5% chloroform/methanol/NH₄OH) to yield a colorless solid. This material was suspended in acetic acid (20mL) and HCl bis (HCl) was addedAlkane solution (4M, 0.6mL) formed a gummy precipitate. The mixture was stirred for 3 hours and then decantedAnd (4) supernatant fluid. The residue was triturated with ethyl acetate and dried in vacuo to give the title compound 170(100mg, 60% yield) as a colorless solid, assuming the trihydrochloride salt.¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.53(br s,2H);8.81(d,J=1.8,1H);8.62(d,J=5.7,1H);8.60(s,1H);8.46(s,1H);8.41(d,J=8.2,1H);8.38-8.25(br s,3H);8.22(dd,J=8.4,2.0,1H);8.05-8.01(m,1H);7.33-7.27(m,1H);7.03(d,J=2.4,1H);6.88(d,J=5.5,1H);4.25-4.20(br s,2H);3.90-3.85(m,1H);2.98-2.90(m,2H);2.58-2.52(m,1H);1.85-1.78(m,2H);1.78-1.70(m,2H);1.55-1.45(m,1H);1.45-1.35(m,1H);0.68-0.63(m,2H);0.44-0.40(m,2H)。LRMS(M+H):597.5。

In analogy to compound 48 (example 31, scheme 15), compounds 171 to 172 (examples 104 to 105) were prepared in one step from the reductive amination of aldehyde 167. Compound 173 (example 106) was synthesized in analogy to compound 168 (example 101, scheme 41) starting from aldehyde 47 (scheme 15).

TABLE 16 characterization of Compounds 171 to 173 (examples 104 to 106)

Scheme 42

Example 107

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2-morpholinoethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (178)

Step 1: 4- (2- (6-bromopyridin-3-yl) ethyl) morpholine (175)

Aldehyde 174(0.76g, 3.8mmol), morpholine (3.3g, 38mmol) and acetic acid (0.44mL, 7.6mmol) were dissolved in dichloromethane (100mL) to give a colorless solution which was stirred for 20 minutes. Sodium triacetoxyborohydride (2.42g, 11.4mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 1M HCl (50mL), the layers were separated, and the organic phase was washed with 1M HCl (50 mL). The combined acidic aqueous phases were basified with 3M NaOH and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, over anhydrous MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography (eluent: 10% methanol/chloroform) to give the title compound 175(1.04g, yield 100%).¹H NMR(400MHz,CDCl₃)δ(ppm):8.23(d,J=1.5,1H);7.41-7.39(m,2H);3.73-3.70(m,4H);2.75(t,J=7.0,2H);2.56(t,6.8,2H);2.51-2.47(m,4H)。LRMS(M+H):271.1,273.1.

Step 2: 4- (2- (6- (7-chlorothieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl) morpholine (176)

To 7-chlorothienopyridine (0.81g, 4.8mmol) in THF (100mL) at-78 ℃ was added n-butyllithium (2.5M in hexane, 2.1mL, 5.1mmol) dropwise. The mixture was warmed to 0 ℃ and zinc chloride (1.0M in ether, 4.8mL, 4.8mmol) was added. The mixture was stirred and warmed to room temperature. Bromide 175(1.0g, 3.7mmol) and tetrakis (triphenylphosphine) palladium (0.85g, 0.74mmol) in THF (75mL) was added dropwise and the resulting mixture was heated to reflux for 2 hours. Then cooled and ammonium chloride (2.0mL) was added and the mixture was concentrated. The residue was partitioned between water and ethyl acetate, resulting in a thick precipitate. The precipitate was isolated by suction filtration and triturated with ethyl acetate to give the title compound 176 as a yellow solid (1.35g, 100% yield, crude product). LRMS (M + H): 360.4.

And step 3: 3-fluoro-4- (2- (5- (2-morpholinoethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) aniline (5)

To 4-amino-2-fluorophenol hydrochloride (0.792g, 4.84 mmo)l) to a solution in DMSO (50mL) was added potassium tert-butoxide (1.05g, 9.31mmol) and the dark mixture was stirred for 30 min. Compound 176(1.34g, 3.72mmol) in DMSO (25mL) was then added and the resulting mixture was heated to 140 ℃ for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water and brine, over anhydrous MgSO₄Dried, filtered and concentrated. Flash column chromatography of the residue (eluent: 10% methanol/chloroform) gave the title compound 177(0.15g, 9% yield). LRMS (M + H):451.5.

And 4, step 4: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2-morpholinoethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (178)

Phenyl chloroformate (0.05mL, 0.4mmol) was added at 0 ℃ to a solution of 177(0.15g, 0.33mmol) and pyridine (0.06mL, 0.07mmol) in DMF (75 mL). The reaction mixture was stirred at 0 ℃ for 1 h, followed by addition of cyclopropylamine (0.07mL, 1.0 mmol). The mixture was allowed to warm to room temperature and stirred for a further 18 hours. Then poured into water to form a precipitate which is isolated by suction filtration. The solid was washed with diethyl ether and dried. Chromatography on silica gel (5 to 10% MeOH in ethyl acetate) of this material followed by Gilson reverse phase HPLC (Luna C) ₁₈30 to 55% MeOH in water, 45 minutes) and freeze dried, after which the residue was dissolved between dichloromethane and 1M NaOH, the organic phase was washed with brine, over anhydrous MgSO₄Drying, filtration and concentration gave the title compound 178(47mg, 27% yield) as a colorless solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.78(s,1H);8.53(d,J=1.6,1H);8.51(d,J=5.5,1H);8.30(s,1H);8.19(d,J=8.2,1H);7.83(dd,J=8.2,2.2,1H);7.73(dd,J=13.7,2.4,1H);7.38(t,J=9.0,1H);7.22-7.18(m,1H);6.65-6.61(m,2H);3.59-3.55(m,4H);2.81(t,J=7.2,2H);2.60-2.51(m,3H);2.48-2.42(m,4H);0.66-0.63(m,2H);0.44-0.41(m,2H)。LRMS(M+H):534.3.

Scheme 43

Example 108

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2-methyl-5, 8,11, 14-tetraoxa-2-azepin-pentanyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (180)

Amine 179(0.15g, 0.23mmol), 40% aqueous formaldehyde (0.70g, 23mmol) and acetic acid (0.13mL, 2.3mmol) were dissolved in dichloromethane (25mL) to give a colorless solution. Sodium triacetoxyborohydride (0.199g, 0.938mmol) was added and the mixture was stirred at room temperature for 10 min. Followed by H₂O, saturated NaHCO₃And the reaction mixture was washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated. Chromatography of the residue on silica gel (15% methanol/chloroform) yielded a partially purified product which was further purified by Gilson reverse phase HPLC (Luna C)₁₈30 to 55% MeOH in water, 45 min) followed by lyophilization. The material was partitioned between 1M NaOH and dichloromethane and the organic phase was collected and concentrated to give the title compound 180 as a colorless solid (0.071g, 46% yield). ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.74(s,1H);8.55(d,J=1.4,1H);8.51(d,J=5.5,1H);8.32(s,1H);8.24(d,J=8.2,1H);7.86(dd,J=8.2,2.2,1H);7.73(dd,J=13.5,2.5,1H);7.38(t,J=8.8,1H);7.22-7.18(m,1H);6.64(d,J=5.3,1H);6.60(d,J=2.4,1H);3.60(s,2H);3.55(t,J=5.9,2H);2.53-3.47(m,10H);3.39(t,J=5.7,2H);3.20(s,3H);2.58-2.52(m,3H);2.21(s,3H);0.66-0.63(m,2H);0.44-0.41(m,2H)。LRMS(M+H):654.7

Scheme 44

Example 109

1- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3, 2-b)]Pyridin-7-yloxy) phenyl) -3- (5-methyliso-ylAzol-3-yl urea (183)

Step 1: 2- (6- (7- (2-fluoro-4- (3- (5-methyliso-soh-))Oxazol-3-yl) ureido) phenoxy) thieno [3,2-b]Pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (182)

To a solution of compound 181(0.25g, 0.46mmol, scheme 64) and DIPEA (0.20mL, 1.2mmol) in THF (60mL) at 0 ℃ was added triphosgene (0.055g, 0.19mmol) and the mixture was stirred for 10 min. Followed by addition of 3-amino-5-methylisoOxazole (0.091g, 0.93mmol) and the mixture stirred for an additional 20 minutes, then warmed to room temperature and stirred for 2 hours. The excess triphosgene was quenched with 1mL of water, and the mixture was concentrated. The residue was partitioned between water and ethyl acetate and the organic phase was collected, washed with water, saturated aqueous sodium bicarbonate solution and brine. Followed by anhydrous MgSO₄Drying, filtration, concentration and purification by flash column chromatography (eluent: 3% methanol/ethyl acetate) gave the title compound 182(0.17g, 56% yield).

Step 2: 1- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3, 2-b) ]Pyridin-7-yloxy) phenyl) -3- (5-methyliso-ylAzol-3-yl urea (183)

Compound 182(0.17g, 0.26mmol) was suspended in dichloromethane (50mL) and TFA (1mL) was added. The solution was stirred for 1 hour, and then the mixture was concentrated. The residue was partitioned between ethyl acetate and water, washed with NaOH and brine, then anhydrous MgSO₄Dried, filtered and concentrated. The residue was triturated with ether and dried in vacuo to give the title compound 183(0.125g, 87% yield).¹HNMR(400MHz,DMSO-d₆)δ(ppm)：9.74(s,1H);9.33(s,1H);8.52(d,J=5.5,1H);8.51-8.50(m,1H);8.29(s,1H);8.18(d,J=8.0,1H);7.81(dd,J=8.2,2.2,1H);7.74(J=12.9,2.5,1H);7.46(t,J=9.0,1H);7.30-7.27(m,1H);6.66(d,J=5.5,1H);6.55(s,1H);3.37(t,J=5.7,2H);3.22(s,1H);2.82-2.75(m,4H);2.68(t,J=5.5,2H);2.37(s,3H)。LRMS(M+H):563.5.

Scheme 45

Example 110

N- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (185)

Step 1: tert-butyl 2- (6- (7- (2-fluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamide) phenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamate (184)

To a solution of compound 181(0.25g, 0.46mmol, scheme 64), 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (0.21g,0.93mmol) and DIPEA (0.32mL, 1.9mmol) in DMF (25mL) was added HATU reagent (0.44g, 1.2mmol) and the resulting mixture was stirred at room temperature for 48 h. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and brine. Followed by anhydrous MgSO ₄It was dried, filtered and concentrated. Chromatography on silica gel (ethyl acetate) of the residue afforded the title compound 184(0.23g, 67% yield).

Step 2: n- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (185)

Compound 184(0.23g, 0.31mmol) was suspended in dichloromethane (50mL) and TFA (1.1mL) was added. The reaction mixture was stirred for 18 hours, then concentrated. Make residue remainedThe mixture was partitioned between ethyl acetate and water, the organic phase was collected, washed with 3M NaOH and brine, then anhydrous MgSO₄Dried, filtered and concentrated. The residue was triturated with ether and dried in vacuo to give the title compound 185(0.16g, 81% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.41(s,1H);10.02(s,1H);8.52(d,J=5.5,1H);8.50-8.48(m,1H);8.29(s,1H);8.18(d,J=8.2,1H);7.90(dd,J=13.1,2.2,1H);7.81(dd,J=8.2,2.2,1H);7.64-7.60(m,2H);7.50-7.45(m,2H);7.18-7.12(m,2H);6.65(d,J=5.5,1H);3.37(t,J=5.7,2H);3.22(s,3H);2.82-2.74(m,4H);2.70-2.66(m,2H);1.47(s,4H)。LRMS(M+H):644.6

Scheme 46

Example 111

N- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenylthiocarbamoyl) -2- (4-fluorophenyl) acetamide (187)

Step 1: tert-butyl 2- (6- (7- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) thioureido) phenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamate (186)

To a solution of compound 181(0.24g, 0.45mmol, scheme 64) in 2-propanol (50mL) was added a solution of 4-fluorophenylacetyl isothiocyanate (0.1M, 0.8mmol) in acetonitrile (8 mL). The resulting mixture was heated to 70 ℃ for 1 hour, then cooled and concentrated. Chromatography of the residue on silica gel (eluent: 5% methanol/chloroform) gave the title compound 186(0.19g, 58% yield).

Step 2: n- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenylthiocarbamoyl) -2- (4-fluorophenyl) acetamide (187)

To a solution of 186(0.19g, 0.26mmol) in acetic acid (10mL) was added aqueous hydrochloric acid (3M, 1.0mL, 3.0 mmol). The mixture was stirred at room temperature for 3 hours, followed by partial concentration. The residue was partitioned between water and ethyl acetate, and the organic phase was collected, washed with saturated aqueous sodium bicarbonate solution and brine. Followed by anhydrous MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography (eluent: 15% methanol/chloroform) to give the title compound 187(80mg, yield 49%).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.53(d,J=5.5,1H),8.50(d,J=1.6,1H),8.30(s,1H),8.18(d,J=7.8,1H),8.04(dd,J=11.2,1.6,1H),7.89(dd,J=8.2,2.2,1H),7.54-7.50(m,2H),7.40-7.35(m,2H),7.22-7.15(m,2H),6.67(d,J=5.5,1H),3.83(s,2H),3.40(s,2H),3.37(t,J=5.7,2H),3.22(s,3H),2.82-2,75(m,4H),2.69(t,J=5.7,2H)。LRMS(M+H):634.4.

Scheme 47

Example 112

1- ((2- (7- (2-fluoro-4-cyclopropylaminocarbonylaminophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -3-isopropyl-1- (2-methoxyethyl) urea (189)

To a solution of 188(85mg, 0.166mmol) in DCM (5mL) was added isopropyl isocyanate (70.8mg, 0.832mmol) and the reaction mixture was stirred at rt overnight. The mixture was diluted with ethyl acetate, then washed with water, over anhydrous Na₂SO₄Dried, filtered, and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate to ethyl acetate with 20% MeOH) to give the title compound 189(57mg, 58% yield) as a white solid. ¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.49(d,J=5.48Hz,1H),7.89(s,1H),7.70(m,1H),7.35(t,J=8.99Hz,1H),7.19(m,1H),6.94(s,1H),6.64(d,J=5.28Hz,1H),6.55(m,1H),6.10(d,J=5.48Hz,1H),4.55(s,2H),3.83(s,3H),3.79(m,1H),3.21(s,3H),2.53(m,1H),1.05(d,J=6.45Hz,6H),0.63(m,2H),0.40(m,2H)。MS(m/z)=596.43(M+H)。

Compounds 190, 193 to 195 (examples 113, 115 to 117) were prepared from the precursors described in WO 2009/109035a1 and compound 113 (example 78, scheme 29) analogously to compound 189 (example 112, scheme 47).

TABLE 17 characterization of Compounds 190 to 195 (examples 113 to 117)

Scheme 48

Example 118

1- (3-fluoro-4- (2- (5- ((2-oxo-1, 3-oxazepin-3-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (201)

Step 1: 3- ((6-Bromopyridin-3-yl) methylamino) propan-1-ol (196)

To a solution of 6-bromonicotinaldehyde (1.25g, 6.72mmol) in DCM (25mL) was added 3-aminopropan-1-ol (1.514g, 20.16mmol) and acetic acid (0.385mL, 6.72mmol) and the reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (3.56g, 16.80mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and extracted with water. The organic phase was removed. The aqueous phase was concentrated and the resulting solid was stirred with a mixture of DCM and acetone, followed by filtration. Collecting filterLiquid through Na₂SO₄Dried and concentrated to give a pale yellow material, which was washed with Et₂Trituration with O afforded the title compound 196(0.9g, 55% yield) as an off white solid. MS:246(MH +).

Step 2: 3- ((6-Bromopyridin-3-yl) methyl) -1, 3-oxazepan-2-one (197)

To a solution of 196(0.9g, 3.67mmol) in DCM (30mL) was added CDI (0.595g, 3.67mmol) and the reaction mixture was stirred at rt over the weekend. The mixture was then concentrated and the residue was purified by flash chromatography (eluent: ethyl acetate) to give the title compound 197(373mg, yield 38%) as a colorless oil. MS:271(M + H).

And step 3: 3- ((6- (7-chlorothieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -1, 3-oxazepan-2-one (199)

To a solution of 197(373mg, 1.376mmol) in toluene (10mL) was added 7-chloro-2- (tributylstannyl) thieno [3, 2-b%]Pyridine 198(631mg, 1.376mmol) and Pd (PPh)₃)₄(159mg, 0.138 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was then cooled to room temperature and concentrated. With Et₂Trituration of the residue afforded the title compound 199(363mg, 73% yield) MS:360(MH +) as a beige solid.

And 4, step 4: 3- ((6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -1, 3-oxazepan-2-one (200)

To a solution of 4-amino-2-fluorophenol (70.7mg,0.556mmol) in DMSO (5mL) was added sodium tert-butoxide (53.4, 0.556mmol) and the reaction mixture was stirred for 30 min. Chloride 199(100mg, 0.278mmol) was added and the reaction mixture was heated at 100 ℃ overnight. The mixture was then cooled to room temperature and poured into water (20mL), and the precipitated product was collected by filtration and purified by Biotage (MeOH/ethyl acetate 0 to 50%, SNAP 25g column) to give the title compound 200 as a beige solid (147mg, 33% yield). MS:451(MH +).

And 5: 1- (3-fluoro-4- (2- (5- ((2-oxo-1, 3-oxazepin-3-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (201)

In a sealed flask, a reaction mixture consisting of amine 200(100mg, 0.222mmol) and 2-isocyanatopropyl (434mg, 5.10mmol) in DCM (3mL) was heated to 80 ℃ overnight. The mixture was then cooled to room temperature and purified by Biotage (Siliaflash 12g column, 0 to 12% MeOH/CHCl)₃) Purification gave, after isolation, the title compound 201 as a beige solid (35mg, 29.4% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.67(s,1H),8.55(d,1H,J=1.8Hz),8.50(d,1H,J=5.3Hz),8.33(s,1H),8.25(d,1H,J=8.2Hz),7.84(dd,1H,J1=2.2Hz,J2=8.2Hz),7.69(dd,J1=2.5Hz,J2=13.7Hz),7.35(t,1H,J=9.0Hz),7.12-7.10(m,1H),6.62(d,1H,J=5.1Hz),6.14(d,1H,J=7.4Hz),4.50(s,2H),4.21(t,2H,J=5.1Hz),3.77-3.72(m,1H),3.30-3.28(m,2H),1.97-1.92(m,2H),1.10(s,3H),1.08(s,3H)。MS:536.4(MH)+

Scheme 49

Example 119

1- (3-fluoro-4- (2- (4- ((2-oxopyrrolidin-1-yl) methyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (205)

Step 1: 1- (4- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl) pyrrolidin-2-one (203)

A mixture of compound 202(1g,2.411mmol), ethyl 4-aminobutyrate hydrochloride (0.808g, 4.82mmol) and DIPEA (1.263mL, 7.23mmol) in acetonitrile (12mL) was heated to reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated using Biotage (MeOH/ethyl acetate, 0 to 20%, SNAP 50g column) to purify the residue to give the title compound 203 as a beige solid (580mg, 52% yield). MS:464(MH +).

Step 2: 1- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) benzyl) pyrrolidin-2-one (204)

A reaction mixture consisting of nitro compound 203(580mg,1.25mmol), iron powder (594mg,10.64mmol) and ammonium chloride (57.6mg,1.076mmol) in an EtOH/water mixture (16mL/8mL) was stirred at 80 ℃ for 2 h. The reaction mixture was filtered while heating. Concentration of the filtrate afforded the title compound 204(542mg, 100% yield) as a brown solid. MS 434(MH) +.

And step 3: 1- (3-fluoro-4- (2- (4- ((2-oxopyrrolidin-1-yl) methyl) phenyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (205)

The title compound 205 was obtained starting from compound 204 and following a procedure analogous to that used for the synthesis of compound 201 (example 118, scheme 48).¹H NMR(400MHz,DMSO-d₆)δ(ppm):1H:8.66(s,1H),8.48(d,1H,J=5.5Hz),8.02(s,1H),7.86-7.84(m,2H),7.70(dd,1H,J1=2.3Hz,J2=13.5Hz),7.37-7.32(m,3H),7.13-7.10(m,1H),6.58(dd,1H,J1=0.8Hz,J2=5.3Hz),6.13(d,1H,J=7.4Hz),4.41(s,2H),3.78-3.74(m,1H),3.27(t,2H,J=7.3Hz),2.29(t,2H,J=8.2Hz),1.94-1.91(m,2H),1.10(s,3H),1.08(s,3H)。MS:519.5(M+H)。

Scheme 50

Example 120

Acetic acid 2- (((2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl ester (208)

Step 1: acetic acid 2- (((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl ester (206)

To a solution of 158(423mg, 0.925mmol, scheme 39) in DMF (18mL) was added 2-acetoxyacetic acid (164mg, 1.387mmol), DIPEA (0.565mL, 3.24mmol) and HATU reagent (1055mg, 2.77 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which NaHCO was added ₃Saturated solution (200mL) and ethyl acetate (300 mL). A white precipitate formed, which was collected by filtration and removed. The organic layer of the filtrate was collected, dried over anhydrous sodium sulfate and concentrated to give a pale yellow solid, which was triturated with ether to give the title compound 206(570mg, 111% yield, crude product), which was used in the next step without further purification. MS 558(MH) +.

Step 2: acetic acid 2- (((2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl ester (207)

A reaction mixture consisting of 206(300mg, 0.538mmol), ammonium chloride (24.75mg, 0.463mmol) and iron powder (255mg, 4.57mmol) in ethanol (6 mL)/water (3.0mL) was heated to reflux for 1 hour. The reaction mixture was filtered while heating, and concentrated. The residue was purified by Biotage (MeOH/DCM, 0 to 20%, SNAP 25g column) to give title compound 207(133mg, 0.252mmol, 47% yield) as a white solid. MS 528(MH) +.

And step 3: acetic acid 2- (((2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) (2-methoxyethyl) amino) -2-oxoethyl ester (208)

To a solution of 207(130mg, 0.246mmol) in THF (20mL) at 0 ℃ were added DIPEA (0.172mL, 0.986mmol) and triphosgene (43.9mg, 0.148 mmol). The reaction mixture was stirred at 0 ℃ for 1h, after which cyclopropylamine (70.3mg, 1.232mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, after which it was concentrated. The residue was purified by Biotage (MeOH/DCM, 0 to 20%, SNAP 25g column) to give the title compound 208(104mg, 0.170mmol, 69% yield) as a white solid. MS:611(MH) +.

Scheme 51

Example 121

N- ((2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) acetamide (212)

Step 1: n- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) acetamide (210)

To a solution of 158(100mg, 0.219mmol, scheme 51) in pyridine (6mL) was added acetic anhydride (0.022mL, 0.230mmol) at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and CuSO₄(l M) between the solutions, the organic layer was collected, washed with 1N HCl followed by water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Biotage (MeOH/DCM, 0 to 15%, SNAP 25g column) to give the title compound 210 as a white solid (80mg, 0.160mmol, 73% yield). MS 500(MH) +.

Step 2: n- ((2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) acetamide (211)

The title compound 211 was obtained starting from compound 210 and following a procedure analogous to that used for the synthesis of compound 207 (scheme 50). MS 470(MH) +.

And step 3: n- ((2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) -N- (2-methoxyethyl) acetamide (212)

The title compound was obtained starting from compound 211 and following a procedure analogous to that used for the synthesis of compound 208 (scheme 50)And (e) an object 212.¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.75(s,1H),8.55(d,1H, J =5.3Hz),7.95 and 7.93(s,1H),7.76(dd,1H, J1=2.3Hz, J2=13.5Hz),7.41(t,1H, J =9.0Hz),7.24-7.21(m,1H),7.08 and 6.92(s,1H),6.70(d,1H, J =5.5Hz),6.60(m,1H),4.74 and 4.70(s,2H),3.88 and 3.86(s,3H),3.45(m,2H),3.36(m,1H),3.28(s,3H),3.24(m,1H),2.60-2.57(m,1H),2.14 and 2.12(s,3H), 0.48 (m, 0.66H), 0.48H (m, 0H). MS:553(MH) +.

Scheme 52

Example 122

2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (2-morpholinoethyl) -1H-imidazole-5-carboxamide (217)

Step 1: 2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazole-5-carboxylic acid (214)

To the suspension of ester 213(1.5g,3.50mmol) in THF (10mL) was added a solution of LiOH (0.419g, 17.51mmol) in water (10.00mL) and the reaction mixture was stirred overnight. THF was evaporated under reduced pressure, water was added and the solution was acidified to pH 1 with 1N HCl, a precipitate formed, collected by filtration and dried to give the title compound 214(1.4g, 3.38mmol, 96% yield) as a white solid. MS415(MH) +.

Step 2: 2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (2-morpholinoethyl) -1H-imidazole-5-carboxamide (215)

To a solution of acid 214(180mg, 0.434mmol) in DMF (8mL) was added 2-morpholinoethylamine (0.114mL, 0.869mmol), DIPEA (0.266mL, 1.520mmol) and HATU reagent (1.303 mmol). The reaction mixture was stirred at room temperature for 4 hours. Addition of NaHCO₃A saturated solution (5mL) and ethyl acetate (5mL) formed a precipitate, which was collected by filtration. Separating the organic layer of the filtrate, and removing waterDry over sodium sulfate, concentrate and combine the residue with the collected precipitate to give the title compound 215(180mg, 0.342mmol, 79% yield) as a white solid. MS 527.5(MH) +.

And step 3: 2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (2-morpholinoethyl) -1H-imidazole-5-carboxamide (216)

A reaction mixture of nitro compound 215(180mg, 0.342mmol), iron powder (162mmol) and ammonium chloride (15.7mg, 0.294mmol) in an EtOH/water mixture (10mL/5mL) was heated to reflux for 1 hour. The reaction mixture was filtered while heating. Concentration of the filtrate afforded the title compound 216(130mg, 0.262mmol, 77% yield) as a white solid. MS 497.5(MH) +.

And 4, step 4: 2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (2-morpholinoethyl) -1H-imidazole-5-carboxamide (217)

To a suspension of aniline 216(130mg, 0.262mmol) in THF (10mL) at 0 ℃ were added DIPEA (0.137mL, 0.785mmol) and triphosgene (38.8mg, 0.131 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour, after which cyclopropylamine (0.054mL, 0.785mmol) was added and the mixture was stirred at 0 ℃ for 10 minutes. The reaction mixture was allowed to warm slowly to room temperature and stirred over the weekend, then partitioned with NaHCO₃Saturated solution and ethyl acetate. The organic layer (suspension) was concentrated and the residue was dry loaded onto a column (Biotage, MeOH/DCM,0 to 25%, SNAP 10g column), purified twice and triturated with ether and acetone to give the title compound 217 as a white solid (30.4mg, 0.052mmol, 20% yield). ¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.75(s,1H),8.59(d,1H, J =5.5Hz),8.48(m,1H),8.07(s,1H),7.78-7.74(m,1H),7.71(s,1H),7.42(t,1H, J =9.0Hz),7.25-7.22(m,1H),6.74(d,1H, J =5.5Hz),6.61-6.60(m,1H),4.22(s,3H),3.62(t,4H, J =4.5Hz), inner 3.38-3.33(m,2H),2.60-2.57(m,1H),2.52-2.46(m,6H),0.71-0.67(m,2H),0.48-0.46(m, 2H). MS:580.6(MH) +

Example 123

2- (7- (2-fluoro-4- (3-isopropylureido) phenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (2-morpholinoethyl) -1H-imidazole-5-carboxamide (218)

The title compound 218 was obtained starting from compound 216 and following a similar procedure as used for the synthesis of compound 201 (scheme 48).¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.73(s,1H),8.59(d,1H, J =5.3Hz),8.48(t,1H, J =5.5Hz),8.07(s,1H),7.76-7.71(m,2H),7.41(t,1H, J =9.0Hz),7.17(d,1H, J =8.2Hz),6.73(d,1H, J =5.1Hz),6.19(d,1H, J =7.7Hz),4.21(s,3H),3.83-3.78(m,1H),3.61(m,4H), inner 3.39(m,2H),2.51-2.46(m,6H),1.15(s,3H),1.14(s, 3H). MS:582.6(MH) +

Scheme 53

Example 124

1-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- (pyrrolidine-1-carbonyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (222)

Step 1: 2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazole-5-carbonyl chloride (219)

To a pre-cooled solution of acid 214(1.25g, 3.02mmol, scheme 52) in THF (12.07mL) was added DMF (0.023mL, 0.302mmol) and oxalyl chloride (0.660mL, 7.54mmol) and the resulting solution was stirred at 0 ℃ for 30 min. The solvent was evaporated, the residue triturated with ether and dried under high vacuum to give the title compound 219 as a beige solid (1.306g, 3.02mmol, 100% yield). MS 429.2(MH +, COOMe),433.1(COCl, MH +).

Step 2: (2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) (pyrrolidin-1-yl) methanone (220)

A suspension of acid chloride 219(700mg, 1.617mmol) and pyrrolidine (0.3mL, 3.63mmol) in DCM (50mL) was stirred at RT overnight. The reaction mixture was concentrated. The residue was triturated with ether to give the title compound 220(756mg, 1.617mmol, 100% yield) as a beige solid. MS:468.3(MH +).

And step 3: (2- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) (pyrrolidin-1-yl) methanone (221)

The title compound 221 was obtained starting from compound 220 and following a similar procedure as used for the synthesis of compound 207 (scheme 50). MS:438.4(MH +).

And 4, step 4: 1-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- (pyrrolidine-1-carbonyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (222)

The title compound 222 was obtained starting from compound 221 and following a similar procedure as used for the synthesis of compound 208 (scheme 50).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.76(s,1H),8.59(d,1H,J=5.3Hz),8.06(s,1H),7.76(dd,1H,J1=2.1Hz,J2=13.5Hz),7.59(s,1H),7.42(t,1H,J=9.0Hz),7.24-7.22(m,1H),6.74(d,1H,J=5.5Hz),6.60(s,1H),4.07(s,3H),3.72-3.69(m,4H),2.60-2.58(m,1H),1.93-1.90(m,4H),0.70-0.67(m,2H),0.47-0.45(m,2H)。MS:521.5(MH)+

Example 125

1- (3-fluoro-4- (2- (1-methyl-5- (pyrrolidine-1-carbonyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (223)

The title compound 223 was obtained starting from compound 221 and following a procedure analogous to that used for the synthesis of compound 201 (scheme 48).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.74(s,1H),8.58(d,1H,J=5.5Hz),8.06(s,1H),7.73(dd,1H,J1=2.1Hz,J2=13.5Hz),7.5(s,1H),7.41(t,1H,J=9.0Hz),7.18-7.16(m,2H),6.74(d,1H,J=5.4Hz),6.19(d,1H,J=7.6Hz),4.07(s,3H),3.83-3.78(m,1H),3.70-3.68(m,4H),1.91(m,4H),1.15(s,3H),1.13(s,3H)。MS:523.2(MH)+

Example 126

2- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-N- (3-morpholinopropyl) -1H-imidazole-5-carboxamide (224)

224: example 126

The title compound 224 was obtained in three steps in analogy to compound 222 (example 123, scheme 53) starting from acid chloride 219.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.75(s,1H),8.59(d,1H,J=5.3Hz),8.53(m,1H),8.07(s,1H),7.76(dd,1H,J1=2.3Hz,J2=13.5Hz),7.71(s,1H),7.42(t,1H,J=9.0Hz),7.25-7.23(m,1H),6.74(d,1H,J=5.3Hz),6.62-6.61(m,1H),4.22(s,3H),3.62-3.60(m,4H),3.31-3.28(m,2H),2.59-2.58(m,1H),2.38-2.34(m,6H),1.73-1.70(m,2H),0.70-0.68(m,2H),0.48-0.46(m,2H)。MS:594.6(MH)+

Scheme 54

Example 127

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (pyrrolidine-1-carbonyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (226)

Step 1: 6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) nicotinic acid (225)

To a suspension of aldehyde 47(200mg, 0.446mmol, scheme 15) in DMF (10mL) at room temperature was added(330mg, 0.535mmol) and the reaction mixture was stirred at 50 ℃ for 16 h. The reaction mixture was cooled to 0 ℃, treated with 1N aqueous HCl (20mL), and stored in the chamber The mixture was stirred for another 1 hour. The resulting precipitate was collected by filtration, washed with water (30mL) and dried. Trituration of the crude material with MeOH afforded the title compound 225 as a beige solid (165mg, 80% yield). NMR (400MHz, CD)₃OD) delta (ppm) 9.66(bs,1H),8.98(dd, J =1.9,0.9Hz,1H),8.51(d, J =5.5Hz,1H),8.31(s,1H),8.22(dd, J =8.1,1.9Hz,1H),8.17(dd, J =8.1,0.9Hz,1H),7.77(dd, J =13.7,2.5Hz,1H),7.45(bs,1H),7.37(t, J =9.1Hz,1H),7.26(dd, J =8.9,1.5Hz,1H),6.62(d, J =5.3,0.8Hz,1H),2.60-2.52(m,1H),0.69-0.56(m,2H), 0.50.50 [ OH ] [ 0.37H ] (carboxylic acid)]。MS:465.3(MH)⁺.

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (pyrrolidine-1-carbonyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (226)

To a solution of acid 225(70mg, 0.151mmol), DIPEA (0.105mL, 0.603mmol) pyrrolidine (0.025mL, 0.301mmol) in DMF (4mL) was added HATU reagent (143mg, 0.377 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH and brine, over anhydrous MgSO₄Dried, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10g column) followed by chromatography (chromatotron) (eluent: MEOH/DCM, 5 to 10%) before Et with mixture ₂Trituration in O/MeOH/acetone afforded the title compound 226(15mg, 0.029mmol, 19% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): deletions from formic acid OH,9.66(bs,1H),8.98(dd, J =1.9,0.9Hz,1H),8.51(d, J =5.5Hz,1H),8.31(s,1H),8.22(dd, J =8.1,1.9Hz,1H),8.17(dd, J =8.1,0.9Hz,1H),7.77(dd, J =13.7,2.5Hz,1H),7.45(bs,1H),7.37(t, J =9.1Hz,1H),7.26(dd, J =8.9,1.5Hz,1H),6.62(d, J =5.3,0.8Hz,1H),2.60-2.52(m,1H),0.69-0.56(m,2H), 0.50-0.50 (m, 2H). MS (M/z):465.3(M + H)

In analogy to compound 226 (example 127, scheme 54), compounds 227 to 233 and 235 to 238 (examples 128 to 134 and 136 to 139) were prepared in one step starting from acid 225. In analogy to compound 61 (example 44, scheme 16), respectively, compounds 239 to 241 (examples 140 to 142) were obtained from basic hydrolysis of compounds 236 to 238.

TABLE 18 characterization of Compounds 227 to 241 (examples 128 to 142)

Scheme 55

Example 143

6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -N-methyl-N- ((2R,3S,4S,5S) -2,3,4,5, 6-pentahydroxyhexyl) nicotinamide (244)

Step 1 (2R,3S,4S,5S) -2,3,4,5, 6-pentakis (tert-butyldimethylsilyloxy) -N-methylhexan-1-amine (242)

To a solution of N-methyl-D-glucamine (0.5g, 2.56mmol) in acetonitrile (25.6mL) was added TBDMSCl (1.930g, 12.81mmol) and DBU (1.930mL, 12.81mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 20 minutes, then warmed to room temperature, followed by stirring overnight. MS shows a mixture of compounds protected by tri and tetra TBDMS. Concentrating The reaction mixture was partitioned between ethyl acetate and H₂Between O, the organic phase was collected, washed with water, 1N HCl solution and brine, dried and concentrated to give the title compound 242 as a pale yellow syrup (1.53g, 2.346mmol, 92% yield) used as such. 538.6,652.7 for MS.

Step 2: 6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -N-methyl-N- ((2R,3S,4S,5S) -2,3,4,5, 6-penta (tert-butyldimethylsilyloxy) hexyl) nicotinamide (243)

To a solution of acid 225(220mg,0.474mmol, scheme 54), amine 242(309mg, 0.474mmol) and DIPEA (0.331mL, 1.895mmol) in DMF (5mL) was added HATU reagent (270mg, 0.710 mmol). The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, 1M NaOH and brine, and over anhydrous MgSO₄Dried, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0 to 15%, SNAP 10g column) to give the title compound 243(250mg, 0.254mmol, 54% yield) as a white solid. MS:985.4(MH +).

And step 3: 6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -N-methyl-N- ((2R,3S,4S,5S) -2,3,4,5, 6-pentahydroxyhexyl) nicotinamide (244)

To a solution of 243(250mg, 0.228mmol) in THF (5mL) was added TBAF (1.0M solution in THF) (0.273mL, 0.273mmol), and the reaction mixture was stirred at rt for 2 h before concentration. From Biotage (MeOH/DCM, 20 to 50%, SNAP 25g column) and Gilson (Phenomenex, Luna, 15. mu.C 18(2)100A,250X50.00mm, 15. mu.m, MeOH/H containing 0.05% formic acid₂O, 40 to 90%, flow rate =30mL/min) to give the title compound 244 as a white solid (10mg, 0.016mmol, 7% yield).¹H NMR(400MHz,CD₃OD)δ(ppm):8.72(d,1H,J=3.9Hz),8.47(s,br,1H),8.19-8.13(m,2H),8.13-8.00(m,1H),7.65(dd,1H,J1=2.5Hz,J2=13.1Hz),7.29(t,1H,J=8.8Hz),7.20-7.17(m,1H),6.64(d,1H,J=5.3Hz),4.20-4.18(m,0.45H),4.07-4.04(m,0.55H),3.83-3.53(m,7H),3.17(s,3H),2.62-2.57(m,1H),0.78-0.73(m,2H),0.54-0.50(m,2H)。MS:642.6(M+H)。

Scheme 56

Example 144

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-methoxyethylamino) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (247)

Step 1: 2- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (246)

To a stirred solution of tert-butyl 2- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-pyrazol-1-yl) ethyl (2-methoxyethyl) carbamate (245,1.22g,2.312mmol) and pyridine (374 μ L,4.62mmol) in DMF (30mL) was added phenyl chloroformate (348 μ L,2.77mmol) at 0 ℃ and the reaction mixture was stirred for 30 min. Cyclopropylamine (407. mu.l, 5.78mmol) was added at 0 ℃ and the reaction mixture was heated for an additional 30 minutes at 60 ℃. After cooling to room temperature, the reaction mixture was quenched by addition of water and saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV 0/100 to 10/90). The desired fractions were collected and concentrated to give the title compound 246 as a yellow solid (722mg, 0.18mmol, 61% yield). MS (M/z) 611.63(M + H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-methoxyethylamino) ethyl) -1H-pyrazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (247)

To a solution of 246(722mg, 0.18mmol) in DCM (30mL) was added TFA (7mL) and the reaction mixture was stirred for 45 min. The reaction mixture was concentrated, diluted with water and 4M NaOH to pH11, and diluted with BAnd (5) extracting with ethyl acetate. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by Biotage (SNAP 50g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV0/00 to 15/85) gave a material which, when triturated with ethyl acetate, gave title compound 247(3.15mg, 0.617mmol, 52% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.71(s,1H),8.44(d, J =5.6Hz,1H),8.33(s,1H),8.01(d, J =0.8Hz,1H),7.72(d, J =2.4 and 13.6Hz,1H),7.68(s,1H),7.35(t, J =9.2Hz,1H),7.22-7.16(m,1H),6.57(d, J =2.4Hz,1H),6.53(d, J =5.6Hz,1H),4.21(t, J =6.0Hz,2H),3.36(t, J =5.6Hz,2H),2.98(s,3H),2.97(t, J =6.0Hz,2H),2.68(t, J =5.6, 2H), 2.59-2.0H, 62.40H, 62H, 0.60H, 1H, 62H, 40H, 1H, and 1H. MS (M/z) 511.54(M + H).

Scheme 57

Example 145

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-methoxyethylamino) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (253)

Step 1: 2- (4-iodo-1H-imidazol-1-yl) -N- (2-methoxyethyl) ethylamine (248)

To a stirred solution of 4-iodoimidazole (8.8g, 45.4mmol) in THF (200mL) under nitrogen was added dropwise 60% NaH (1.99g,49.9mmol) at 0 ℃. After 15 minutes, 1-bromo-2-chloroethane (4.53mL, 54.4mmol) was added at 0 ℃. The reaction mixture was heated at 60 ℃ for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340g column; MeOH/ethyl acetate: over 20CV 0/100 to 5/95) to give the crude product 1- (2-chloroethyl) -4-iodo-1H-imidazole (not shown in scheme 57) as a colorless oil (7g, 27.26mmol, 60% yield). MS (M/z) 256.83(M + H).

To a stirred solution of the crude product 1- (2-chloroethyl) -4-iodo-1H-imidazole (7g, 27.26mmol) in DMSO (20mL) was added 2-methoxyethylamine (7.75mL, 89 mmol). The reaction mixture was heated at 60 ℃ for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340g column; MeOH/ethyl acetate: via 20CV 0/100 to 13/87) to give the title compound 248(2.64g, 8.94mmol, 60% yield) as a colorless oil. MS (M/z) 296.12(M + H).

Step 2: 2- (4-iodo-1H-imidazol-1-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (249)

To a stirred solution of 248(2.64g, 8.94mmol) in DCM (30mL) was added di-tert-butyl dicarbonate (2.75g, 12.60 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated. The residue was purified by Biotage (SNAP 100g column; ethyl acetate/hexane: via 20CV 20/80 to 100/0) to give the title compound 249 as a pale yellow oil (2.16g, 5.47mmol, 56% yield). MS (M/z) 396.07(M + H).

And step 3: 2- (4- (7-chlorothieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (250)

7-chlorothiophene [3,2-6 ] stirred at-15 deg.C]To a solution of pyridine (1.39g, 8.20mmol) in THF (30mL) was added n-butyllithium (3.28mL, 8.20 mmol). After 30 minutes, ZnCl was added at-15 ℃₂(1.12g,8.20mmol) and the reaction mixture was allowed to warm to room temperature over 45 minutes. A solution of tetrakis (triphenylphosphine) palladium (0.126g, 0.11mmol) and iodide 249(2.16g, mmol) in THF (10mL) was added and the mixture was heated to reflux for 45 min, then concentrated. The reaction mixture was diluted with water and ammonium hydroxide and extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 250 as a light brown solid (2.37g, 5.43mmol, 99% yield). MS(m/z):437.45(M+H)。

And 4, step 4: 2- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (251)

To a stirred solution of 4-amino-2-fluorophenol hydrochloride (1.96g, 11.96mmol) in NMP (15mL) was added potassium tert-butoxide (2.93g, 26.1 mmol). After 30 minutes, chloride 250(4.75g, 10.87mmol) was added and the reaction mixture was heated at 100 ℃ for 2 hours.

In a separate flask, a solution of 4-amino-2-fluorophenol hydrochloride (1.96g, 11.96mmol) in NMP (15mL) was treated with potassium tert-butoxide (2.93g, 26.1mmol) and the resulting phenoxide solution was added to the original reaction mixture at 100 ℃. After 30 min, the reaction was quenched by addition of water and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 0/100 to 10/90) to give the title compound 251(1.2g, 2.27mmol, 21% yield) as a light brown solid. MS (M/z) 528.64(M + H).

And 5: 2- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (252)

To a stirred solution of amine 251(1.2g, 2.27mmol) and pyridine (368. mu.L, 4.55mmol) in DMF (11mL) at 0 ℃ was added phenyl chloroformate (342. mu.L, 2.73mmol) and the reaction mixture was stirred for 30 minutes. Cyclopropylamine (401 μ l,5.69mmol) was added at 0 ℃ and the reaction mixture was heated for an additional 45 minutes at 60 ℃. After cooling to room temperature, the reaction mixture was diluted with water and saturated ammonium chloride solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 252(1g, 1.63mmol, 72% yield) as a beige solid. MS (M/z) 611.70(M + H).

Step 6: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (2-methoxyethylamino) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (253)

To a solution of 252(1g, 1.63mmol) in DCM (50mL) was added TFA (15mL) and the reaction mixture was stirred for 1.5 h, concentrated, diluted with water and 4M NaOH to pH 11 and extracted with DCM/MeOH. The extract was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM containing 2% ammonium hydroxide: 20CV 0/100 to 10/90) to give title compound 253(800mg, 1.56mmol, 96% yield) as a beige solid. ¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.69(s,1H),8.42(d, J =5.6Hz,1H),7.91(d, J =1.2Hz,1H),7.75(d, J =0.8Hz,1H),7.72(dd, J =2.4 and 13.6Hz,1H),7.66(s,1H),7.36(t, J =8.8Hz,1H),7.21-7.16(m,1H),6.57(d, J =2.85Hz,1H),6.54(d, J =5.6Hz,1H),4.06(t, J =6.4Hz,2H),3.36(t, J =5.6Hz,2H),3.22(s,3H),2.89(t, J =6.4, 2H),2.67(t, J =5.6Hz,2H), 2.67(t = 5.68H), 2.58H, 0.53H, 0.40H), 0.53 (m,1H), 0.61H, 1H, 0.6 Hz. MS (M/z) 511.56(M + H).

Compound 254 (example 146) was synthesized starting from compound 247 (scheme 56) and following a similar procedure as described above for the synthesis of compound 114 (example 79, scheme 29). Compound 254-a (example 146-a) was synthesized from compound 253 (scheme 57) and as described in the synthesis of compound 114 (example 79, scheme 29) above. Compounds 255 to 256 (examples 147 to 148) were prepared in one step by reacting the corresponding secondary amine precursors 247 (scheme 56) and 253 (scheme 57) with ethyl isocyanate.

TABLE 19 characterization of Compounds 254 to 256 (examples 146 to 148)

In analogy to compound 31 (example 17, scheme 13) from the corresponding secondary amine precursors 247 (scheme 56), 253 (scheme 57) and 171 (table 16); and acetoxyacetic acid to prepare compounds 257 to 259 (example 149 to example 151) in two steps. Compound 259-a (example 151-a) was prepared from amine precursor 25 (scheme 11) following the procedure described above for the synthesis of compound 115-a (example 80-a, scheme 29).

TABLE 20 characterization of Compounds 257 to 259 (examples 149 to 151)

Scheme 58

Example 153

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (266)

Step 1: 1- (2, 2-diethoxyethyl) -4-iodo-1H-imidazole (260)

To a stirred solution of 4-iodoimidazole (10g,51.6mmol) and bromoacetaldehyde diethyl acetal (9.31mL) in DMSO (30mL) was added K₂CO₃(10.69g,77 mmol). The reaction mixture was heated at 110 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. By Biotage (SNAP 80)g, column; ethyl acetate/hexane: the residue was purified via 20CV 0/100 to 50/50). The desired fractions were collected and concentrated to give the title compound 260 as a yellow oil (11.29g, 36.4mmol, 71% yield). MS (M/z) 310.97(M + H).

Step 2: 7-chloro-2- (1- (2, 2-diethoxyethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridine (261)

7-chlorothiophene [3,2-b ] stirred at-15 DEG C]To a solution of pyridine (9.26g,54.6mmol) in THF (88mL) was added n-butyllithium (21.84mL, 54.6 mmol). After 30 minutes, 0.5M ZnCl was added at-15 ℃ ₂Solution in THF (109mL,54.6mmol) and the reaction mixture was allowed to warm to room temperature over 45 minutes. A solution of tetrakis (triphenylphosphine) palladium (0.841g, 0.73mmol) and iodide 260(11.29g, 36.4mmol) in THF (33mL) was added and the mixture was heated to reflux for 3 hours, then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by Biotage (SNAP 80g column; ethyl acetate/hexane: via 20CV 0/100 to 100/0) gave a material which, when triturated with MTBE, gave the title compound 261 as a light brown solid (1.2g, 3.41mmol, 9% yield). MS (M/z) 437.45(M + H).

And step 3: 4- (2- (1- (2, 2-diethoxyethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluoroaniline (262)

To a stirred solution of 4-amino-2-fluorophenol hydrochloride (1.39g, 8.53mmol) in DMSO (20mL) was added potassium tert-butoxide (1.99g, 17.76 mmol). After 30 min, chloride 261(2.5g, 7.11mmol) was added and the reaction mixture was heated at 100 ℃ for 1 h.

In a separate flask, a solution of 4-amino-2-fluorophenol hydrochloride (1.39g, 8.53mmol) in DMSO (20mL) was treated with potassium tert-butoxide (1.99g, 17.76mmol) and the resulting phenoxide solution was added to the original reaction mixture at 100 ℃. After 30 min, the mixture was poured into water (300mL) to form a precipitate, which was collected by filtration and dried under high vacuum to give the title compound 262 as a light brown solid (2.86g, 6.46mmol, 91% yield). MS (M/z) 443.44(M + H).

And 4, step 4: 1-cyclopropyl-3- (4- (2- (1- (2, 2-diethoxyethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (263)

To a stirred solution of amine 262(2.86g, 6.46mmol) and pyridine (1.04mL, 12.93mmol) in DMF (50mL) at 0 ℃ was added phenyl chloroformate (973. mu.L, 7.76 mmol). After 30 minutes, cyclopropylamine (1.14mL, 16.16mmol) was added at 0 ℃ and the reaction mixture was heated at 60 ℃ for 45 minutes. Cyclopropylamine (1mL, 14.18mmol) was added and the reaction mixture was heated at 60 ℃ for an additional 10 minutes. After cooling to room temperature, the reaction mixture was quenched by addition of water to form a precipitate. The solid was collected by filtration, washed with water and dried under vacuum for 2 hours. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV0/100 to 10/90). The desired fractions were collected, concentrated, triturated with MTBE and dried under high vacuum to give the title compound 263 as a pink solid (2.95g, 5.61mmol, 87% yield). MS (M/z) 526.60(M + H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2-oxoethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (264)

To acetal 263(2.95g, 5.61mmol) in acetic acid/H₂To a solution in O (20/20mL) was added concentrated HCl (2mL) and the reaction mixture was heated at 90 ℃ for 1 hour. The reaction mixture was concentrated, diluted with water and 4m naoh to pH 10 to form a precipitate, which was collected by filtration, washed with water and dried in vacuo. This material was then purified by Biotage (SNAP 100g column; MeOH/DCM with 2% ammonium hydroxide: 20CV0/100 to 15/85) to afford the title compound 264(1.2g, 2.66mmol, 47% yield) as a brown solid. MS (M/z) 484.51(M + H).

Step 6: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (266)

To a solution of 264(300mg, 0.66mmol), N-methylpiperazine (74. mu.l, 0.66mmol) and acetic acid (76. mu.l, 1.33mmol) in NMP (10mL) was added sodium triacetoxyborohydride (422mg, 1.99mmol) and the reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic extracts were washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 40g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV 0/100 to 15/85) and by Gilson (Phenomenex, Luna 15. mu. C18(2)100A, 250X50.0mm, 15 μm; MeOH/water with 0.05% formic acid: 60 min 20/80 to 95/5, flow rate: 30mL/min) to give the title compound 266(180mg, 0.33mmol, 51% yield, diformate) as a white solid.

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.42(bs,1H),8.41(d, J =5.6Hz,1H),8.29(bs,2H),7.90(d, J =0.8Hz,1H),7.76(d, J =1.2Hz,1H),7.73(dd, J =2.4 and 13.6Hz,1H),7.65(s,1H),7.33(t, J =8.8Hz,1H),7.23(bs,1H),7.23-7.19(m,1H),6.54(d, J =5.6Hz,1H),4.13(t, J =6.0Hz,2H),2.66(t, J =6.4Hz,2H),2.57-2.52(m,1H),2.50-2.25(m,8H),2.19(s,3H),0.65 (m, 0.44H), 0.44-2.44 (m, 2H). MS (M/z):536.3(M + 1).

Compound 267 is prepared from aldehyde 264 in analogy to compound 169 (example 102, scheme 41).

TABLE 21 characterisation of Compound 267 (example 154)

Scheme 59

Example 155

1-cyclopropyl-3- (3-fluoro-4- (2- (1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (271-A)

Step 1: 3-fluoro-4- (2-iodothieno [3,2-b ] pyridin-7-yloxy) aniline (268)

To a solution of 4-amino-2-fluorophenol (1.83g, 14.38mmol) in DMSO (30mL) was added potassium tert-butoxide (1.61g,14.38 mmol). After 15 minutes 7-chloro-2-iodothieno [3,2-b ] was added]Pyridine (2.5g,8.46mmol, Ragan J.A.et al, Organic Process Research and Development,2003,7,676 and 683), and heating the reaction mixture at 100 ℃ for 60 minutes. The mixture was cooled to room temperature, then poured into water (250mL) at 40 ℃ to 45 ℃ and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, dried and purified by flash chromatography on silica gel (eluent: hexane containing 60% ethyl acetate) to give the title compound 268(1.06g, 32% yield) as a brown solid.¹H NMR(300MHz,CDCl₃)δ(ppm):8.41(d,J=5.4Hz,1H),7.75(s,1H),7.03(t,J=9.0Hz,1H),6.57-6.45(m,3H),3.83(s,2H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2-iodothieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (269)

Pyridine (0.55mL, 6.77mmol) was added to a solution of amine 268(1.7g, 3.98mmol) in DMF (7mL) at room temperature and the solution was stirred under Ar atmosphere to yield a solution for 10 min. Phenyl chloroformate (0.75mL, 5.97mmol) was added at 0 ℃ and the mixture was stirred at room temperature for 40 minutes. Cyclopropylamine (1.1mL, 15.9mmo1) was added to the mixture and the reaction mixture was warmed to 50 ℃ and stirred for 2 hours. The mixture was then cooled to room temperature, then poured into water (150mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried. Trituration of the crude material with ethyl acetate afforded the title compound 269(1.75g, 86% yield) as a pale purple solid. ¹H NMR(300MHz,DMSO-d6)δ(ppm):8.70(br,1H),8.45(d,J=5.4Hz,1H),7.91(s,1H),7.72(dd,J=13.5,2.4Hz,1H),7.35(t,J=9.0Hz,1H),7.23(m,1H),6.62(d,J=5.4Hz,1H),6.56(br,1H),2.60-2.40(m,1H),0.70-0.60(m,2H),0.48-0.35(m,2H).

And step 3: 4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (270)

Iodide 269(2g, 4.26mmol), 1-N-Boc-4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine (1.85g,5.96mmol), NaHCO₃(1.1g,12.8mmol) and tetrakis (triphenylphosphine) palladium (0.49g, 0.43mmol) were suspended in a mixture of DME/water (80mL/16 mL). The mixture was degassed with a stream of Ar, heated at 80 ℃ and stirred for 16 hours. The mixture was then cooled and filtered through a pad of celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound 270 as a white solid (1.7g, 78% yield).¹H NMR(300MHz,DMSO-d6)δ(ppm):8.73(s,1H),8.45(d,J=5.4Hz,1H),7.72(dd,J=13.5,2.4Hz,1H),7.55(s,1H),7.35(t,J=9.0Hz,1H),7.24-7.16(m,1H),6.60(br,1H),6.57(d,J=5.4Hz,1H),6.40(br,1H),4.15-4.00(m,2H),3.63-3.54(m,2H),2.70-2.40(m,3H),1.44(s,9H),0.70-0.60(m,2H),0.48-0.35(m,2H).

And 4, step 4: 1-cyclopropyl-3- (3-fluoro-4- (2- (1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea dihydrochloride (271)

To a suspension of 270(996mg, 1.90mmol) in ethyl acetate (20mL) was added 1N Cl-ethyl acetate (11.4mL, 11.4 mmol). The reaction mixture was stirred for 18 hours, and the precipitate was collected by filtration, washed with ethyl acetate (30mL) and dried to give the title compound 271(962mg, yield 100%) as a pale yellow solid. ¹H NMR(300MHz,DMSO-d6)δ(ppm):9.22(br,2H),9.03(s,1H),8.58(d,J=6.0Hz,1H),7.74(dd,J=13.5,2.7Hz,1H),7.70(s,1H),7.38(t,J=9.0Hz,1H),7.25-7.15(m,1H),6.77(d,J=6.0Hz,1H),6.72(s,1H),6.47(s,1H),4.80-4.30(br，1H),3.85-3.75(m,2H),3.42-3.31(m,2H),2.90-2.80(m,2H),2.60-2.40(m,1H),0.70-0.60(m,2H),0.48-0.35(m,2H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (271-A)

Stirring to the rightStirred dihydrochloride 271(150mg, 0.302mmol) in ethyl acetate (50mL) NaHCO₃Saturated solution (50 mL). The reaction mixture was stirred for 1 hour to give a suspension. The solid was collected by filtration, washed with water, dried in vacuo and purified by Biotage (SNAP 25g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV 0/100 to 15/85) to give the title compound 271-a as a white solid when triturated with ethyl acetate (45mg, 0.106mmol, 35% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm):8.75(s,1H),8.43(d, J =5.6Hz,1H),7.71(dd, J =2.0 and 13.6Hz,1H),7.47(s,1H),7.34(t, J =9.2Hz,1H),7.23-7.16(m,1H),6.62(s,1H),6.55(d, J =5.6Hz,1H),6.43(s,1H),3.40(bs,2H),2.93(t, J =5.6Hz,2H),2.59-2.50(m,1H),2.46(bs,2H),0.66-0.62(m,2H),0.44-0.40(m, 2H). MS (M/z) 425.42(M + H)

Scheme 60

Example 156

4- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) -4-oxobutanoic acid (273)

Step 1: 4- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) -4-oxobutanoic acid methyl ester (272)

To a stirred suspension of 271(150mg, 0.302mmol) and DIPEA (123. mu.L, 0.707mmol) in DMF (10mL) was added methylsuccinyl chloride (65. mu.L, 0.53 mmol). The reaction mixture was stirred at room temperature for 2.5 days. Water was added and the reaction mixture was extracted with DCM. The organic layer was washed successively with brine, dried over anhydrous sodium hydrophosphate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 272(120mg, 0.223mmol, 63% yield) as an off-white solid. MS (M/z):539.5(M + H).

Step 2: 4- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -5, 6-dihydropyridin-1 (2H) -yl) -4-oxobutanoic acid (273)

To a stirred suspension of 272(120mg, 0.223mmol) in THF/MeOH (5/5mL) was added 1M NaOH (3mL, 3.00 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was then diluted with water and extracted with DCM/MeOH. The organic layer was washed successively with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 15/85) to give a material which when triturated with ethyl acetate gave the title compound 273(10mg, 0.019mmol, 9% yield) as a white solid. ¹HNMR(400MHz,DMSO-d₆)δ(ppm)：8.90-8.79(bs,1H),8.35(d,J=5.6Hz,1H),7.64-7.56(m,1H),7.32-7.29(m,1H),7.27-6.96(m,4H),6.68-6.60(m,1H),6.48-6.40(m,1H),5.14-5.01(m,1H),3.94-3.88(m,1H),3.68-3.48(m,2H),2.63-2.56(m,2H),2.50-2.30(m,3H),2.20-2.08(m,1H),1.92-1.79(m,1H),0.57-0.52(m,2H),0.34-0.30(m,2H)。MS(m/z):525.39(M+H)。

Compound 274 (example 157) was prepared in one step in analogy to compound 272 (scheme 60) from compound 271 and 2- (2-methoxyethoxy) acetyl chloride.

TABLE 22 characterization of Compound 274 (example 157)

Scheme 61

Example 158

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (275)

To the stirred compound 271(150mg, 0.302mmol) and K₂CO₃(180mg, 1.302mmol) to a suspension in DMF (10mL) was added 2,5,8, 11-tetraoxatridec-13-yl methanesulfonate (112mg,0.39mmol, K.Fukase, et. al. SynLett.,2005, 2342-2346). The reaction mixture was stirred at room temperature for 2.5 days, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV 0/100 to 15/85) to give a material which was purified with Et₂Trituration of this material with O/hexane afforded unexpected compound 275(35mg, 0.07mmol, 21% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.71(s,1H),8.45(d, J =5.6Hz,1H),7.71(dd, J =2.8 and 13.6Hz,1H),7.57(s,1H),7.35(t, J =8.8Hz,1H),7.22-7.16(m,1H),6.02-5.95(m,2H),6.44(t, J =3.2Hz,1H),3.95-3.90(m,2H),3.42(t, J =6.4Hz,2H),2.96(s,3H),2.58-2.50(m,1H),0.68-0.62(m,2H),0.44-0.41(m, 2H). MS (M/z) 503.3(M + H).

Example 159

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (3-morpholinopropyl) -1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (276)

To a stirred solution of compound 271(150mg, 0.302mmol) and DIPEA (227. mu.l, 1.302mmol) in DMF (10mL) was added 4- (3-chloropropyl) morpholine (53.3mg, 0.325 mmol). The reaction mixture was stirred at 50 ℃ for 2 hours. 4- (3-chloropropyl) morpholine (212mg,1.3mmol) was added over 4 hours and the reaction mixture was heated at 50 ℃ for a further 19 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by Biotage (SNAP 80g column; MeOH/DCM: 20CV 0/100 to 15/85) gave a material which, when triturated with ethyl acetate, gave the title compound 276(40mg, 0.07mmol, 22% yield) as a beige solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.77(s,1H),8.44(d, J =5.2Hz,1H),7.71(dd, J =2.4 and 13.6Hz,1H),7.48(s,1H)7.34(t, J =9.2Hz,1H),7.22-7.18(m,1H),6.60(d, J =2.4Hz,1H),6.55(d, J =5.2Hz,1H),6.37(s,1H),3.56(q, J =4.8Hz,4H),3.12(bs,2H),2.70-2.62(m,2H),2.62-2.58(m,2H),2.58-2.50(m,1H),2.43(t, J =7.2Hz,2H),2.40-2.32(m,2H),2.30(t, J =7.2Hz,2H),1.64 (quintuple, J =6.8Hz,2H),0.66-0.62(m,2H),0.44-0.41(m, 2H). MS (M/z):552.4.(M + H).

Scheme 62

Example 160

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (4-hydroxybutyl) -1,2,3, 6-tetrahydropyridin-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (277)

To a stirred suspension of compound 271-A (80mg, 0.188mmol) and acetic acid (12. mu.l, 0.207mmol) in DCM (10mL) was added 2,5,8, 11-tetraoxatridec-13-al (78mg,0.377mmol, L.Gorini, et.al.SynLett.,2006, 948-one 950). After 30 min, sodium triacetoxyborohydride (120mg, 0.565mmol) was added and the reaction mixture was stirred at room temperature for 1 h. DMF (1mL) and THF (2mL) were added to the suspension and stirred at room temperature for an additional 18 h. The reaction mixture was diluted with water and concentrated. Purification of the residue by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 15/85) afforded a material which, when triturated with MTBE, gave the unexpected compound 277 as a beige solid (30mg, 0.06mmol, 32% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.78(s,1H),8.44(d, J =5.2Hz,1H),7.71(dd, J =2.4 and 13.6Hz,1H),7.47(s,1H),7.33(t, J =9.2Hz,1H),7.22-7.15(m,1H),6.63(d, J =2.0Hz,1H),6.55(d, J =5.2Hz,1H),6.37(s,1H),3.40(t, J =6.4Hz,1H),3.14-3.09(m,2H),2.68-2.50(m,5H),2.40(t, J =6.4Hz,2H),1.56-1.41(m,4H),0.68-0.61(m,2H),0.44-0.40(m, 2H). MS (M/z) 497.2(M + H).

Scheme 63

Example 161

1-cyclopropyl-3- (3-fluoro-4- (2- (6- ((2-oxopyrrolidin-1-yl) methyl) pyridin-3-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (283)

Step 1: 5-bromo-2- (1, 3-di)Alk-2-yl) pyridines (278)

To a solution of 5-bromo-2-formylpyridine (10g, 53.8mmol), 1, 3-propanediol (3.89mL, 53.8mmol) in toluene (30mL) was added CSA (1.249g,5.38 mmol). The reaction mixture was heated to reflux in the presence of a Dean-Stark trap (Dean-Stark trap) for 4 hours. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 278(13.37g, 54.8mmol, 101% yield, crude product) as a brown solid which was used in the next step without further purification. MS (M/z) 244.06-246.06(M + H).

Step 2: 2- (6- (1, 3-di)Alk-2-yl) pyridin-3-yl) -7-chlorothieno [3,2-b]Pyridine (279)

7-chlorothiophene [3,2-6 ] stirred at-15 deg.C]To a solution of pyridine (12.08g, 71.2mmol) in THF (138mL) was added n-butyllithium (30.7mL, 77.0 mmol). After 30 minutes, 0.5M ZnCl was added at-15 ℃₂Solution in THF (142mL, 71.2mmol) and the reaction mixture was allowed to warm to room temperature over 45 minutes. A solution of tetrakis (triphenylphosphine) palladium (1.266g, mmol) and bromide 278(13.37g, 54.8mmol) in THF (18.5mL) was added, and the mixture was heated to reflux for 2 hours, then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, Dried over anhydrous sodium sulfate, filtered and concentrated. Trituration of the residue with MTBE afforded the title compound 279(10.70g, 32.2mmol, 59% yield) as a light brown solid. MS (M/z) 333.33(M + H).

And step 3: 4- (2- (6- (1, 3-di)Alk-2-yl) pyridin-3-yl) thieno [3,2-b]Pyridin-7-yloxy) -3-fluoroaniline (280)

To a stirred solution of 4-amino-2-fluorophenol hydrochloride (5.79g,35.4mmol) in DMSO (40mL) was added potassium tert-butoxide (8.66g,77.0 mmol). After 30 min, chloride 279(10.70g, 32.2mmol) was added and the reaction mixture was heated at 100 ℃ for 1.5 h. A further solution of 4-amino-2-fluorophenol hydrochloride (860mg, 7.70mmol) and potassium tert-butoxide (0.86g, 7.70mmol) in DMSO (4mL) was added to the reaction mixture and heated at 100 ℃ for an additional 15 minutes. The reaction mixture was then poured into water (300mL) to form a precipitate, which was collected by filtration, dried under high vacuum and triturated with MTBE to give the title compound 280 as a beige solid (12.39g, 29.3mmol, 91% yield). MS (M/z) 424.39(M + H).

And 4, step 4: 1- (4- (2- (6- (1, 3-di)Alk-2-yl) pyridin-3-yl) thieno [3,2-b]Pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (281)

To a stirred solution of compound 280(6.32g, 14.92mmol) and pyridine (2.41mL, 17.91mmol) in DMF (70mL) at 0 ℃ was added phenyl chloroformate (2.25mL, 17.91 mmol). After 30 minutes, cyclopropylamine (2.63mL, 37.3mmol) was added at room temperature and the reaction mixture was heated at 60 ℃ for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with water to form a precipitate, which was collected by filtration, dried and purified by Biotage (SNAP 100g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV0/100 to 10/90) to yield a material which, when triturated with ethyl acetate, gave the title compound 281(2.71g, 5.35mmol, 36% yield) as a beige solid. MS (M/z) 507.2(M + H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (6-formylpyridin-3-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (282)

A solution of 281(2.71mg, 5.35mmol) in an acetic acid/water mixture (32mL/8mL) was heated at 90 ℃ for 29 h. After cooling to room temperature, the reaction mixture was diluted with water to form a precipitate, which was collected by filtration and dried in vacuo to give the title compound 282(2.25g, 5.02mmol, 94% yield) as a brown solid. MS (M/z) 449.2(M + H).

Step 6: 1-cyclopropyl-3- (3-fluoro-4- (2- (6- ((2-oxopyrrolidin-1-yl) methyl) pyridin-3-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (283)

To a stirred solution of aldehyde 282(0.5g, 1.115mmol) and acetic acid (128. mu.l, 2.23mmol) in DMF (10mL) was added 4-aminobutyric acid (345mg, 3.34 mmol). After 40 min, sodium triacetoxyborohydride (945mg, 4.46mmol) was added and the reaction mixture was stirred at room temperature for 22 h. The reaction mixture was then diluted with water to form a precipitate, collected by filtration, dried in vacuo and purified by Biotage (SNAP 50g column; MeOH/DCM containing 2% ammonium hydroxide: via 20CV 0/100 to 15/85) and by Gilson (Phenomenex, Luna 15. mu.a, C18(2)100A,250X50.0mm, 15. mu.m; MeOH/water containing 0.05% formic acid: via 60 minutes 30/80 to 95/5, flow: 30mL/min) to give the title compound 283(20mg, 0.04mmol, 3% yield) as a white solid. ¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.28(s,1H),9.06(d, J =2.4Hz,1H),8.53(d, J =5.6Hz,1H),8.42(bs,1H),8.26(dd, J =2.4 and 8.0Hz,1H),8.25(s,1H),7.74(dd, J =2.0 and 13.6Hz,1H),7.41-7.34(m,2H),7.24-7.20(m,1H),7.08(bs,1H),6.62(d, J =5.6Hz,1H),4.53(s,2H),2.58-2.51(m,1H),2.32(t, J =8.0Hz,2H),1.98 (quintuple peak, J =7.2Hz,2H),0.65-0.60(m, 2.60H), 0.45H, 0.40H). MS (M/z):518.5(M + H).

Scheme 64

Example 162

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (288)

Step 1: 2- (6-Bromopyridin-3-yl) -N- (2-methoxyethyl) ethylamine (284)

To a solution of aldehyde 174(6.93g, 34.6mmol, scheme 42), 2-methoxyethylamine (9.04mL, 104mmol) and acetic acid (2.08mL, 36.4mmol) in DCM (77mL) was added sodium triacetoxyborohydride (18.36g, 87mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by addition of 10% HCl and the mixture was extracted with 10% HCl. The acidic aqueous extract was basified with 4M aqueous NaOH (pH 10) at 0 ℃ and further extracted with DCM. The organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 284(6.79g, 26.2mmol, yield 76%, crude product) as a yellow oil, which was used in the next step without additional purification. ¹H)。MS(m/z):258.9-260.9(M+H)。

Step 2: 2- (6-Bromopyridin-3-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (285)

To a solution of crude 284(6.79g, 26.2mmol) in DCM (52mL) was added di-tert-butyl dicarbonate (9.13mL, 93.3 mmol). The reaction mixture was stirred at room temperature for 18 hours, followed by concentration. The residue was purified by Biotage (SNAP 100g column; ethyl acetate/hexane: via 20CV 0/100 to 30/70). The desired fractions were collected and concentrated to give the title compound 285 as a pale yellow oil (5.53g, 15.39mmol, 59% yield). MS (M/z):359.1-361.1(M + H).

And step 3: 2- (6- (7-chlorothieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamic acid tert-butyl ester (286)

7-chlorothiophene [3,2-b ] stirred at-15 DEG C]To a solution of pyridine (4.26g,25.09mmol) in THF (64mL) was added n-butyllithium (10.77mL, 25.09 mmol). After a lapse of 30 minutes, the reaction mixture was,ZnCl addition at-15 ℃₂(3.42g, 25.09mmol), and the reaction mixture was allowed to warm to room temperature over 45 minutes. A solution of tetrakis (triphenylphosphine) palladium (0.387g, 0.335mmol) and bromide 285(6.01g, 16.73mmol) in THF (20mL) was added and the mixture was heated to reflux for 1 h and concentrated. The reaction was quenched by addition of water and ammonium hydroxide, and the mixture was extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340g column; ethyl acetate/hexane: via 20CV 50/50 to 100/0) to give the title compound 286 as a pale yellow oil (3.74g, 8.35mmol, 50% yield). MS (M/z) 448.48(M + H).

And 4, step 4: tert-butyl 2- (6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamate (181, scheme 44)

To a stirred solution of 4-amino-2-fluorophenol hydrochloride (2.01g, 12.32mmol) in NMP (13mL) was added potassium tert-butoxide (3.0g, 26.7 mmol). After 30 min, chloride 286(4.6g, 10.27mmol) was added and the reaction mixture was heated at 100 ℃ for 1.5 h. The reaction mixture was then poured into water (100mL) to form a precipitate, which was collected by filtration, dried and triturated with MTBE to give the title compound 181 as a beige solid (2.98g,5.53mmol, 54% yield). MS (M/z) 538.8(M + H).

And 5: tert-butyl 2- (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl (2-methoxyethyl) carbamate (287)

To a stirred solution of compound 181(1.0g, 1.58mmol) and pyridine (450mL, 5.56mmol) in DMF (25mL) at 0 ℃ was added phenyl chloroformate (582. mu.l, 4.64 mmol). After 2 hours, cyclopropylamine (643. mu.l, 9.28mmol) was added at room temperature and the reaction mixture was heated at 60 ℃ for 5 hours. After cooling to room temperature, the reaction was quenched by addition of water and the mixture was extracted with ethyl acetate. The extract was washed successively with water, 1N NaOH, saturated ammonium chloride solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM: 20CV 1/99 to 10/90) to give the title compound 287 as a pink solid (840mg, 1.35mmol, 86% yield). MS (M/z) 622.5(M + H).

Step 6: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2- (2-methoxyethylamino) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (288)

To a solution of 287(840mg, 1.35mmol) in DCM (25mL) was added TFA (10mL) and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated, diluted with water and 4N NaOH to pH 13 to form a precipitate, collected by filtration, washed with water and dried and purified twice by Biotage (SNAP 50 g; MeOH/DCM: 20CV 1/99 to 15/85) to yield the title compound 288(338mg, 0.65mmol, 48% yield) as a white solid when triturated with MeOH.¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.54-8.49(m,2H),8.30(s,1H),8.19(d,J=8.2Hz,1H),7.81(dd,J=8.0,2.2Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.1Hz,1H),7.20(bd,J=8.6Hz,1H),6.63(d,J=5.5Hz,1H),6.58(bd,J=2.5Hz,1H),3.37(t,J=5.7Hz,2H),3.23(s,3H),2.84-2.73(m,4H),2.68(t,J=5.7Hz,2H),2.59-2.51(m,1H),2.00-1.50(m,1H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS(m/z):522.6(M+H)。

Scheme 65

Example 163

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2- (2-oxopyrrolidin-1-yl) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (295)

Step 1: 2- (6-bromopyridin-3-yl) ethanol (289)

To a solution of aldehyde 174(1.4g, 7.0mmol, scheme 42 and scheme 64) in methanol (100mL) was added sodium borohydride (0.27g, 7.0mmol) and the mixture was stirred at room temperature for 30 min. Water (1mL) was added, concentrated and mixedA compound (I) is provided. The residue was then partitioned between ethyl acetate and water. Drying (anhydrous MgSO)₄) The organic phase was filtered and concentrated. Chromatography on silica gel (10% methanol/ethyl acetate) residue afforded title compound 289(1.0g, 71% yield) as a colorless solid. MS (M + H):202.1, 204.1

Step 2: 2-bromo-5- (2-bromoethyl) pyridine (290)

Alcohol 289(1.75g, 8.66mmol) was treated with phosphine tribromide (5.0mL, 53mmol) and the mixture was heated for 5 minutes until the solid melted and re-solidified. The mixture was cooled, treated with ice and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was collected, washed with saturated aqueous sodium bicarbonate and brine, and dried (anhydrous MgSO)₄) Filtered and concentrated. Chromatography on silica gel (eluent DCM) residue gave the title compound 290(2.0g,7.6mmol, 87% yield) as a colorless solid. MS (M + H): 266.0.

And step 3: 1- (2- (6-bromopyridin-3-yl) ethyl) pyrrolidin-2-one (291)

To a mixture of dibromide 290(1.7g, 6.4mmol) in 2-pyrrolidone (10mL, 130mmol) was added a dispersion of 40% sodium hydride in mineral oil (1.16g, 19.3mmol) at room temperature. The reaction mixture was then heated to 100 ℃ for 2 hours, then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was collected and washed with water, saturated aqueous ammonium chloride and brine. Followed by drying (anhydrous MgSO)₄) Filtered and concentrated. Chromatography on silica gel (10% methanol/ethyl acetate) residue afforded the title compound 291 as a colorless solid (1.3g, 75% yield). ¹H NMR(400MHz,CDCl₃) δ (ppm) 8.17-8.16(m,1H), 7.42-7.37(m,2H), 3.49(t, J =7.4,2H), 3.28(t, J =6.9,2H), 2.79(t, J =7.2,2H), 2.30(t, J =7.8,2H), 1.95 (quintuple peak, 7.6, 2H). MS (M + H):269.1,271.1.

And 4, step 4: 1- (2- (6- (7-chlorothieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl) pyrrolidin-2-one (292)

To 7-chlorothienopyridine (0.95g,5.6mmol) in THF (75mL) at-78 deg.C was added n-butyllithium (2.5M in hexane, 2.4mL, 6.0mmol) dropwise. The solution was stirred for 30 min, then warmed to 0 ℃ and zinc chloride (1.0M in ether, 6.5mL, 6.5mmol) was added. The reaction mixture was stirred for 20 minutes, then THF (15mL) containing bromide 291(1.25g, 4.64mmol) and tetrakis (triphenylphosphine) palladium (0.54g,0.46mmol) was added. The mixture was then heated to reflux for 3 hours and cooled to room temperature. The excess base was quenched with 1mL of saturated aqueous ammonium chloride solution and the mixture was concentrated. The residue was partitioned between water and diethyl ether to give a yellow precipitate, isolated by suction filtration, triturated with ethyl acetate and dried in vacuo to give the title compound 292(1.2g, 72%). MS (M + H): 358.3.

And 5: 1- (2- (6- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl) pyrrolidin-2-one (293)

To chlorothienopyridine 292(1.2g, 3.4mmol) in diphenyl ether (20mL) were added 2-fluoro-4-nitrophenol (1.58g,10.1mmol) and potassium carbonate (2.32g, 16.8mmol) and the resulting mixture was heated to 200 ℃ for 10 hours. 2-fluoro-4-nitrophenol (1.58g,10.1mmol) and potassium carbonate (2.32g, 16.8mmol) were added and the mixture was heated at 200 ℃ for an additional 6 hours. The mixture was cooled to room temperature, partitioned between ethyl acetate and 1M aqueous NaOH, and then filtered through celite. The organic phase was collected, washed with water and brine, and dried (anhydrous MgSO)₄) Filtered and concentrated. The residue was purified by silica gel chromatography (10% methanol/ethyl acetate) to give the title compound 293(0.76g, 47% yield) as a yellow solid, contaminated with about 10% of starting material 292. MS (M + H) 479.5.

Step 6: 1- (2- (6- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) ethyl) pyrrolidin-2-one (294)

To EtOH (75mL) containing impure 293(0.76g, 1.6mmol) was added zinc dust (1.04g, 15.9mmol), iron filings (0.89g, 16mmol) and saturated aqueous ammonium chloride (2 mL). The resulting mixture was heated to reflux for 18 hours, then cooled, filtered through celite, concentrated and redissolved in dichloromethane. The solution was washed with water, 1M NaOH and brine, dried (anhydrous MgSO) ₄) Filtration, concentration and purification of the residue by silica gel chromatography (15% MeOH/chloroform) gave the title compound 294(0.33g, 46% yield). MS (M + H): 449.2.

And 7: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- (2- (2-oxopyrrolidin-1-yl) ethyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (295)

Phenyl chloroformate (0.12mL, 0.96mmol) was added at 0 ℃ to a solution of 294(0.33g, 0.74mmol) and pyridine (0.13mL, 1.6mmol) in DMF (15 mL). The reaction mixture was stirred for 15 minutes, followed by the addition of cyclopropylamine (2.0mL, 28 mmol). The mixture was allowed to warm to room temperature, stirred for an additional 18 hours and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, 1M NaOH and brine, and dried (anhydrous MgSO)₄) Filtered and concentrated. The residue was purified by silica gel chromatography (20% methanol/ethyl acetate) to give the title compound 295(0.21g, 54%).¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.71(s,1H), 8.52-8.50(m,2H), 8.31(s,1H), 8.20(d, J =8.2,1H), 7.82(dd, J =8.2,2.2,1H), 7.73(dd, J =13.5,2.5,1H), 7.38(t, J =9.0,1H), 7.22-7.18(m,1H), 6.64(d, J =5.5,1H), 6.59(d, J =2.5,1H), 3.48(t, J =7.0,2H), 3.35(t?, hidden by a water peak, 2.85(t, J =6.8,2H), 2.58-2.52(m,1H), 2.16(t, J =7.8,2H), 2.89 (t, 0.89, 4.4H), 4.45-0.4H, 4H, 0H, 4H, 0H. MS (calculated) 531.17 (found) 532.4(MH) ⁺.

Scheme 66

Example 164

1-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- (morpholinomethyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (298)

Step 1: 4- ((2- (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) -1-methyl-1H-imidazol-5-yl) methyl) morpholine (296)

To a suspension of aldehyde 131(0.8g, 2.008mmol, scheme 33) and morpholine (0.437mL, 5.02mmol) in dichloromethane (40.2mL) was added acetic acid (0.230mL, 4.02mmol) and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (1.277g, 6.02mmol) was added and the mixture was stirred for an additional 4 hours. The reaction mixture was extracted with 1M HCl and the organic phase was removed. The aqueous phase was neutralized with 3M NaOH and extracted with dichloromethane. The DCM extract was washed with brine and dried (anhydrous Na)₂SO₄) And evaporation gave the title compound 296(907mg, 1.932mmol, 96% yield, crude product). This material was used in the next step without additional purification. MS 470(MH) +.

Step 2: 3-fluoro-4- (2- (1-methyl-5- (morpholinomethyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) aniline (297)

A mixture of nitro compound 296(907mg, 1.932mmol), iron powder (917mg, 16.42mmol) and ammonium chloride (89mg, 1.661mmol) in a solvent system of ethanol (24.0mL) and water (12.0mL) was heated to 90 ℃ for 1 hour. The reaction mixture was filtered while heating, and concentrated. The residue was purified by Biotage (MeO H. DCM: 0 to 20%, SNAP 25g column) to give the title compound 297 as a white solid (700mg, 1.593mmol, 82% yield). MS:440(MH +).

And step 3: 1-cyclopropyl-3- (3-fluoro-4- (2- (1-methyl-5- (morpholinomethyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (298)

To a solution of aniline 297(200mg, 0.455mmol) in THF (20mL) at 0 ℃ were added DIPEA (0.318mL,1.820mmol) and triphosgene (81mg, 0.273 mmol). The mixture was stirred at 0 ℃ for 1 hour, after which cyclopropylamine (0.160mL, 2.275mmol) was added and allowed to warm to room temperature over 1 hour. The mixture was concentrated and purified by Biotage (MeOH/DCM, 0-22%, SNAP 25g column) to give the title compound 298 as a white solid (54mg, 0.103mmol, 22.7% yield).¹HNMR(400MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.50(d,1H,J=5.5Hz),7.89(s,1H),7.70(dd,1H,J1=2.3Hz,J2=13.9Hz),7.35(t,1H,J=9.0Hz),7.18-7.16(m,1H),6.96(s,1H),6.65(d,1H,J=5.5Hz),6.55-6.54(m,1H),3.91(s,3H),3.55(t,4H,J=3.4Hz),3.51(s,2H),2.54-2.51(m,1H),2.37(m,4H),0.65-0.61(m,2H),0.42-0.38(m,2H)。MS:523.6(MH)+.

Example 165

1- (3-fluoro-4- (2- (1-methyl-5- (morpholinomethyl) -1H-imidazol-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) -3-isopropylurea (299)

The title compound 299 was obtained starting from compound 297 and following a procedure analogous to that used for the synthesis of compound 201 (scheme 48).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.73(s,1H),8.55(d,1H,J=5.4Hz),7.94(s,1H),7.73(dd,1H,J1=2.4Hz,J2=13.5Hz),7.40(t,1H,J=9.0Hz),7.17-7.15(m,1H),7.02(s,1H),6.69(d,1H,J=5.5Hz),6.19(d,1H,7.6Hz),3.97(s,3H),3.83-3.78(m,1H),3.62-3.60(t,4H,J=4.1Hz),3.57(s,2H),2.43(m,4H),1.15(s,3H),1.14(s,3H).525.5(MH)+.

Scheme 67

1-cyclopropyl-3- (2, 3-difluoro-4- (2- (5-formylpyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (167, scheme 41)

Step 1: 2-bromo-5- (1, 3-dioxolan-2-yl) pyridine (300)

To a solution of 6-bromonicotinaldehyde (10.1g,51.6mmol) in toluene (400mL) was added ethylene glycol (11.4mL, 206mmol) and p-toluenesulfonic acid (0.98g, 5.16mmol) and the reaction mixture was heated to reflux while water was removed azeotropically using a dean-Stark trap for 2.5 hours. The mixture was cooled and saturated NaHCO ₃The solution and brine were washed. Over anhydrous MgSO₄The organic phase was dried and concentrated to give the title compound 300 as a brown solid (11.7g, 98% yield), which was used in the next step without further purification.¹H NMR(300MHz,DMSO-d6)δ(ppm):8.46(d,J=2.7Hz,1H),7.65(dd,J=8.1,2.7Hz,1H),7.51(d,J=8.1Hz,1H),5.83(s,1H),4.20-4.00(m,4H).

Step 2: 2- (5- (1, 3-dioxolan-2-yl) pyridin-2-yl) -7-chlorothieno [3,2-b ] pyridine (301)

At-78 ℃ to 7-chlorothiophene [3,2-b]To a solution of pyridine (14g, 82.4mmol) in THF (137mL) was added a solution of n-butyllithium (34.4mL, 89.3mmol, 2.6M in hexane), and the reaction mixture was stirred for 10 minutes. Addition of ZnCl₂Solution (89mL,89.3mmol, 1.0M Et₂O solution), and the mixture was stirred at room temperature for 10 minutes. Addition of Pd (PPh)₃)₄(3.18g, 2.75mmol) and 300(15.8g, 68.7mmol) in THF (50mL), and the reaction mixture was heated to reflux under a nitrogen atmosphere for 1 hour. The reaction mixture was then cooled to room temperature and partitioned between saturated ammonium hydroxide solution and ethyl acetate. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The resulting material was triturated with ethyl acetate to give the title compound 301 as a beige solid (21.4g, 98% yield).¹H NMR(300MHz,DMSO-d6)δ(ppm):8.71(d,J=2.1Hz,1H),8.67(d,J=5.1Hz,1H),8.49(s,1H),8.36(d,J=8.1Hz,1H),8.01(dd,J=8.1,2.1Hz,1H),7.61(d,J=5.1Hz,1H),5.91(s,1H),4.16-3.96(m,4H).

And step 3: 4- (2- (5- (1, 3-dioxolan-2-yl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -2, 3-difluoroaniline (302)

To a solution of 4-amino-2, 3-difluorophenol (1.59g, 7.49mmol) in DMSO (10mL) was added potassium tert-butoxide (1.1g, 8.98mmol) and the reaction mixture was stirred for 2 hours. Chloride 301(1.6g, 4.99mmol) was added and the reaction mixture was heated at 100 ℃ for 2 hours. The mixture was cooled, then poured into water (150mL) at 40 ℃ to 45 ℃ and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried overnight. Trituration of the crude material with ethyl acetate/hexanes (2/1, 100mL) for 1 h gave the title compound 302 as a pale purple solid (1.7g, 79% yield).¹H NMR(300MHz,DMSO-d6)δ(ppm):8.70(d,J=2.1Hz,1H),8.53(d,J=5.4Hz,1H),8.39(s,1H),8.31(d,J=8.1Hz,1H),7.98(dd,J=8.1,2.1Hz,1H),7.10-7.00(m,1H),6.71(d,J=5.1Hz,1H),6.72-6.61(m,1H),5.90(s,1H),5.64(s,2H),4.16-3.96(m,4H).

And 4, step 4: 1- (4- (2- (5- (1, 3-dioxolan-2-yl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -2, 3-difluorophenyl) -3-cyclopropylurea (303)

Pyridine (0.55mL, 6.77mmol) was added to a solution of 302(1.7g, 3.98mmol) in DMF (7mL) at room temperature and the resulting reaction mixture was stirred under Ar atmosphere for 10 min. Phenyl chloroformate (0.75mL, 5.97mmol) was added at 0 ℃ and the mixture was stirred at room temperature for an additional 40 minutes. Cyclopropylamine (1.1mL, 15.9mmol) was added to the mixture and the reaction mixture was warmed to 50 ℃ and stirred for 2 hours. The mixture was then cooled, poured into water (150mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with ethyl acetate for 1 hour and collected by filtration to give the title compound 303 as a pale purple solid (1.75g, 86% yield). ¹H NMR(300MHz,DMSO-d6)δ(ppm):8.71(d,J=2.1Hz,1H),8.55(d,J=5.4Hz,1H),8.46(s,1H),8.42(s,1H),8.33(d,J=8.1Hz,1H),8.10-7.95(m,1H),7.99(dd,J=8.1,2.1Hz,1H),7.40-7.22(m,1H),6.87(br，1H),6.78(d,J=5.1Hz,1H),5.90(s,1H),4.16-3.96(m,4H),2.64-2.50(m,1H),0.75-0.60(m,2H),0.50-0.35(m,2H).

And 5: 1-cyclopropyl-3- (2, 3-difluoro-4- (2- (5-formylpyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (167, scheme 41)

To a suspension of 303(1.75g, 3.43mmol) in THF (56mL) at 0 ℃ was added 5n hcl aqueous solution (14mL, 70mmol) and the reaction mixture was stirred at rt. After 2 hours, the mixture was concentrated, basified with 5N aqueous NaOH and stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to give the title compound 167(1.55g, 97% yield) as a beige solid.¹H NMR(300MHz,DMSO-d6)δ(ppm):10.14(s,1H),9.14(d,J=2.1Hz,1H),8.59(d,J=5.4Hz,1H),8.59(s,1H),8.54(d,J=8.1Hz,1H),8.49(s,1H),8.10-8.00(m,1H),7.35-7.25(m,1H),6.89(br,1H),6.82(d,J=5.1Hz,1H),2.64-2.50(m,1H),0.75-0.60(m,2H),0.50-0.35(m,2H).

Scheme 68

Example 166

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (piperazin-1-yl) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (308)

Step 1: 4- (2- (4-iodo-1H-imidazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (304)

To a stirred solution of 4-iodoimidazole (25g, 129mmol) and 1-bromo-2-chloroethane (12.87ml, 155mmol) in DMSO (250ml) under nitrogen was added K₂CO₃(26.7g,193 mmol). The reaction mixture was heated at 80 ℃ for 30 minutes. 1-bromo-2-chloroethane (1.28ml,15.5mmol) was added and the reaction mixture was heated at 80 ℃ for a further 30 minutes. Finally, 1-Boc-piperazine (28.8g, 155mmol) was added and the reaction mixture was reacted at 80 ℃ for 1 hour, cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340g column; hexane/ethyl acetate: from 15CV 40/60 to 0/100) and then re-purified under different conditions (SNAP 100g column; MeOH/DCM: from 15CV 0/100 to 5/95) to give the title compound 304(4g, 9.85mmol, 8% yield) as a white solid. MS (M/z) 407.18(M + H).

Step 2: 4- (2- (4- (7-chlorothieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (305)

7-chlorothiophene [3, 2-6 ] stirred at-15 deg.C]To a solution of pyridine (2.95g, 17.39mmol) in THF (60mL) was added n-butyllithium (2.5M, 6.96mL, 17.39 mmol). After 30 minutes, ZnCl was added at-15 ℃₂Solution in THF (1M, 17.39mL, 17.39mmol) and the reaction mixture was allowed to warm to room temperature over 45 minutes. Tetrakis (triphenylphosphine) palladium (0.268g, 0.232mmol) and 304(4.71g,11.59mmol) in THF (18mL), followed by heating the mixture to reflux for 1 hour, followed by concentration. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Trituration of the residue with a mixture of MTBE/hexanes provided the title compound 305 as a beige solid (3.75g, 8.37mmol, 72% yield). MS (M/z) 448.46(M + H).

And step 3: 4- (2- (4- (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (306)

To a stirred solution of 4-amino-2-fluorophenol hydrochloride (1.64g, 10.05mmol) in NMP (30mL) was added potassium tert-butoxide (2.25g,20.1 mmol). After 30 min, compound 305(3.75g, 8.37mmol) was added and the reaction mixture was heated at 100 ℃ for 1 h. In a separate flask, a solution of 4-amino-2-fluorophenol hydrochloride (1.64g, 10.05mmol) in NMP (30mL) was treated with potassium tert-butoxide (2.25g,20.1mmol) and the resulting phenate solution was added to the reaction mixture at 100 ℃. After 30 minutes, the reaction was quenched by addition of water and the precipitate was collected by filtration, dried and triturated with MTBE to give the title compound 306 as a beige solid (2.10g, 3.90mmol, 47% yield). MS (M/z) 539.39(M + H).

And 4, step 4: 4- (2- (4- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) -1H-imidazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (307)

To a stirred solution of 306(2.10g, 3.90mmol) and pyridine (631. mu.l, 4.68mmol) in DMF (20mL) at 0 ℃ was added phenyl chloroformate (587. mu.l, 4.68 mmol). After 45 min, cyclopropylamine (687 μ l,9.75mmol) was added at 0 ℃ and the reaction mixture was heated at 60 ℃ for 30 min. After cooling to room temperature, the reaction mixture was quenched by addition of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 100g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 307(1.4g,2.25mmol, 58% yield) as a beige solid. MS (M/z) 622.33(M + H).

And 5: 1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (piperazin-1-yl) ethyl) -1H-imidazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (308)

To a solution of 307(1.4g,2.25 mmol) in DCM (30mL) was added TFA (2mL) and the reaction mixture was stirred for 1 h. TFA (3mL) was added and the reaction mixture was stirred for an additional 3 hours, then concentrated and diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, washed with water and dried. The residue was purified by Biotage (SNAP 80g column; MeOH/DCM containing 2% ammonium hydroxide: 30CV0/100 to 35/65) to give the title compound 308 as a beige solid (870mg, 1.67mmol, 74% yield). ¹H NMR(400MHz,DMSO-d₆)8.75(s,1H),8.42(d, J =5.6Hz,1H),7.91(s,1H),7.76(s,1H),7.72(dd, J =2.4 and 13.6Hz,1H),7.65(s,1H),7.35(t, J =8.8Hz,1H),7.19(d, J =8.8Hz,1H),6.60(bs,1H),6.54(d, J =5.6Hz,1H),4.12(t, J =6.0Hz,2H),2.68(t, J =4.8Hz,4H),2.62(t, J =6.0Hz,2H),2.59-2.50(m,1H),2.41-2.30(m,4H),0.69-0.60(m,2H), 0.45-0.40H (m, 0H). MS (M/z) 522.6(M + H).

Compounds 309 (example 167) and 310 (example 168) were prepared in analogy to compound 30 (scheme 13) by reacting compound 307 (scheme 68) and compound 49 (scheme 15) with acetoxyacetic acid. Compound 311 (example 169) was synthesized following the procedure described above for the synthesis of compound 49 (scheme 15). Compounds 312 (example 170) and 313 (example 171) were obtained in analogy to compound 31 (scheme 13). Compound 314 (example 172) was synthesized following the procedure described above for the synthesis of compound 75 (scheme 20).

TABLE 23 characterization of Compounds 309 to 314 (examples 167 to 172)

Scheme 69

Example 173

1-cyclopropyl-3- (4- (2- (5- ((3, 3-difluoropyrrolidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (315)

3, 3-difluoropyrrolidine hydrochloride (0.200g, 1.39mmol) was suspended in DCM and washed with 3M NaOH. The organic phase was separated and dried over anhydrous MgSO ₄Dried and filtered to a solution of aldehyde 47(0.090g, 0.20mmol) and acetic acid (0.03mL, 0.5mmol) in a 10:1 dichloromethane/DMF mixture (45mL) and stirred at room temperature for 20 min. Sodium triacetoxyborohydride (0.128g, 0.60mmol) was then added and the reaction mixture was stirred at room temperature for 18 hours and partitioned between dichloromethane and water. With saturated NaHCO₃The organic phase was washed with an aqueous solution and then dried (anhydrous MgSO)₄) And concentrated. Chromatography on silica gel (10% methanol/ethyl acetate) of the residue, followed by a second column (10% methanol/chloroform), gave the title compound 315 as a colorless solid (0.045g, 42% yield).¹H NMR(400MHz,DMSO-d₆)8.74(s,1H), 8.57(d, J =2.7,1H), 8.52(d, J =5.3,1H), 8.34(s,1H), 8.26(d, J =8.0,1H), 7.88(dd, J =8.2,2.1,1H), 7.73(dd, J =13.7,2.5,1H), 7.38(t, J =9.0,1H), 7.22-7.19(m,1H), 6.65(d, J =5.3,1H), 6.60(d, J =2.7,1H), 3.71(s,2H), 2.92(t, J =13.3,2H), 2.73(t, J =7.0,2H), 2.57-2.52(m,1H), 2.27 (t = 0, 7.0,2H), 2.63-7.45H, 0.45-7H. MS (M/z) 540.6(M + 1).

Example 174

1-cyclopropyl-3- (4- (2- (5- ((4, 4-difluoropiperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (316)

3, 3-Difluoropiperidine hydrochloride (0.250g, 2.06mmol) was suspended in DCM and washed with 3M NaOH. The organic phase was separated and dried over anhydrous MgSO ₄Dried and filtered to a solution of acid 47(0.100g, 0.22mmol) and acetic acid (0.04mL,0.7mmol) in a 10:1 dichloromethane/DMF mixture (45mL) and stirred at room temperature for 20 min. Sodium triacetoxyborohydride (0.142g, 0.67mmol) was then added and the reaction mixture was stirred at room temperature for 18 hours and partitioned between dichloromethane and water. With saturated NaHCO₃The organic phase was washed with an aqueous solution and then dried (anhydrous MgSO)₄) And concentrated. Chromatography on silica gel (10% methanol/chloroform) of the residue afforded the title compound 316(0.055g, 45% yield) as a colorless solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.72(s,1H), 8.56(d, J =2.7,1H), 8.52(d, J =5.3,1H), 8.32(s,1H), 8.23(d, J =8.0,1H), 7.88(d, J =8.2,1H), 7.73(dd, J =13.7,1H), 7.38(t, J =9.0,1H), 7.22-7.18(m,1H), 6.65(d, J =5.3,1H), 6.60(s,1H), 3.62(s,2H), 3.35-3.30(m,4H?, under the water peak), 2.57-2.52(m,1H), 2.00-1.90(m 2H), 0.67-0.63(m,2H), 0.45-0.41H (m, 1H). MS (M/z):554.6(M + 1).

Compounds 317 (example 175) and 318 (example 176) were synthesized by the procedure described above for the synthesis of compound 49 (scheme 15). Compounds 319 (example 177) and 320 (example 178) were prepared from compound 317 and compound 318 in analogy to compound 31 (scheme 13). Compound 321 (example 179) was obtained following the procedure described above for the synthesis of compounds 315 and 316 (scheme 69). Compound 322 (example 180) [ alkylation with (2-bromoethoxy) (tert-butyl) dimethylsilane followed by TBAF to remove the tert-butyldimethylsilyloxy) ethyl ] -intermediate protecting group ] was synthesized from compound 308 (scheme 68).

TABLE 24 characterization of Compounds 317 to 322 (examples 175 to 180)

Compound 323 (example 181) was synthesized by the procedure described above for the synthesis of compound 315 (example 173, scheme 69). In analogy to compound 48 (example 31, scheme 15), compounds 324 to 328 (examples 182 to 186) and 330 (example 188) were prepared in one step from compound 47. Compound 329 (example 187) was obtained from basic hydrolysis of compound 328 in a similar procedure as described above for the synthesis of compound 31 (example 17, scheme 13).

TABLE 25 characterization of Compounds 323 to 330 (examples 181 to 188)

Scheme 70

Example 189

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2-morpholinoethoxy) phenylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (331)

To a solution of aldehyde 47(0.161g, 0.359mmol), 4- (2-morpholinoethoxy) aniline (0.120g, 0.540mmol) and dibutyltin dichloride (0.197g, 0.648mmol) in DMF (5mL) was addedA solution of phenylsilane (0.047g, 0.434mmol) in DMF (2mL) was added. The reaction mixture was stirred at room temperature for 3 hours and with brine/saturated NaHCO₃And (5) treating the mixture of the solutions. A precipitate formed, which was collected by filtration, washed with water and dried. The crude material was purified by flash column chromatography (eluent: 10 to 20% gradient of ethyl acetate with MeOH) to give the title compound 331(139mg, 59.1% yield). ¹H NMR(400MHz,DMSO-d₆)8.72(s,1H);8.62(d,J=1.6Hz,1H);8.51(dd,J=5.5Hz,1H);8.30(s,1H);8.22(d,J=8.2Hz,1H);7.88(dd,J=8.2,2.2Hz,1H);7.73(dd,J=13.5,2.5Hz,1H);7.38(t,J=9.2Hz,1H);7.20(dd,J=8.81.2Hz,1H);6-72-6.69(m,2H);6.63(dd,J=5.5,0.8Hz 1H);6.58-6.54(m,3H);5.95(t,J=6.3Hz,1H);4.30(d,J=6.1Hz,2H);3.82(t,J=5.9Hz,2H);3.55(t,J=4.5Hz,4H);2.60(t,J=5.7Hz,2H);2.57-2.62(m,1H);2.42(t,J=4.5Hz,4H);0.68-0.63(m,2H);0.47-0.41(m,2H)。MS(m/z):655.6(M+1)⁺

Compounds 332 to 335 and 339 to 341 (examples 190 to 193 and 197 to 199, table 26) were synthesized following a procedure analogous to that described above for the synthesis of compound 331 (example 190, scheme 70).

TABLE 26 characterization of Compounds 332 to 341 (examples 190 to 199)

See scheme 99 for the synthesis of (2,5,8, 11-tetraoxatridec-13-yloxy) aniline.

Scheme 71

Example 200

1- (4- (2- (5- ((4-aminopiperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (343)

Step 1: 1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-ylcarbamic acid tert-butyl ester (342)

Tert-butyl piperidin-4-ylcarbamate (1.34g, 6.69mmol) was added to a solution of aldehyde 47(2.0g, 4.46mmol) in a mixture of NMP (20mL) and glacial acetic acid (0.250 mL). The reaction mixture was stirred for 30 minutes. Followed by addition of NaBH (OAc)₃And the reaction mixture was stirred for an additional 2.5 hours. The reaction mixture was then poured into saturated NaHCO₃In aqueous solution. A precipitate formed, which was collected by filtration, washed with water and air dried. The crude material was purified by column chromatography using a gradient of 5 to 20% MeOH in ethyl acetate as eluent to give the title compound 343(1.45g, 51.4% yield). MS (M/z) 633.6(M + l) +.

Step 2: 1- (4- (2- (5- ((4-aminopiperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (343)

A solution of Boc-protected compound 342 in TFA (25mL) was stirred at room temperature for 1.5 h, followed by evaporation. To the residue was added 3N aqueous NaOH and the suspension was stirred at room temperature overnight, collected by filtration, washed with water and dried to give the title compound 343(1.177g, 96% yield).¹H NMR(400MHz,DMSO-d₆)8.75(s,1H), 8.53-8.51(m,2H), 8.32(s,1H), 8.23(d, J =8.2Hz,1H), 7.84(dd, J =8.2,2.2Hz,1H), 7.73(dd, J =13.5,2.3Hz,1H), 7.38(t, J =9.0Hz,1H), 7.20(dd, J =8.81.2Hz,1H), 6.64(d, J =5.5Hz1H), 6.61(d, J =2.3Hz,1H), 3.52(s,2H), 2.74(d, J =11.3Hz,2H), 2.58-2.52(m,1H), 1.99(t, J =9.8Hz,2H), 1.66(d, J =11.3Hz, 1H), 1.63-1H, 29.68 (m,1H), 0.63-0.45H, 0.8H, 1H, 8H, 1₂-a signal of a group; NH (NH)₂the-CH-signal is masked by the peak of the residual water]。MS(m/z):533.5(M+l)+。

Compound 342-A (example 199-A) was synthesized analogously to compound 342 from aldehyde 47 and tert-butyl methyl (piperidin-4-yl) carbamate. Compounds 344 to 350 (examples 201 to 207) were synthesized following a similar procedure as described above for the synthesis of compounds 30 and 31 (scheme 13) starting from compound 343 (scheme 71). Compounds 351 to 355 (examples 208 to 212) were prepared in one step from compound 343 in analogy to compound 128 (example 87, scheme 32).

TABLE 27 characterization of compound 342-A, compound 344 through 355 (example 199-A, example 201 through example 212).

Scheme 72

Example 213

N- (1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) -4-methylpiperazine-1-carboxamide (357)

Step 1: phenyl 1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-ylcarbamate (356)

To a solution of amine 343(0.9g, 1.69mmol) in NMP (10mL) at 0 ℃ was added pyridine (0.3mL, 3.71mmol) followed by chloroformate (0.3mL, 2.38 mmol). The mixture was stirred at 0 ℃ for 40 min, then at room temperature for 120 min by addition of brine NaHCO₃The solution was quenched. A white precipitate formed, which was collected by filtration and dried. The crude material was purified by flash column chromatography (eluent: 5 to 10% gradient of MeOH in DCM containing 2% ammonia) to afford the title compound 356(0.528g, 47.9% yield). MS (M/z) 653.6(M + l) +.

Step 2: n- (1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) -4-methylpiperazine-1-carboxamide (357)

To a solution of phenyl carbamate 356(0.11g, 0.169mmol) in DMF at room temperature was added N-methylpiperazine (0.057mL, 0.51 mmol). The reaction mixture was heated at 90 ℃ to 95 ℃ for 2 hours, cooled to room temperature, and then diluted with brine and saturated NaHCO₃And (4) solution treatment. A white precipitate formed, which was collected by filtration and dried. The crude material was purified by flash column chromatography (eluent: 12% to 30% MeOH in DCM containing 2% ammonia) to give the title compound 357(0.088g, 79% yield).¹HNMR(400MHz,CD₃OD-d₆)8.65(d, J =1.4Hz,1H), 8.47(d, J =5.5Hz,1H), 8.15-8.11(m,2H), 7.98(dd, J =8.2,2.0Hz,1H), 7.67(dd, J =13.1,2.3Hz,1H), 7.30(t, J =9.0Hz,1H), 7.20(br.d, J =9.0Hz,1H), 6.64(d, J =5.5Hz 1H), 3.94(s,2H), 3.68-3.65(m,1H), 3.57(br.s,4H), 3.18(br.d, J =10.4Hz,2H), 2.89(br.s,4H), 2.65(s,3H), 2.63-2.58 (br.s, 3H), 2.9H = 2H), 2.18 (br.d, J =10.4Hz,2H), 2.89(br.s,4H), 2.65 (m,3H), 2.63-2.58H = 0.5 Hz,1H), 2H, 3.9H, 2H, 3.5 Hz,2H, 3H, 2H, 3.5H, 2H])。MS(m/z):659.5(M+1)+.

Example 214

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- ((2-hydroxyethyl-methylamino) carbonylamino) piperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (358)

The title compound 358 was obtained by the procedure described above for the synthesis of compound 357 (example 214). ¹H NMR(400MHz,CD₃OD-d₆)8.60(d, J =1.6Hz,1H);8.47(d, J =5.7Hz,1H);8.12-8.09(m,2H);7.93(dd, J =8.0,2.2Hz,1H);7.67(dd, J =13.1,2.5Hz,1H);7.30(t, J =8.8Hz,1H);7.20(dd, J =8.8,1.4Hz,1H);6.64(dd, J =5.5,1.0Hz 1H);3.72(s,2H);3.66(t, J =5.5Hz,2H);3.63-3.57(m,1H);3.37(t, J =5.2Hz,2H);2.98(br.d, J =11.2Hz,2H);2.93(br.s,3H);2.63-2.58(m,1H);2.33(br.t, J =11.0Hz,2H);1.92(br.d, J =10.0Hz,2H);1.65-1.55(m,2H);0.90-0.74(m,2H);0.55-0.52(m,2H) [ no signal for OH-and NH-protons was observed.]。MS(m/z):634.5(M+l)+。

Scheme 73

Example 215

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (362)

Step 1- (2-fluoro-4-nitrophenoxy) -2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridine (360)

To NaN₃(49.6mg, 0.764mmol) in DMSO (5mL) was added l- (2-chloroethyl) pyrrolidine (102mg, 1.2 equiv., 0.764mmol) and KI (127mg, 1.2 equiv., 0.764mmol) and the reaction mixture was stirred at room temperature for 12 h. Add Compound 359(200mg, 0.636mmol) and Cu (OAc)₂.H₂O (34.7mg, 0.3 eq, 0.191mmol), and the dark red reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with water and the precipitated solid was collected by filtration to give the title compound 360(150mg, 52% yield), which was used in the next step without additional purification. MS (M/z):455.5(M + H).

Step 2-fluoro-4- (2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) aniline (361)

To a solution of 360(150mg, 0.329mmol) in MeOH (l0mL) was added water (1mL) containing ammonium chloride (35.3mg, 2 equivalents, 0.660mmol) and zinc powder (86mg, 4 equivalents, 1.320mmol), and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated to give the title compound 361(98mg, yield 70%) which was used in the next step without additional purification. MS (M/z):425.5(M + H).

Step 3-cyclopropyl-3- (3-fluoro-4- (2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (362)

To a stirred solution of 361(98mg, 0.231mmol) and pyridine (0.057mL, 3 equivalents, 0.9mmol) in DMF (5mL) under nitrogen was added phenyl chloroformate (0.072mL, 2.5 equivalents, 0.577mmol) at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 2 hours. Cyclopropylamine (66mg, 5 eq, 1.154mmol) was added and the reaction mixture was heated at 55 ℃ for 5 h. Followed by The reaction mixture was diluted with ethyl acetate, washed successively with sodium hydrogencarbonate solution, saturated ammonium chloride solution and brine, followed by anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate to 30% MeOH in ethyl acetate) before re-using Et₂After O trituration, the title compound 362 was obtained as a white solid (50mg, 42% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.8(s,1H),8.71(s,1H),8.48(d,J=5.48Hz,1H),7.91(s,1H),7.70(m,1H),7.36(m,1H),7.18(d,J=8.99Hz,1H),6.61(d,J=5.48hz,1H),6.55(s,1H),4.55(m,2H),2.93(m,2H),2.50(m,1H),1.67(m,4H),0.65(m,2H),0.41(m,2H)。MS(m/z):508.54.

Compounds 363 to 369 (examples 216 to 222) were synthesized following a similar procedure to that described above for the synthesis of compound 362 (example 215, scheme 73) starting from compound 359 (scheme 73).

TABLE 28 characterization of Compounds 363 to 369 (examples 216 to 222)

Scheme 74

Example 223

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2-oxo-2- (piperidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea

Step 1- (2-ethynylthieno [3,2-b ] pyridin-7-yloxy) -3-fluoroaniline (370)

To a solution of 359(120mg, 0.382mmol) in EtOH (5ml) was added SnCl₂.2H₂O (431mg,5 equivalents, 1.91mmol) and the reaction mixture was heated to reflux for 30 minutes (Bellamy, F.D.; Ou, K.tetrahedron Lett.1984, 25,839). The mixture was cooled slightly and poured into ice. Addition of saturated NaHCO ₃Solution and DCM and the resulting cloudy mixture was stirred for 15 minutes. The mixture was then filtered and the two-phase filtrate was separated. The aqueous phase was extracted with DCM and the organic extracts were combined over anhydrous MgSO₄Dried, filtered and concentrated to give the title compound 370(102mg, 94% yield), which was used in the next step without additional purification. MS (M/z) 285.17(M + H).

Step 2-cyclopropyl-3- (4- (2-ethynylthieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (371)

To a stirred solution of 370(102mg, 0.359mmol) and pyridine (0.058mL, 2 equiv, 0.718mmol) in THF (5mL)/DMF (2mL) under nitrogen at 0 ℃ was added phenyl chloroformate (0.068mL, 1.5 equiv, 0.538mmol) and the reaction mixture was stirred at 0 ℃ for 1 hour. Cyclopropylamine (102mg, 5 eq, 1.794mmol) was added and the reaction mixture was heated at 55 ℃ for 3 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and then sequentially with saturated NH₄Cl solution, saturated NaHCO₃The solution and brine were washed. Through anhydrous Na₂SO₄The organic phase was dried, filtered and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate to ethyl acetate with 40% MeOH) in Et₂After O trituration, the title compound 371 was obtained as an off white powder (100mg, 76% yield). MS (M/z) 368.23(M + H)

Step 3-cyclopropyl-3- (3-fluoro-4- (2- (1- (2-oxo-2- (piperidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (372)

To a solution of 2-chloro-1- (piperidin-1-yl) ethanone (106mg, 2 equiv., 0.653mmol) in DMSO (2ml) was added sodium azide (42.5mg, 2 equiv., 0.653mmol) and KI(108mg, 2 eq, 0.653mmol) and the reaction mixture was stirred at room temperature overnight. Addition of alkyne (120mg, 0.0.327mmol), Cu (OAc)₂.2H₂O (17.8mg, 0.3 eq, 0.098mmol) and sodium ascorbate (38.8mg, 0.6 eq, 0.196mmol), and the light orange mixture was stirred at room temperature for 15 min. The mixture was then poured into ice and a few drops of NH were added₄OH (about pH 10). The mixture was extracted with DCM and the organic phase was collected over anhydrous Na₂SO₄Dried, filtered and concentrated. Purification by column chromatography (ethyl acetate to 20% MeOH in ethyl acetate) afforded an oil which was dissolved in acetone/Et₂And O in a mixture. Et was added again₂O; a precipitate formed and was collected by filtration to give the title compound 372(84mg, 48% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.77(s,1H),8.71(s,1H),8.50(d,J=5.48Hz,1H),7.96(s,1H),7.73(m,1H),7.39(t,J=8.99Hz,1H),7.38(m,1H),6.64(6,1H),6.63(s,1H),5.58(s,2H),3.38(m,4H),2.55(m,1H),1.61(m,4H),1.48(m,2H),0.64(m,2H),0.43(m,2H)。MS(m/z):536.52(M+H)。

Compound 373, compound 375 to compound 388 (example 224, example 226 to example 239) were synthesized following a similar procedure as described above for the synthesis of compound 372 (example 223, scheme 74) starting from compound 359.

TABLE 29 characterization of Compound 373 Compound 388 (example 224 to example 239)

Scheme 75

Example 240

1-cyclopropyl-3- (3-fluoro-4- (2- (1- (2-oxo-2- (piperazin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (389)

To a solution of 388(800mg, 1.256mmol) in a solvent mixture of DCM (70mL) and DMF (10mL) was added HCl bisAlkane solution (0.882mL, 10 equiv., 12.56mmol, 4.0M solution) and the reaction mixture was stirred for 24 h. The mixture was poured into saturated NaHCO₃In solution and the resulting solid was collected by filtration, then washed with water and dried to give the title compound 389(350mg, yield 52%) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.6(m,2H),8.71(d,J=5.30Hz,1H),8.49(d,J=4.05Hz,1H),7.95(m,1H),7.76(d,J=11.50Hz,1H),7.45(s,1H),7.35(t,J-9.1Hz,1H),7.24Hz(m,1H),6.62(m,1H)4.43(m,1H),4.30(m,5H),2.75(m,1H),2.66(m,1H),2.53(m,1H),1.21(m,1H),0.61(m,2H),0.42(m,2H)。MS(m/z)=537.4(M+H)。

Compounds 390 to 392 (examples 241 to 243) were synthesized in analogy to the procedure described above for the synthesis of compound 30 and compound 31 (scheme 13) starting from compound 389 (example 239, scheme 75). Compound 393 (example 244) was synthesized following a similar procedure as described above for the synthesis of compound 389 (example 240, scheme 75) starting from compound 392. Compound 394 (example 245) was synthesized following a similar procedure to that described above for the synthesis of compound 128 (example 87, scheme 32) starting from compound 389. Compound 395 (example 246) was synthesized starting from compound 387 following a similar procedure as described above for the synthesis of compound 13 (example 10, scheme 9).

TABLE 30 characterization of Compounds 390 to 395 (examples 241 to 246)

Compounds 396 to 398 (example 247 to example 249) are prepared analogously to compound 226 (example 127, scheme 54). Compound 399 and compound 400 (example 249 and example 250) were prepared in one step in analogy to compound 72 (example 52, scheme 19) by removing the Boc protecting group from compound 397 and compound 398. Compounds 401 to 402 (examples 252 to 253) were synthesized by the procedure described above for the synthesis of compound 49 (scheme 15).

TABLE 31 characterization of Compounds 396 to 401 (examples 247 to 252)

Scheme 76

Example 254

1- (4- (2- (5- ((azetidin-3-yloxy) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (405)

Step 1: methanesulfonic acid (6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl ester (403)

To a solution of 64(510mg, 1.13mmol, scheme 17) in DMF (15mL) at 0 ℃ was added TEA (0.79mL, 5.65mmol) and methanesulfonyl chloride (0.35mL, 4.52 mmol). After 30 min, TEA (0.48mL, 3.39mmol) and methanesulfonyl chloride (0.22mL, 2.82mmol) were added at 0 ℃. The reaction mixture was poured into water to form a precipitate, which was collected by filtration and washed with water to give the title compound 403 (crude product) as a beige powder, which was used in the next step without further purification. MS (M/z) 529.39(M + H).

Step 2: 3- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methoxy) azetidine-1-carboxylic acid tert-butyl ester (404)

To a stirred suspension of NaH (271mg, 60% dispersion in mineral oil, 6.72mmol) in DMF (2mL) at 0 ℃ was added tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0g,5.65 mmol). After 30 min, a solution of 403(1.13mmol) in DMF (6mL) and KI (183mg, 1.13mmol) were added at 0 ℃. The reaction mixture was heated to 80 ℃ for 30 minutes. Quench the reaction by adding water and extract with ethyl acetate/MeOHAnd (3) mixing. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Via Biotage [ linear gradient 0 to 10%, methanol/dichloromethane; SiliaFlash 25g column]The residue was purified. The title compound 404 was obtained as a beige solid (221mg, 32% yield over 2 steps).¹H NMR(400MHz,DMSO-d6)δ(ppm):8.71(s,1H),8.62(d,J=2.4Hz,1H),8.52(d,J=5.2Hz,1H),8.37(s,1H),8.28(d,J=8.0Hz,1H),7.94(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.23-7.18(m,1H),6.64(d,J=5.2Hz,1H),6.57(brd,1H),4.53(s,2H),4.42-4.36(m,1H),4.09-4.00(m,2H),3.77-3.68(m,2H),2.59-2.50(m,1H),1.37(s,9H),0.68-0.62(m,2H),0.47-0.41(m,2H)。MS(m/z):606.48(M+H)。

And step 3: 1- (4- (2- (5- ((azetidin-3-yloxy) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (405)

To a suspension of 404(221mg, 0.365mmol) in DCM (5mL) was added TFA (1mL) and the reaction mixture was stirred for 4 h, then concentrated and diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, washed with water and dried. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM containing 2% ammonium hydroxide: 10/90 to 30/70) to give the title compound 405(155mg, 84% yield) as a beige solid. ¹H NMR(400MHz,DMSO-d6)δ(ppm):8.77(s,1H),8.55(brd,J=1.6Hz,1H),8.52(d,J=5.6Hz,1H),8.35(s,1H),8.27(d,J=7.2Hz,1H),7.91(dd,J=8.0,2.4Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.24-7.18(m,1H),6.65(d,J=5.2Hz,1H),6.62(brd,J=2.8Hz,1H),4.48(s,2H),4.40-4.41(m,1H),3.56-3.49(m,2H),3.47-3.50(m,2H),2.58-2.51(m,1H),0.68-0.62(m,2H),0.47-0.41(m,2H)。MS(m/z):506.14(M+H)。

Compounds 406 to 409 (example 255 to example 258) were prepared in one step in analogy to compound 128 (example 87, scheme 32) by reacting the corresponding amine precursors 399, 401, 402 (table 31) and 405 (scheme 76) with ethyl isocyanate. Compound 410 (example 259) was prepared by reacting compound 401 (table 31) with methyl isocyanate instead of ethyl isocyanate.

TABLE 32 characterization of Compounds 406 to 410 (examples 255 to 259)

In analogy to compound 30 (scheme 13), the reaction was performed from amine precursor 401 (table 31) to prepare compounds 411 to 412 (examples 260 to 261) in one step. Compound 413 (example 262) was obtained in analogy to compound 31 (scheme 13). In analogy to compound 31 (scheme 13), compounds 414 to 415 (examples 263 to 264) were prepared in two steps from the corresponding amine precursors 402 (table 31) and 405 (scheme 76).

Compounds 416 to 418 (examples 265 to 267) were prepared in one step in analogy to compound 275 (scheme 61) by reacting amine precursor 401 (table 31) with the corresponding alkylating agent.

TABLE 33 characterization of Compounds 411 to 418 (examples 255 to 267)

Scheme 77

Example 268

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2-fluoroethyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (420)

Step 1: methanesulfonic acid 2-fluoroethyl ester (419)

To a stirred solution of 2-fluoroethanol (0.100mL, 1.72mmol) in DCM (2mL) at 0 ℃ was added TEA (0.312mL, 2.24mmol) and methanesulfonyl chloride (0.16mL, 2.06 mmol). The reaction mixture was stirred at 0 ℃ for 0.5 h, quenched with water and extracted with DCM. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated to give the title compound 419 as an orange oil (140mg, 57% yield), which was used in the next step without further purification.¹H NMR(400MHz,CDCl3)δ(ppm)：4.75-4.72(m,1H),4.63-4.60(m,1H),4.52-4.49(m,1H),4.45-4.42(m,1H),3.08(s,3H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2-fluoroethyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (420)

To a solution of 49(70mg, 0.111mmol, scheme 26) in DMF (2mL) was added K₂CO₃(77mg, 0.555mmol) and 419(79mg, 0.555 mmol). The mixture was heated to 80 ℃ for 16 hours. Water was added to form a precipitate, collected by filtration, rinsed with water and purified via Biotage [ linear gradient 0 to 20%, methanol/dichloromethane; siliaflash 10g column]And (5) purifying. The title compound 420 was obtained as a white solid (38.9mg, 62% yield).¹H NMR(500MHz,DMSO-d6)δ(ppm)：8.68(s,1H),8.53(d,J=1.7Hz,1H),8.51(d,J=5.4Hz,1H),8.31(s,1H),8.23(d,J=8.2Hz,1H),7.85(dd,J=8.1,2.0Hz,1H),7.72(dd,J=13.5,2.4Hz,1H),7.37(t,J=9.0Hz,1H),7.22-7.17(m,1H),6.64(d,J=5.4Hz,1H),6.54(bd,J=2.3Hz,1H),4.55(t,J=4.9Hz,1H),4.45(t,J=4.9Hz,1H),3.54(s,2H),2.89-2.83(m,2H),2.62(t,J=5.0Hz,1H),2.59-2.51(m,1H),2.56(t,J=5.1Hz,1H),2.50-2.32(m,8H),0.68-0.62(m,2H),0.45-0.40(m,2H)。MS(m/z):565.23(M+H)。

Example 269

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- ((2-fluoroethyl) (methyl) amino) piperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (421)

Compound 421 (example 269) was prepared in one step in analogy to compound 420 (example 268, scheme 77) by reacting amine precursor 401 (table 31) with compound 419.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.73(s,1H),8.54(d,J=1.6Hz,1H),8.52(d,J=5.6Hz,1H),8.33(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.22-7.18(m,1H),6.64(d,J=5.2Hz,1H),6.56(bd,J=2.8Hz,1H),4.51(t,J=5.2Hz,1H),4.39(t,J=5.2Hz,1H),3.54(s,2H),2.90-2.82(m,2H),2.77-2.63(m,2H),2.59-2.50(m,1H),2.40-2.30(m,1H),2.22(s,3H),2.02-1.91(m,2H),1.69-1.61(m,2H),1.50-1.38(m,2H),0.68-0.62(m,2H),0.45-0.40(m,2H)。MS(m/z):593.59(M+H)。

Scheme 78

Example 270

Ethyl 2- ((1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) (methyl) amino) acetate (422)

To a suspension of 401(109mg, 0.20mmol) in DMF (2mL) was added K₂CO₃(33mg，0.24mmol) and ethyl bromoacetate (33mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water was added to form a precipitate, collected by filtration, rinsed with water and purified via Biotage [ linear gradient 0 to 20%, methanol/dichloromethane; siliaflash 10g column]And (5) purifying. The title compound 422 was obtained as a beige solid (92mg, 72% yield).¹H NMR(500MHz,DMSO-d6)δ(ppm)：8.71(s,1H),8.54(d,J=1.8Hz,1H),8.51(d,J=5.4Hz,1H),8.32(s,1H),8.24(d,J=8.1Hz,1H),7.84(dd,J=8.2,2.0Hz,1H),7.72(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.0Hz,1H),7.22-7.18(m,1H),6.63(d,J=5.4Hz,1H),6.56(bd,J=2.0Hz,1H),4.05(q,J=7.1Hz,2H),3.52(s,2H),3.28(s,2H),2.86-2.79(m,2H),2.58-2.51(m,1H),2.45-2.37(m,1H),2.26(s,3H),1.98-1.91(m,2H),1.72-1.66(m,2H),1.42-1.32(m,2H),1.16(t,J=7.1Hz,3H),1.45-1.38(m,2H),0.68-0.62(m,2H),0.45-0.40(m,2H)。MS(m/z):633.45(M+H)。

Example 271

2- ((1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) (methyl) amino) acetic acid (423)

To a suspension of 422(78mg, 0.12mmol) in MeOH (3mL) was added 1N NaOH (0.6mL, 0.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, diluted with water, and the pH adjusted to 6 to 7 by the addition of 1N HCl. The resulting suspension was stirred for 30 minutes, and the solid was collected by filtration, washed with water, air dried and dried under high vacuum to give the title compound 423 as a beige solid (50.3mg, 67% yield). ¹H NMR(400MHz,DMSO-d6)δ(ppm)：8.81(s,1H),8.55(brd,1H),8.51(d,J=5.6Hz,1H),8.33(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.2,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.24-7.18(m,1H),6.59-6.42(m,2H),3.56(s,2H),3.26(s,2H),2.93-2.84(m,3H),2.58-2.51(m,1H),2.53(s,3H),2.06-1.95(m,2H),1.88-1.80(m,2H),1.61-1.49(m,2H),0.68-0.62(m,2H),0.47-0.41(m,2H)。MS(m/z):605.59(M+H)。

Example 272

3- ((1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) (methyl) amino) propanoic acid (424)

Compound 424 (example 272) was prepared in two steps in analogy to compound 423 (example 271, scheme 77) starting from amine precursor 401 (table 31).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.78(s,1H),8.55(brd,1H),8.51(d,J=5.2Hz,1H),8.33(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.23-7.18(m,1H),6.64(d,J=5.2Hz,1H),6.67-6.62(m,1H),3.54(s,2H),3.17(s,2H),2.90-2.83(m,2H),2.74(t,J=6.8Hz,2H),2.58-2.45(m,2H),2.30(t,J=6.8Hz,2H),2.26(s,3H),2.04-1.95(m,2H),1.70-1.63(m,2H),1.57-1.46(m,2H),0.68-0.62(m,2H),0.47-0.40(m,2H)。MS(m/z):619.54(M+H)。

Scheme 79

Example 273

Ethyl 2- (3- (1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) ureido) acetate (425)

To a suspension of 343(106mg,0.20mmol, scheme 71) in THF (3mL) was added ethoxycarbonylmethyl isocyanate (0.068mL, 0.6mmol) and stirred at room temperature for 3 h. To the mixture was added DMF (2mL) and stirred for 1 hour. The mixture was then concentrated, water was added to form a precipitate, collected by filtration, rinsed with water and purified via Biotage [ linear gradient 2 to 20%, methanol/dichloromethane; siliaflash 10g column]And (5) purifying. The title compound 425 was obtained as a white solid (79.5mg, yield 60%).¹H NMR(400MHz,DMSO-d6)δ(ppm):8.73(s,1H),8.54(brd,1H),8.52(d,J=5.6Hz,1H),8.33(s,1H),8.24(d,J=8.0Hz,1H),7.85(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.23-7.18(m,1H),6.64(d,J=5.2Hz,1H),6.59(bd,1H),6.15(d,J=8.0Hz,1H),6.06(t,J=8.0Hz,1H),4.06(q,J=6.4Hz,2H),3.74(d,J=6.50Hz,2H),3.54(s,2H),2.77-2.66(m,2H),2.58-2.51(m,2H),2.13-2.04(m,2H),1.78-1.70(m,2H),1.40-1.30(m,2H),1.18(t,J=6.8Hz,3H),0.68-0.62(m,2H),0.45-0.40(m,2H)。MS(m/z):662.28(M+H)。

Example 274

2- (3- (1- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperidin-4-yl) ureido) acetic acid (426)

To a suspension of 425(78mg, 0.12mmol) in MeOH (3mL) was added 1N NaOH (0.6mL, 0.6 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then concentrated, diluted with water, and the pH adjusted to 6 to 7 by the addition of 1N HCl. To the resulting suspension, MeOH was added to dissolve the mixture to clear, and via Biotage [ KP-C18-HS 30g, gradient 20% to 95% (methanol/water) ]And (5) purifying. The title compound 426(79.5mg, 60% yield) was obtained as a white solid.¹H NMR (400MHz, DMSO-d6) delta (ppm) lacking a carboxylic acid H,10.17(brs,1H),8.53(d, J =1.6Hz,1H),8.51(d, J =5.2Hz,1H),8.29(s,1H),8.20(d, J =8.0Hz,1H),8.02(brs,1H),7.81(dd, J =8.0,2.0Hz,1H),7.76(dd, J =14.0,2.4Hz,1H),7.33(t, J =9.0Hz,1H),7.28(dd, J =9.2,2.0Hz,1H),6.65(d, J =4.4Hz,1H),6.25(d, J =7.6, 1H),5.59(t =3.6, J = 3.65, 1H), 2.65 (d, J =4.4Hz,1H),6.25(d, J =7.6, 1H),5.59(t =3.6, 6, 1H = 6, 1H), 2.65 (d, 2.51, 2.5.9, 2.5.5, 2.6, 2.5, 2.5.5, 2, 1H), 2.5.5.5, 1H, 11, 2.9, 2, 2H) 1.38-1.25(m,2H),0.63-0.56(m,2H),0.44-0.38(m, 2H). MS (M/z) 634.5(M + H).

Compounds 427 to 428 (examples 275 to 276) were prepared in two steps starting from amine precursors 401 and 402 (table 31) in analogy to compound 426 (example 274, scheme 79). In analogy to compound 426 (example 274, scheme 79), compound 429 (example 277) was prepared in a first step using ethyl 3-isocyanatopropionate instead of ethoxycarbonylmethyl isocyanate.

TABLE 34 characterization of Compounds 427 to 429 (examples 275 to 277)

Scheme 80

Example 278

2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (1- (ethylcarbamoyl) azetidin-3-yl) amino) acetic acid (434)

Step 1: 3- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methylamino) azetidine-1-carboxylic acid tert-butyl ester (430)

To a suspension of aldehyde 47(1.0g, 2.25mmol, scheme 15) in NMP (12mL) was added 3-amino-1-N-Boc-azetidine (0.600g,3.38mmol) and acetic acid (0.19mL, 3.38mmol) at room temperature and stirred for 30 min. Followed by addition of NaBH (OAc)₃(1.2g, 5.63mmol) and stirred for 3 days. The reaction mixture was poured into saturated NaHCO₃A precipitate formed in aqueous solution, collected by filtration, washed with water and purified by Biotage [ linear gradient 2 to 20%, methanol/dichloromethane; SiliaFlash 25g column]And (5) purifying. The title compound 430 was obtained as a beige solid (960mg, 71% yield).¹H NMR (400MHz, DMSO-d6) delta (ppm): 8.71(s,1H),8.56(d, J =1.2Hz,1H),8.51(d, J =5.2Hz,1H),8.32(s,1H),8.23(d, J =8.0Hz,1H),7.89(dd, J =8.0,2.0Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.0Hz,1H),7.23-7.18(m,1H),6.64(dd, J =5.2,1.2Hz,1H),6.56(bd, J =2.4Hz,1H),3.98-3.83(m,2H),3.69(s,2H),3.62-3.47(m,3H),2.58-2.51(m,1H), 0.36.51 (m, 0.40H), 0.45H), one deletion. MS (m/z) 605.46(M+H)。

Step 2: 3- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (2-ethoxy-2-oxoethyl) amino) azetidine-1-carboxylic acid tert-butyl ester (431)

To a solution of 430(300mg, 0.496mmol) in DMF (6mL) was added ethyl bromoacetate (0.06mL, 0.546 mmol). The reaction mixture was stirred at room temperature for 3 days, quenched with water and extracted with DCM. Collecting organic phase, passing through anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by Biotage (SNAP 10g column; MeOH/DCM: 0/100 to 10/90) to give the title compound 431 as a beige solid (93mg, 27% yield).¹H NMR(400MHz,DMSO-d6)δ(ppm)：8.76(s,1H),8.54(brd,J=1.6Hz,1H),8.52(d,J=5.6Hz,1H),8.35(s,1H),8.25(d,J=8.0Hz,1H),7.88(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.23-7.18(m,1H),6.65(dd,J=5.2,0.8Hz,1H),6.61(brd,J=2.8Hz,1H),4.05(q,7.2Hz,2H),3.93-3.75(m,5H),3.79(s,2H),3.31(s,2H),2.58-2.52(m,1H),1.37(s,9H),1.17(t,J=7.2Hz,3H),0.68-0.62(m,2H),0.47-0.41(m,2H))。MS(m/z):691.64(M+H)。

And step 3: ethyl 2- (azetidin-3-yl ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) amino) acetate (432)

To a solution of 431(93mg, 0.135mmol) in DCM (5mL) was added 4M HCl in 1, 4-bisAlkane (0.17mL,0.675mmol) and stirred at room temperature for 6 hours. The mixture was then concentrated to give the title compound 432 (assumed to be the hydrochloride salt) as a beige solid, which was used in the next step without further purification.¹H NMR(400MHz,DMSO-d6)δ(ppm)：9.13(s,1H),8.98-8.86(m,1H),8.78-8.66(m,1H),8.69(d,J=6.0Hz,1H),8.63(d,J=1.2Hz,1H),8.40(s,1H),8.34(d,J=8.4Hz,1H),7.94(dd,J=8.0,2.0Hz,1H),7.77(dd,J=13.6,2.4Hz,1H),7.44(t,J=9.0Hz,1H),7.25-7.21(m,1H),6.92(d,J=5.2Hz,1H),6.77(brs,1H),4.08(q,J=7.2Hz,2H),4.15-3.80(m,7H),3.16(s,2H),2.58-2.51(m,1H),1.19(t,J=7.2Hz,3H),0.68-0.62(m,2H),0.45-0.39(m,2H)。MS(m/z):591.58(M+H)。

And 4, step 4: ethyl 2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (1- (ethylcarbamoyl) azetidin-3-yl) amino) acetate (433)

To a suspension of 432(0.135mmol) in THF (5mL) were added TEA (0.094mL, 0.675mmol) and ethyl isocyanate (0.032mL, 0.405mmol) and stirred at room temperature for 1 hour. The mixture was then concentrated, water was added to form a precipitate, which was collected by filtration, washed with water, and air-dried to give the title compound 433 as a beige solid (78mg, 88% yield over 2 steps). ¹H NMR(400MHz,DMSO-d6)δ(ppm)：8.71(s,1H),8.55(d,J=1.6Hz,1H),8.52(d,J=5.6Hz,1H),8.34(s,1H),8.25(d,J=8.4Hz,1H),7.88(dd,J=8.0,2.0Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.0Hz,1H),6.65(dd,J=5.6,0.8Hz,1H),6.57(bd,J=2.8Hz,1H),6.27(t,J=5.6Hz,1H),4.06(q,J=7.2Hz,2H),3.84-3.75(m,5H),3.69-3.61(m,2H),3.02-2.94(m,2H),2.59-2.51(m,1H),1.18(t,J=7.2Hz,3H),0.97(t,J=7.2Hz,3H),0.68-0.62(m,2H),0.45-0.40(m,2H)。MS(m/z):662.60(M+H)。

And 5: 2- (((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) (1- (ethylcarbamoyl) azetidin-3-yl) amino) acetic acid (434)

To a solution of 433(78mg, 0.118mmol) in MeOH (3mL) was added 1n naoh (0.59mL, 0.59mmol) and stirred at room temperature for 3 hours. The mixture was then concentrated, diluted with water, and the pH adjusted to 6 to 7 by the addition of 1N HCl. To the resulting suspension, MeOH was added to visibly dissolve the mixture and via Biotage [ KP-C18-HS 30g, gradient 20 to 95% (methanol/water)]And (5) purifying. Title compound 434 was obtained as a white solid (79.5mg, 60% yield).¹H NMR(400MHz,DMSO-d6)δ(ppm):10.94(brs,1H),8.71(s,1H),8.62-8.57(m,1H),8.38(d,J=5.6Hz,1H),8.19(s,1H),8.15(d,J=8.0Hz,1H),7.89(dd,J=8.0,2.0Hz,1H),7.82(dd,J=14.0,2.4Hz,1H),7.20(t,J=9.2Hz,1H),7.09-7.05(m,1H),6.42(d,J=4.8Hz,1H),6.22(t,J=5.6Hz,1H),3.84-3.72(m,5H),3.63-3.58(m,2H),3.01-2.94(m,2H),2.86(s,2H),2.59-2.50(m,1H),0.97(t,j=7.2Hz,3H),0.61-0.56(m,2H),0.45-0.40(m,2H)。MS(m/z):634.60(M+H)。

Scheme 81

Example 279

1-cyclopropyl-3- (3-fluoro-4- (2- (4-methylpiperazine-1-carbonyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (429)

Step 1: (7-chlorothieno [3,2-b ] pyridin-2-yl) (4-methylpiperazin-1-yl) methanone (436)

1-Methylpiperazine (0.574mL, 5.17mmol) was added to 7-chlorothiophene [3,2-b ]]Pyridine-2-carbonyl chloride (435.1g,4.31mmol) and Et₃Suspension of N (l.80mL, 12.93mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with water and saturated aqueous ammonium chloride solution, and extracted with DCM. The organic layer was washed successively with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25g column; MeOH/DCM: 20CV 0/100 to 10/90) to give the title compound 436(1.16g, 3.93mmol, 91% yield) as a yellow solid. MS (M/z) 296.2(M + H).

Step 2: (7- (2-fluoro-4-nitrophenoxy) thieno [3,2-b ] pyridin-2-yl) (4-methylpiperazin-1-yl) methanone (437)

MgSO (MgSO)₄(1.41g, 11.78mmol) was added to 436(1.16g, 3.93mmol), 2-fluoro-4-nitrophenol (1.23g, 7.85mmol) and Na₂CO₃(1.24g,11.78mmol) in Ph₂Suspension in O (10 mL). The suspension was heated at 160 ℃ for 1.5 hours and 190 ℃ for 2 hours. After cooling to room temperature, DCM (30mL) was added and the reaction mixture was filtered and concentrated. From biotage (SNAP25g column; ethyl acetate/hexane: 5CV 10/90 followed by MeOH/DCM purification of the residue via 20CV 0/100 to 10/90) gave title compound 437 as a yellow solid (1.20g,2.88mmol, 73% yield). MS (M/z):417.2(M + H).

And step 3: (7- (4-amino-2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) (4-methylpiperazin-1-yl) methanone (438)

Zinc (0.75g, 11.53mmol) was added to a suspension of 437(1.2g, 2.88mmol) and ammonium chloride (0.31g, 5.76mmol) in a mixture of MeOH (30mL) and water (5.10 mL). The suspension was heated to reflux for 50 minutes. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was partitioned between DCM, water and ammonium hydroxide. The organic layer was collected, washed successively with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 50g column; MeOH/DCM: 30CV 0/100 to 20/80) to give the title compound 438(733mg,1.89mmol, 66% yield) as a yellow solid. MS (M/z) 387.4(M + H).

Step 4-cyclopropyl-3- (3-fluoro-4- (2- (4-methylpiperazine-1-carbonyl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (439)

Phenyl chloroformate (0.136mL, 1.08mmol) was added at 0 ℃ to a solution of 438(350mg,0.91mmol) and pyridine (0.147mL, 1.81mmol) in DMF (10 mL). After 20 minutes, cyclopropylamine (0.16mL, 2.26mmol) was added at 0 ℃ and the reaction mixture was heated at 60 ℃ for 30 minutes. Cyclopropylamine (0.16mL, 2.26mmol) was added and the reaction mixture was heated at 60 ℃ for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by biotage (SNAP25g column; MeOH/DCM: 20CV 0/100 to 10/90), triturated with MTBE (25mL) and dried to give the title compound 439(330mg, 0.70mmol, 78% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm)1H:8.71(s,1H),8.58(d, J =5.6Hz,1H),7.83(s, H),7.73(dd, J =2.4 and 13.6Hz,1H),7.37(t, J =8.8Hz,1H),7.23-7.17(m,1H),6.72(d, J =5.6Hz,1H),6.57(d, J =2.4Hz,1H),3.72-3.66(m,4H),2.58-2.51(m,1H), 2.41H), 2.58-1H-2.35(m,4H),2.21(s,H),0.68-0.62(m,2H),0.45-0.41(m,2H)。MS(m/z):470.4(M+H).

Compounds 440 to 458 (example 280 to example 298) were prepared in four steps according to procedures analogous to those used for the synthesis of compound 439 (example 279, scheme 81).

TABLE 35 characterization of Compounds 440 to 458 (examples 280 to 298)

Compounds 460 to 466 (example 300 to example 306) were synthesized following the procedure described above for the synthesis of compound 31 (example 17) (scheme 13). Compounds 467 to 470 (examples 307 to 310) were synthesized following the procedures described above for the synthesis of compound 114 (example 79) (scheme 13). Compounds 471 to 474 (examples 311 to 314) were synthesized using the corresponding amines in analogy to the procedure described above for the synthesis of compound 13 (example 10) (scheme 9).

TABLE 36 characterization of Compounds 460 to 474 (examples 300 to 314)

Compounds 475 to 481 (examples 315 to 321) were synthesized following analogous procedures as described above for the synthesis of compound 48 (example 31) (scheme 15) using the corresponding amines.

TABLE 37 characterization of Compounds 475 to 481 (examples 315 to 321)

Compound 482 compound 494 (example 322 to example 334) was synthesized following the procedure described above for the synthesis of compound 12 (scheme 9) starting from acid 62 (example 45, table 7) and the corresponding amine.

TABLE 38 characterization of Compounds 482 to 494 (examples 322 to 334)

Compounds 495 to 496 (example 335 to example 336) were synthesized following an analogous procedure to that described above for the synthesis of compound 13 (example 10, scheme 9). Compounds 497 to 499 (example 337 to example 339) were synthesized in the same manner as described above for compound 17 (example 31, scheme 13). Compound 500 (example 340) was synthesized following the procedure described for the synthesis of compound 582 (example 412, scheme 91).

TABLE 39 characterization of Compounds 495 to 500 (examples 335 to 340)

Scheme 82

Example 502

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) thiourea (502)

Step 1: tert-butyl (6- (7- (4- (3-cyclopropylthioureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl (2-methoxyethyl) carbamate (501)

Cyclopropyl isothiocyanate (0.353mL, 3.81mmol) was added to a solution of compound 11[1g, 1.91mmol, scheme 9] in NMP (20 mL). The solution was heated at 80 ℃ for 3 hours and at 100 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was quenched by addition of water and extracted with DCM. The organic layer was washed successively with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP100g column; MeOH/DCM: 20CV 0/100 to 5/95) to give the title compound 501(1.3g) as a brown oil. MS (M/z) 624.7(M + H).

Step 2: 1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((2-methoxyethylamino) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) thiourea (502)

To a solution of 501(1.3g) in acetic acid (10mL) was added 1M HCl (5.72mL, 5.72 mmol). The reaction mixture was heated at 40 ℃ for 1 hour. 1M HCl (2mL) was added and the reaction mixture was heated at 40 ℃ for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and the pH was adjusted to pH 9 by addition of 4m naoh. Finally, the mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by biotage (SNAP 100g column; MeOH/DCM: 20CV 0/100 to 10/90) and triturated with MTBE/ethyl acetate to give the title compound 502(325mg, 0.62mmol, 33% yield) as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.62(bs,1H),8.57(s,1H),8.54(d,J=5.6Hz,1H),8.33(s,1H),8.23(d,J=8.8Hz,1H),7.92-7.85(m,2H),7.46(t,J=9.2Hz,1H),7.37(bs,1H),6.66(d,J=5.6Hz,1H),3.78(s,2H),3.41(t,J=5.6Hz,2H),3.24(s,3H),2.65(t,J=5.6Hz,2H),0.81-0.75(m,2H),0.63-0.57(m,2H)。MS(m/z):524.6(M+1)。

Compound 503 (example 342) was synthesized following the procedure described above for the synthesis of compound 128 (example 87) (scheme 32). Compound 504 (example 343) was synthesized according to the procedure described above for the synthesis of compound 114 (example 79) (scheme 29). Compound 505 (example 344) was synthesized following the procedure described above for the synthesis of compound 17 (example 31) (scheme 13).

TABLE 40 characterization of Compounds 503 to 505 (examples 342 to 344)

Compound 506 (example 345) is prepared in one step in analogy to compound 85 (example 63, scheme 23) by reacting compound 49 (example 32, scheme 15) with methylmalonyl chloride reagent. In analogy to compound 81 (example 59, scheme 22), compound 49 (example 32, scheme 15) is reacted with the appropriate michael acceptor to prepare compounds 507 to 509 (example 346, example 348) in one step. In analogy to compound 61 (example 44, scheme 16), compounds 510 to 511 (example 349 to example 350) were prepared in one step by hydrolysis of esters 506 and 509 with sodium hydroxide at room temperature or 60 ℃ and final purification by preparative HPLC.

TABLE 41 characterization of Compounds 506 to 511 (examples 345 to 350)

Scheme 83

Example 351

1- (4- (2- (5- ((4- (2- (1H-tetrazol-5-yl) ethyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) -3-cyclopropylurea (512)

To a stirred suspension of 49(300mg, 0.578mmol, scheme 15) and DIPEA (303. mu.l, 1.74mmol) in DMSO (5ml) at room temperature under nitrogen was added 5- (2-chloroethyl) -1H-tetrazole (137mg, 1.03mmol) and the reaction mixture stirred at room temperature for 1 hour, heated at 60 ℃ C Overnight, then returned to room temperature. 5- (2-chloroethyl) -1H-tetrazole (300mg, 2.27mmol) is further added and the reaction mixture is heated at 60 ℃ to 65 ℃ for 24 hours, then returned to room temperature. The reaction mixture was diluted with water and sonicated. The solid was collected by filtration, rinsed with water and air dried. The crude material was purified three times by Biotage (Snap 25g column: MeOH/DCM containing 2% ammonium hydroxide: from 20CV 5/95 to 25/75 followed by from 20CV25/75 to 50/50; Silia Sep HP 12g column: MeOH/DCM containing 2% ammonium hydroxide: from 20CV 10/90 to 30/70 followed by from 20CV 30/70 to 40/60; Snap 30g KP-C18-HS (reverse phase): MeOH/water (Millipore): from 40CV 20/80 to 95/05) to give the desired product 512 as a beige sticky solid (14mg, 0.02mmol, 3.9% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) lacks an NH,8.74(s,1H),8.54(bd, J =1.6Hz,1H),8.52(d, J =5.5Hz,1H),8.32(s,1H),8.24(d, J =8.0Hz,1H),7.85(dd, J =8.2,2.2Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.0Hz,1H),7.20(dd, J =9.0,1.4Hz,1H),6.64(dd, J =5.4,0.7Hz,1H),6.60(bd, J =2.5Hz,1H),3.55(s,2H),2.95(t, J =7.4, 2H),2.68(t, t = 2H), 7.59.60 (t, 2.5H), 0.5H, 5H, 3.55 (t, 2H, 5H, 0.5H, 5H, 0.60 (m-0H). MS (M/z) 615.7(M + H).

Scheme 84

Example 352

Ethyl 3- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) butanoate (515)

Step 1: 4- (4-ethoxy-4-oxobut-2-yl) piperazine-1-carboxylic acid tert-butyl ester (513)

A solution of piperazine-1-carboxylic acid tert-butyl ester (1g, 5.37mmol), ethyl acetoacetate (883. mu.l, 6.98mmol) in DCM (30ml) was stirred at room temperature under nitrogen for 30 min, followed by the addition of NaBH (OAc)₃(2.4g, 10.74 mmol). The reaction mixture was stirred at room temperature overnight, quenched by the addition of water; stirring for 15 minutesAnd slowly diluted with saturated aqueous sodium bicarbonate (pH about 8 to 9). The reaction mixture was shaken for 1 hour. After separation, the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 50g column, MeOH/DCM: 20CV 0/100 to 5/95, no UV activity) to give the desired product 513 as a colorless viscous oil (1.03g, 3.43mmol, 63% yield). MS (M/z) 301.4(M + H).

Step 2: 3- (piperazin-1-yl) butanoic acid ethyl ester (514)

A solution of 513(1.02g, 3.40mmol) and TFA (10mL) in DCM (50mL) was stirred at room temperature for 3 h. The reaction mixture (azeotrope with DCM) was concentrated, diluted with water, and adjusted to pH about 8 to 9 with saturated aqueous sodium bicarbonate and 1N NaOH, and extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the desired product 514(411mg, 2.05mmol, 60% yield) as a yellow viscous oil, which was used as crude product in the next step without any further purification. MS (M/z) 201.3(M + H).

And step 3: ethyl 3- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) butanoate (515)

A solution of 47(500mg, 1.12mmol, scheme 15), 514(268mg, 1.34mmol) and acetic acid (128. mu.l, 2.23mmol) in NMP (5ml) was sonicated under nitrogen at room temperature and stirred for 1 hour. Followed by addition of NaBH (OAc)₃(746mg, 3.34mmol), and the reaction mixture stirred at room temperature overnight, quenched by the addition of water, stirred for 20 minutes and slowly diluted with saturated aqueous sodium bicarbonate. The resulting mixture was shaken for 10 minutes and sonicated. The solid was collected by filtration, washed with water and air dried, then purified twice by Biotage (Snap 50g column, MeOH/DCM: over 20CV 1/99 to 12/88; SiliAFlash 40g column, MeOH/DCM: over 30CV 1/99 to 15/85) to give the desired product 514(297mg, 0.469mmol, 42% yield) as an ivory viscous solid.¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.71(s,1H),8.53(bd,J=1.6Hz,1H),8.52(d,J=5.5Hz,1H),8.32(s,1H),8.23(d,J=8.2Hz,1H),7.84(dd,J=8.2,2.0Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.0Hz,1H),7.20(dd, J =8.9,1.5Hz,1H),6.64(dd, J =5.5,0.8Hz,1H),6.58(bd, J =2.5Hz,1H),4.10-3.98(m,2H),3.52(s,2H),3.01 (hexapeak, J =7.0Hz,1H),2.59-2.51(m,1H),2.50-2.30(m,9H),2.22(dd, J =14.3,7.6Hz,1H),1.17(t, J =7.0Hz,3H),0.96(d, J =6.7Hz,3H), 0.72-0.72H, 0.58H, 0.49H), 0.49H (d, J =6.7Hz, 3H). MS (M/z) 633.5(M + H).

Example 353

3- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) butyric acid (516)

To a stirred solution of 515(252mg, 0.40mmol) in a mixture of MeOH/THF (10/10mL) was added 1N NaOH (3.19 mL). The reaction mixture was heated at 60 ℃ for 2 hours, concentrated, diluted with water, neutralized with saturated aqueous ammonium chloride (pH about 5 to 6), and ground for 30 minutes, treated with sonication. The resulting gel was isolated by filtration and air dried. The solid residue was suspended in MeOH and water, collected by filtration, rinsed with water, air dried and dried under high vacuum. The dry solid was redissolved in a mixture of DCM and MeOH, the solution was filtered, the filtrate was concentrated and the residue was triturated with minimal MeOH, sonicated for 10 minutes, collected by filtration, rinsed with MeOH, air dried and dried under high vacuum to give the desired product 515(130mg, 0.206mmol, 51% yield) as an off white solid.¹H NMR(400MHz,DMSO-d₆) δ (ppm): lacking one carboxylic acid OH, 8.75(s,1H),8.56(bd, J =1.6Hz,1H),8.52(d, J =5.3Hz,1H),8.33(s,1H),8.25(d, J =8.0Hz,1H),7.86(dd, J =8.0,2.0Hz,1H),7.73(dd, J =13.6,2.4Hz,1H),7.38(t, J =9.1Hz,1H),7.20(bd, J =9.0Hz,1H),6.65(d, J =4.9Hz,1H),6.60(bd, J =2.5Hz,1H),3.58(s,2H),3.14-3.04(m,1H),2.74-2.64(m,2H), 2.34-2.34 (m,2H), 6.5H, 1H),3.58 (dd, 2H), 6.14-3.04 (m,1H), 2.64(m = 2H), 2.34H, 6.5H, 1H), 3.5H, 1H, 3.5 (dd, 1H). MS (M/z) 605.5(M + H).

Scheme 85

Example 355

5- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) pentanoic acid (518)

Step 1: ethyl 5- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) pentanoate (517)

To a stirred solution of 49(200mg, 0.39mmol, scheme 15) and DIPEA (202. mu.l, 1.16mmol) in DMSO (5ml) was added ethyl 4-bromon-valerate (85. mu.l, 0.58mmol) under nitrogen at room temperature and the reaction mixture was heated at 50 ℃ to 55 ℃ for 1 hour, then returned to room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SiliaFlash 25g column: MeOH/DCM containing 2% ammonium hydroxide: via 20CV 1/99 to 10/90 followed by 10CV 10/90 to 15/85; Snap25g column: MeOH/DCM containing 2% ammonium hydroxide: via 30CV 1/99 to 15/85) to give the desired product 517(94mg, 0.145mmol, 37% yield) as a colorless viscous solid. MS (M/z) 647.75(M + H).

Step 2: 5- (4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazin-1-yl) pentanoic acid (518)

To a stirred solution of 517(94mg, 0.145mmol) in a mixture of MeOH/THF (5/5mL) was added 1N NaOH (1.45 mL). The reaction mixture was heated at 60 ℃ for 1.5 hours, then returned to room temperature. The reaction mixture was concentrated, diluted with water, and neutralized with 1N HCl (pH about 5 to 6) until precipitation occurred. The suspension was shaken for 15 min, and the gel was collected by filtration, rinsed with water, and dried under high vacuum to give the desired product 518 as a white loose solid (66mg, 0.107mmol, 73% yield).¹H NMR(400MHz,DMSO-d₆) δ (ppm) absence of carboxylic acid OH,8.78(s,1H),8.56(bd, J =1.4Hz,1H),8.52(d, J =5.5Hz,1H),8.33(s,1H),8.25(d, J =8.0Hz,1H),7.86(dd, J =8.2,2.0Hz,1H),7.73(dd, J =13.6, 2.4H)Hz,1H),7.38(t,J=9.1Hz,1H),7.20(dd,J=8.9,1.3Hz,1H),6.65(dd,J=5.4,0.7Hz,1H),6.60(bd,J=2.5Hz,1H),3.58(s,2H),2.70-2.30(m,11H),2.26-2.18(m,2H),1.56-1.40(m,4H),0.72-0.58(m,2H),0.49-0.36(m,2H)。MS(m/z):619.5(M+H)。

Compounds 519 to 522 (examples 356 to 359) were prepared in two steps starting from 49 (example 32, scheme 15) in analogy to compound 518 (example 355, scheme 85).

TABLE 43 characterization of Compounds 519 to 522 (examples 356 to 359)

Compound 523, compound 525, compound 527, and compound 530 (example 360, example 362, example 364, and example 367) were prepared in analogy to compound 49 (example 32, scheme 15) in two steps. Compound 524, compound 526, compound 529, and compound 531 (example 361, example 363, example 366, and example 368) were prepared in two steps starting with 523, 525, 527, and 530, respectively, in analogy to compound 31 (example 17, scheme 13). Compound 528 (example 365) is a precursor of compound 529 (example 366) and is prepared analogously to compound 30 (scheme 13).

TABLE 44 characterization of Compounds 523 to 531 (examples 360 to 368)

In analogy to compound 48 (example 31, scheme 15), compounds 532 to 533 (examples 369 to 370) were prepared in one step from reductive amination of compound 47 with the appropriate amine.

TABLE 45 characterization of Compounds 532 to 534 (examples 369 to 371)

Compounds 535 through 543 (examples 372 through 380) are prepared in one step from an amide coupling of compound 49 with the appropriate carboxylic acid in analogy to compound 75 (scheme 20).

TABLE 46 characterization of Compounds 535 to 543 (examples 372 to 380)

In analogy to compound 61 (example 44, scheme 16), compounds 544 to 546 (examples 381 to 383) were prepared in one step by hydrolysis of esters 541 and 542 or lactone 543, respectively, at 45 ℃ to or 60 ℃ in the presence of sodium hydroxide and final purification by preparative HPLC.

TABLE 47 characterization of Compounds 544 to 546 (examples 381 to 383)

Scheme 86

Example 384

(E) -1-cyclopropyl-3- (4- (2- (5- ((4- (4- (dimethylamino) but-2-enoyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (547)

Stirring of trans-4-bis under nitrogen at room temperature A solution of methylaminobutenoic acid hydrochloride (124mg, 0.75mmol), EDC hydrochloride (248mg, 1.29mmol) and triethylamine (139. mu.l, 0.995mmol) in NMP (10ml) for 40 min. 49(150mg, 0.25mmol, 0.7TFA salt) was then added, and the reaction mixture was stirred at room temperature overnight. Trans-4-dimethylaminobutyric acid hydrochloride (124mg, 0.75mmol), EDC hydrochloride (248mg, 1.29mmol) are added and the reaction mixture is stirred at 45 ℃ overnight, then back to room temperature. Finally, quench by addition of water and react with saturated aqueous sodium bicarbonate solution (gel formation). The gel was collected by filtration, rinsed with water and air dried. The crude product was purified by Biotage (Snap 25g column: MeOH/DCM containing 2% ammonium hydroxide: 30CV 1/99 to 30/70) to afford the desired product 547(38mg, 0.06mmol, 24% yield) as a pale ivory viscous solid.¹HNMR(500MHz,DMSO-d₆) δ (ppm):8.78(s,1H),8.56(bd, J =1.7Hz,1H),8.51(d, J =5.4Hz,1H),8.34(s,1H),8.25(d, J =8.2Hz,1H),7.87(dd, J =8.2,2.0Hz,1H),7.72(dd, J =13.6,2.4Hz,1H),7.37(t, J =9.1Hz,1H),7.19(bd, J =8.9Hz,1H),6.64(d, J =5.4Hz,1H),6.60(bs,1H),6.36(bd, J =11.6Hz,1H),5.95(dt, J =11.6,6.9Hz,1H),3.59(s,2H), 3.43.36 (bd, J =11.6Hz,1H), 3.95 (dt, 19H, 69, 19H, 1H), 3.9 Hz, 3.59H, 3.9H, 69H, 47.9H, 2.47H, 47H, 2.47H, 2H, 23H, 2H. MS (M/z) 630.6(M + H).

Scheme 87

Example 385

1-cyclopropyl-3- (4- (2- (5- ((4- ((2E, 4E, 6E, 8E) -3, 7-dimethyl-9- (2,6, 6-trimethylcyclohex-1-enyl) non-2, 4,6, 8-tetraalkenoyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (548)

To a stirred solution of all-trans retinoic acid (ATRA) (130mg, 0.43mmol) in a mixture of DMF (1ml) and DCM (6.5ml) was added oxalyl chloride (76 μ l,0.87mmol) dropwise under nitrogen at 0 ℃. The reaction mixture was stirred at room temperature for 50 minutes. DCM was removed under reduced pressure (no heat!) and washed withDMF (2ml) diluted the remaining solution. To a stirred solution of 49(150mg, 0.29mmol) and triethylamine (120. mu.l, 0.87mmol) in DMF (5ml) at 0 ℃ under nitrogen was slowly added a solution of the acid chloride intermediate. After 1 hour, the reaction mixture was quenched by addition of water at 0 ℃. The resulting suspension was shaken, then the solid was collected by filtration, rinsed with water and air dried. The crude material was purified twice by Biotage (Snap 25g column; MeOH/DCM: 30CV 0/100 to 5/95 followed by 10CV 05/95 to 10/90; Snap 25g column; MeOH/DCM: 30CV 1/99 to 10/90). The desired fractions were combined and concentrated. The residue was dissolved in MeOH and concentrated until precipitation occurred. The solid was collected by filtration, washed with MeOH and dried to give the desired product 548 as a bright yellow loose solid (56mg, 0.07mmol, 24% yield). ¹H NMR(400MHz,DMSO-d₆)δ(ppm)：8.72(s,1H),8.57(bd,J=1.8Hz,1H),8.52(d,J=5.5Hz,1H),8.34(s,1H),8.26(d,J=8.2Hz,1H),7.88(dd,J=8.2,1.9Hz,1H),7.73(dd,J=13.6,2.4Hz,1H),7.38(t,J=9.1Hz,1H),7.19(dd,J=9.0,1.4Hz,1H),6.82(dd,J=15.3,11.3Hz,1H),6.65(dd,J=5.5,0.8Hz,1H),6.59(bd,J=2.5Hz,1H),6.39(d,J=15.1Hz,1H),6.25-6.10(m,4H),3.60(s,2H),3.57-3.43(m,4H),2.59-2.51(m,1H),2.45-2.34(m,4H),2.04-1.96(m,5H),1.95(s,3H),1.68(s,3H),1.61-1.52(m,2H),1.46-1.40(m,2H),1.00(s,6H),0.72-0.58(m,2H),0.49-0.36(m,2H)。MS(m/z):801.8(M+H)。

Scheme 88

Example 386

1-cyclopropyl-3- (4- (2- (5- ((4- (2- (2- (dimethylamino) ethylamino) acetyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) -3-fluorophenyl) urea (549)

To a stirred solution of 49(100mg, 0.19mmol) and triethylamine (107 μ l,0.77mmol) in DCM (10ml) was added chloroacetyl chloride (19 μ l,0.23mmol) under nitrogen and the reaction mixture was stirred at room temperature for 25 min. Adding dimethylHydroxyethylidene diamine (134 μ l,1.16mmol), and the reaction mixture was stirred at room temperature overnight, heated at 40 ℃ for 5 hours, then returned to room temperature. The reaction mixture was concentrated, diluted with water and a few drops of 1N NaOH and sonicated. The resulting gel was collected by filtration, rinsed with water and air dried. Prepared from Biotage [ Snap 30g column KP-C18-HS (reverse phase) x2 MeOH/water (Millipore): 40CV 20/80 to 95/05; analogix SF 25-40g column; MeOH/DCM 2% ammonium hydroxide over 60CV 1/99 to 50/50]The crude product was purified three times to give the desired compound 549(13mg, 0.02mmol, 10% yield) as a light yellow viscous solid.¹H NMR(500MHz,DMSO-d₆) δ (ppm): 8.75(s,1H),8.56(bd, J =1.7Hz,1H),8.51(d, J =5.4Hz,1H),8.32(s,1H),8.24(d, J =8.1Hz,1H),7.87(dd, J =8.2,1.9Hz,1H),7.72(dd, J =13.6,2.4Hz,1H),7.37(t, J =9.1Hz,1H),7.20(bd, J =8.9Hz,1H),6.64(d, J =5.4Hz,1H),6.61(bd, J =1.9Hz,1H),3.58(s,2H),3.50-3.36(m,4H),3.33(s,2H),2.59-2.51(m,1H, 2 = 2H), 2.52(t = 1H),3.58(s,2H),3.50-3.36(m,4H),3.33(s,2H),2.59-2.51(m = 2H), 2H = 0.47 (t, 2H), 2H, 0.47H, 0.5.5.5H, 1H), 2H, 1H, 2H, 3.47H, 2H, 3.5H. MS (M/z) 647.6(M + H).

Compound 550 (example 387) was prepared in two steps by coupling 225 (scheme 54) with 1-Boc-piperazine in analogy to compound 226 (example 127, scheme 54) followed by removal of the Boc protecting group in analogy to compound 49 (example 32, scheme 15).

TABLE 48 characterization of Compound 550 (example 387)

Compounds 551 to 555 (examples 388 to 392) were prepared in one step in analogy to compound 128 (example 87, scheme 32) by reacting 49 (example 32) with an isocyanate reagent. Compound 556 and compound 557 (example 393 and example 394) were prepared in one step by reacting 527 (example 364, table 44) and 550 (example 387, table 48), respectively, with ethyl isocyanate.

TABLE 49 characterization of Compounds 551 to 557 (examples 388 to 394)

In analogy to compound 61 (example 44, scheme 16), compounds 558 to 560 (examples 395 to 397) were prepared in one step by hydrolysis of esters 553 to 555 in the presence of sodium hydroxide at room temperature and finally purified by preparative HPLC.

TABLE 50 characterization of Compounds 558 to 560 (examples 395 to 397)

Compound 562 (example 399) was prepared in one step in analogy to compound 512 (example 351, scheme 83) starting from 49 (example 32, scheme 15) and the corresponding alkylating reagent.

TABLE 51 characterization of Compound 562 (example 399)

Scheme 89

2-methyl-1- (piperazin-1-yl) propan-2-ol (564)

Step 1: 4- (2-hydroxy-2-methylpropyl) piperazine-1-carboxylic acid tert-butyl ester (563)

To a stirred solution of 1-Boc-piperazine (1.00g, 5.37mmol) and DIPEA (1.41ml, 8.05mmol) in DMSO (20ml) was added 1-chloro-2-methyl-2-propanol (1.65ml, 16.11mmol) under nitrogen at room temperature and the reaction mixture was heated at 65 ℃ to 70 ℃ overnight. NaI (161mg, 1.07mmol) and further 1-chloro-2-methyl-2-propanol (1.65ml, 16.11mmol) were added and the reaction mixture was heated at 70 to 75 ℃ over the weekend. The reaction mixture was then diluted with ethyl acetate and successively with 10% Na₂S₂O₅Washed with water, saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 25g column: MeOH/DCM: 20CV0/100 to 5/95 followed by 5CV 5/95 to 10/90) to give the desired product 563 as a dark yellow oil (460mg, 1.78mmol, 33% yield). MS (M/z) 203.11 and 259.23(M + H).

Step 2: 2-methyl-1- (piperazin-1-yl) propan-2-ol (564)

A solution of 563(460mmol, 1.78mmol) and TFA (5mL) in DCM (20mL) was stirred at room temperature for 5 h. The reaction mixture (azeotrope with DCM) was concentrated, diluted with water and stirred for 10 min. The pH was adjusted to about 10 with 1N NaOH and the basic solution was extracted with DCM. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in high vacuum to give the desired product 564 as a dark orange viscous solid (170mg, 1.07mmol, 60% yield). The crude product was used in the next step without any further purification. MS (M/z) 159.13(M + H).

(R) -2-methyl-3- (piperazin-1-yl) propionic acid methyl ester (566)

Step 1: (R) -4- (3-methoxy-2-methyl-3-oxopropyl) piperazine-1-carboxylic acid tert-butyl ester (565)

To a stirred solution of 1-Boc-piperazine (1.00g, 5.37mmol) and DIPEA (2.81ml, 16.11mmol) in DMSO (20ml) was added methyl (S) - (-) -3-bromo-2-methylpropionate (1.03ml, 8.05mmol) under nitrogen at room temperature and the reaction mixture was heated over the weekend at 60 to 65 ℃. Additional methyl (S) - (-) -3-bromo-2-methylpropionate (1.03ml, 8.05mmol) was added and the reaction mixture was heated at 65 ℃ overnight. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous sodium bicarbonate solution and brine. The aqueous layers were combined, extracted with ethyl acetate and washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 205g column: MeOH/DCM: 20CV0/100 to 5/95 followed by 5CV 05/95 to 10/90) to give the desired product 565 as a dark yellow oil (523mg, 1.83mmol, 34% yield). MS (M/z) 231.13 and 287.27(M + H).

Step 2: (R) -2-methyl-3- (piperazin-1-yl) propionic acid methyl ester (566)

A solution of 565(523mmol, 1.83mmol) and TFA (5mL) in DCM (15mL) was stirred at room temperature for 3.5 h. The reaction mixture (azeotrope with DCM) was concentrated, diluted with water, stirred for 10 min, and the pH adjusted to about 9 with saturated aqueous sodium bicarbonate and 1N NaOH. Extracting the alkaline solution with DCM; the extract was dried over anhydrous magnesium sulfate, filtered and concentrated in high vacuum to give the desired product 566(314mg, 1.68mmol, 92% yield) as a yellow oil, which was used as crude product in the next step without any further purification. MS (M/z) 187.2(M + H).

2, 2-dimethyl-3- (piperazin-1-yl) propionic acid methyl ester (569)

Step 1: 2, 2-dimethyl-3-oxopropanoic acid methyl ester (567)

To a stirred solution of methyl 2, 2-dimethyl-3-hydroxypropionate (1g, 7.57mmol) in DCM (50ml) was added Dess-martin oxidant (3.21g,7.57mmol) in one portion at 0 ℃ under nitrogen and the reaction mixture was stirred at 0 ℃ for 1 h, followed by 45 min at room temperature. The reaction mixture was cooled to 0 ℃ and poured into 1N NaOH solution (30mL) and extracted with DCM. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and partially evaporated under reduced pressure (at about 25 ℃) to give a 567 solution which was stored in a freezer and used in the next step without any further purification.

Step 2: 4- (3-methoxy-2, 2-dimethyl-3-oxopropyl) piperazine-1-carboxylic acid tert-butyl ester (568)

A solution of 567(0.57mmol, crude product in 25ml DCM) and 1-Boc-piperazine (1.175g, 6.31mmol) in DCM (50ml) was stirred under nitrogen at room temperature for 1 h, then cooled to 0 ℃. Add NaBH (OAc) to the cold solution in one portion₃(4.22g, 18.93 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature overnight, quenched by addition of water, stirred for 1 hour and slowly neutralized with saturated aqueous sodium hydrogen chloride solution (pH =7 to 8). The basic solution was extracted with DCM. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 25g column, MeOH/DCM: 30CV 0/100 to 10/90) to give the desired product 568 as a colorless oily liquid (1.137g, 3.79mmol, 60% yield). MS (M/z) 301.3(M + H).

And step 3: 2, 2-dimethyl-3- (piperazin-1-yl) propionic acid methyl ester (569)

A solution of 568(1.137g, 3.79mmol) and TFA (15mL) in DCM (30mL) was stirred at room temperature for 2.5 h. The reaction mixture (azeotrope with DCM) was concentrated, diluted with water, stirred for 1 hour, and the pH was adjusted to about 9 to 10 with 1N NaOH. The basic solution was extracted with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, concentrated and dried under high vacuum to give the desired product 569 as a pale yellow viscous liquid (667mg, 3.33mmol, 88% yield). The crude material was used in the next step without any further purification. MS (M/z) 201.1(M + H).

Compounds 570 to 572 (examples 400 to 402) were prepared in one step in analogy to compound 48 described above (example 31, scheme 15) by reductive amination of compound 47 with the appropriate amine. In analogy to compound 226 (example 127, scheme 54), compound 573 (example 403) was prepared in one step by coupling 225 (scheme 54) with methyl 2, 2-dimethyl-3- (piperazin-1-yl) propionate 569.

TABLE 52 characterization of Compounds 570 to 573 (examples 400 to 403)

In analogy to compound 61 (example 44, scheme 16), compounds 574 to 576 (examples 404 to 406) were prepared in one step by hydrolysis of esters 571 to 573 at 65 ℃ to 70 ℃ in the presence of excess sodium hydroxide and final purification by preparative HPLC.

TABLE 53 characterization of Compounds 574 to 576 (examples 404 to 406)

Intermediates 577 through 579 (examples 407 through 409) were prepared in one step in analogy to compound 512 (example 351, scheme 83) starting from 550 (example 387), 527 (example 364) and 530 (example 367), respectively, and an excess of (2-bromoethoxy) -tert-butyldimethylsilane. Compound 580 (example 410) was prepared in analogy to compound 512 (example 351, scheme 83) in one step starting from 550 (example 351) and excess methyl 3-bromopropionate.

TABLE 54 characterization of intermediates 577 through 579 and final compound 580 (example 410)

Scheme 90

Example 411

1-cyclopropyl-3- (3-fluoro-4- (2- (5- (4- (2-hydroxyethyl) piperazine-1-carbonyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (581)

A solution of 577(190mmol, 0.275mmol) and wet TFA (2mL) in DCM (5mL) was stirred at room temperature for 1.5 h. TFA (2mL) was added and the reaction mixture was stirred at room temperature for 3.5 hours and stored in a freezer overnight. The reaction mixture (azeotrope with DCM) was then concentrated, diluted with water, stirred for 5 minutes and adjusted to pH about 12 to 13 with 1N NaOH. The resulting suspension was stirred and sonicated for 30 minutes; the solid was collected by filtration, rinsed with water, and air dried. The crude product was purified by Biotage (Snap25g column, MeOH/DCM containing 2% ammonium hydroxide: 30CV 1/99 to 15/85) to give the desired product 581 as an off-white powder (109mg,0.19mmol, 68% yield). ¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.72(s,1H),8.67(dd,J=2.2,0.8Hz,1H),8.54(d,J=5.5Hz,1H),8.46(s,1H),8.36(dd,J=8.1,0.9Hz,1H),7.99(dd,J=8.2,2.2Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.39(t,J=9.0Hz,1H),7.21(dd,J=9.0,1.2Hz,1H),6.68(dd, J =5.3,0.8Hz,1H),6.58(bd, J =2.5Hz,1H),4.46(t, J =5.4Hz,1H),3.74-3.56(m,2H),3.51(q, J =5.9Hz,2H),3.44-3.32(m,2H),2.59-2.51(m,1H), one CH₂Hidden, 2.43(t, J =6.2Hz,4H),0.72-0.58(m,2H),0.49-0.37(m, 2H). MS (M/z) 577.4(M + H).

Scheme 91

Example 412

(S) -1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2-hydroxyethyl) -3-methylpiperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (582)

To a stirred solution of 578(134mg,0.20mmol) in THF (5ml) was added a solution of TBAF (0.4ml, 0.4mmol) at-30 ℃. The reaction mixture was allowed to warm to room temperature over 2 hours and TBAF (1ml, 1mmol) was added. After 2 hours at room temperature, the reaction mixture was concentrated, diluted with water and sonicated for 30 minutes. The solid was collected by filtration, rinsed with water and air dried. Purify the crude by Biotage (Snap 25g column, MeOH/DCM containing 2% ammonium hydroxide: 20CV 1/99 to 20/80) to give the desired product 578 as a white viscous solid (99mg, 0.17mmol, 86% yield).¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.72(s,1H),8.54(bd,J=1.6Hz,1H),8.52(d,J=5.5Hz,1H),8.32(s,1H),8.24(dd,J=8.1,0.7Hz,1H),7.85(dd,J=8.1,2.1Hz,1H),7.73(dd,J=13.5,2.5Hz,1H),7.38(t,J=9.0Hz,1H),7.20(dd,J=8.8,1.4Hz,1H),6.64(dd,J=5.3,0.8Hz,1H),6.57(bd,J=2.5Hz,1H),4.50-4.22(m,1H),3.51(s,2H),3.49-3.41(m,2H),2.88-2.51(m,5H),2.48-2.10(m,4H),1.98-1.80(m,1H),0.96(d,J=6.3Hz,3H),0.72-0.58(m,2H),0.50-0.36(m,2H)。MS(m/z):577.5(M+H)。

Compound 583 (example 413) was prepared in one step by removal of the protecting group with TBAF starting from 579 (example 409) in analogy to compound 582 (example 412). Compound 584 (example 414) was prepared in two steps starting from 550 (example 387) analogously to compound 31 (example 17, scheme 13). Compound 585 (example 415) was prepared in analogy to compound 78 (scheme 21) in one step by coupling 74 (example 54, scheme 20) with the corresponding protected amino acid in the presence of DMAP and DCC.

TABLE 55 characterization of Compounds 583 to 585 (examples 413 to 415)

Scheme 92

Example 418

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4- (2- (2- (2-methoxyethoxy) ethoxy) acetyl) piperazin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (588)

To a solution of compound 49(0.050g, 0.10mmol, scheme 15), 2- (2- (2-methoxyethoxy) ethoxy) acetic acid (0.35g, 0.20mmol) and TEA (0.040g, 0.40mmol) in NMP (1mL) was added EDCI (0.037g, 1.9 mmol). The resulting mixture was stirred at room temperature for 24 hours, diluted with water and extracted with ethyl acetate. Wash the organic layer with water, brine; over MgSO₄Dried and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate/MeOH) to give 588(0.022g, 34% yield) as a white powder.¹H NMR(300MHz,MeOH-d₄)δ(ppm):8.62(d,J=1.5Hz,1H),8.50(d,J=5.4Hz,1H),8.12(d,J=7.2Hz,1H),8.11(s,1H),7.96(dd,J=1.8,8.1Hz,1H),770(dd, J =2.7,13.2Hz,1H),7.33(t, J =8.7Hz,1H),7.25-7.21(m,1H),6.67(d, J =5.7Hz,1H),4.28(s,2H),3.70-3.54(m,14H),3.68(s,3H),2.63(tt, J =3.9Hz,1H),2.61-2.54(m,4H),0.83-0.75(m,2H),0.60-0.53(m,2H). [ two NH proton peaks are not observed ]]。MS(m/z):679.2(M+H)。

Compound 589 (example 419) was prepared in one step by coupling compound 49 with the appropriate acid in analogy to compound 588 (example 418, scheme 92).

TABLE 56 characterization of Compounds 589 through 591 (examples 419 through 421)

Scheme 94

Example 495

4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) piperazine-1-carboxamide (596)

Step 1: 4-nitrophenyl 4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) piperazine-1-carboxylate (595)

To a solution of compound 49(0.50g, 0.96mmol, scheme 15) and pyridine (0.11g, 1.4mmol) in DMF (4mL) was added 4-nitrophenyl chlorocarbonate (0.23g, 1.1 mmol). The resulting mixture was stirred at room temperature for 1 hour with saturated NH₄Aqueous Cl was diluted and extracted with ethyl acetate-THF (4: l mixture). The organic layer was collected with saturated NaHCO₃Aqueous solution, water and brine, over MgSO₄Dried and concentrated. Trituration of the residue with t-BuOMe gave the product as a beige solidThe title compound 595(0.42g, 64% yield).¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.72(s,1H),8.60(s,1H),8.53(d,J=5.4Hz,1H),8.35(s,1H),8.30-8.26(m,3H),7.91(d,J=8.1Hz,1H),7.74(dd,J=2.4,10.8Hz,1H),7.45(d,J=8.7Hz,2H),7.39(t,J=9.0Hz,1H),7.21(d,J=9.0Hz,1H),6.66(d,J=5.1Hz,1H),6.58(s,1H),3.65(brs,4H),3.49(brs,2H),3.34(brs,4H),2.58-2.54(m,1H),0.70-0.63(m,2H),0.47-0.43(m,2H).

Step 2: 4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) piperazine-1-carboxamide (596)

To a solution of 595(0.10g, 0.15mmol) in NMP (4mL) was added (2- (2-methoxyethoxy) ethoxy) ethylamine (0.073g, 45 mmol). The resulting mixture was stirred at 70 ℃ for 32 hours, saturated NH₄Aqueous Cl was diluted and extracted with ethyl acetate-THF (4: l mixture). The organic layer was collected with saturated NaHCO₃Aqueous solution, water and brine, over MgSO₄Dried and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate/MeOH) to give the title compound 596(0.058g, 56% yield) as an amorphous solid.¹H NMR(300MHz,MeOH-d₄) δ (ppm):8.61(d, J =1.8Hz,1H),8.49(d, J =5.4Hz,1H),8.12(d, J =7.8Hz,1H),8.11(s,1H),7.95(dd, J =2.4,8.1Hz,1H),7.70(dd, J =2.7,13.2Hz,1H),7.33(t, J =8.7Hz,1H),7.25-7.21(m,1H),6.67(dd, J =1.2,5.4Hz,1H),3.70-3.61(m,8H),3.57-3.52(m,4H),3.50-3.43(m,4H),3.40-3.25(m,5H),2.64(tt, J =3.6, 2.62H), 2.50-3.43 (m,4H),3.40-3.25(m,5H),2.64(tt, J =3.6, 2H), 2.62H, 0.54H), 0.54H, 0.54H, 0, 0.54, 0H, and two peaks are observed]。MS(m/z):708.4(M+H)。

Scheme 95

Example 498

1-cyclopropyl-3- (3-fluoro-4- (2- (5- ((4-hydroxypiperidin-1-yl) methyl) pyridin-2-yl) thieno [3,2-b ] pyridin-7-yloxy) phenyl) urea (599)

To a suspension of aldehyde 47(0.3g, 0.669mmol) in a mixture of DCM (9mL) and DMF (3mL) at room temperature was added 4-hydroxypiperidine (0.135g, 1.34mmol) and acetic acid (0.08mL, 1.34 mmol). The reaction mixture was stirred for 30 minutes; addition of NaBH (OAc) ₃(0.425g, 2.00mmol) and the reaction mixture was stirred overnight. Further, 4-hydroxypiperidine (0.135g, 1.34mmol) and NaBH (OAc) were added thereto₃(0.425g, 2.00mmol) to the reaction mixture, stirred at room temperature for 4 hours, followed by addition of saturated NaHCO₃The solution was quenched and extracted with DCM/MeOH. The organic layer was washed with brine and over MgSO₄Dried and concentrated. Purify the crude by flash chromatography on silica gel (DCM/MeOH: 90/10-75/25) followed by trituration with MeOH to give the title compound 599 as a brown solid (0.17g, 48% yield).¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.71(s,1H),8.56-8.53(m,1H),8.52(d,J=5.4Hz,1H),8.31(s,1H),8.23(d,J=8.1Hz,1H),7.85(dd,J=8.4,2.4Hz,1H),7.73(dd,J=13.5,2.4Hz,1H),7.38(t,J=9.0Hz,1H),7.24-7.18(m,1H),6.65(d,J=5.4Hz,1H),6.56(d,J=2.1Hz,1H),4.58(d,J=4.2Hz,1H),3.54(s,2H),3.50-3.40(m,1H),2.75-2.65(m,2H),2.60-2.50(m,1H),2.19-2.05(m,2H),1.80-1.65(m,2H),1.50-1.35(m,2H),0.71-0.64(m,2H),0.48-0.40(m,2H).

Scheme 98

Example 501

N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (piperidin-4-yl) acetamide (609)

Step 1: 4- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methylamino) piperidine-1-carboxylic acid tert-butyl ester (607)

Aldehyde 47(0.3g, 0) at room temperature669mmol) to a suspension in a mixture of DCM (9mL) and DMF (3mL) was added 4-amino-Boc-piperidine (0.27g, 1.34mmol) and acetic acid (80. mu.L, 1.34 mmol). The reaction mixture was stirred for 1.5 h, using NaBH (OAc)₃(0.425g, 2.00mmol) and stirred overnight, then treated by addition of saturated NaHCO₃The solution was quenched and extracted with DCM/MeOH. The extract was washed with brine, over MgSO ₄Dried and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate/MeOH: 93/7 to 84/16) to give the title compound 607(0.355g, 84% yield) as a light brown solid.¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.69(s,1H),8.58(brs,1H),8.51(d,J=5.7Hz,1H),8.30(s,1H),8.22(d,J=8.1Hz,1H),7.91(dd,J=8.4,1.8Hz,1H),7.72(dd,J=13.5,1.8Hz,1H),7.37(t,J=9.0Hz,1H),7.25-7.15(m,1H),6.64(d,J=5.4Hz,1H),6.55(d,J=2.7Hz,1H),3.85-3.75(m,2H),3.81(s,2H),2.90-2.65(m,2H),1.85-1.75(m,2H),1.45-1.35(m,1H),1.39(s,9H),1.25-1.10(m,2H),0.71-0.62(m,2H),0.48-0.40(m,2H).

Step 2: 4- (N- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) acetamido) piperidine-1-carboxylic acid tert-butyl ester (608)

To a solution of 607(0.355g, 0.561mmol) in DMF (5mL) at room temperature was added TEA (0.2mL, 1.4mmol) and acetic anhydride (0.12mL, 1.12 mmol). The reaction mixture was stirred at 55 ℃ overnight, diluted with water and extracted with ethyl acetate/MeOH. The organic layer was washed with brine, over MgSO₄Dried and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate/MeOH: 90/10) to give the title compound 608(0.314g, 83%) as a white amorphous solid.¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.70(s,1H),8.55-8.47(m,2H),8.34(s,0.32H),8.30(s,0.78H),8.26(d,J=8.4Hz,0.3H),8.18(d,J=8.4Hz,0.7H),7.83-7.69(m,2H),7.38(t,J=9.0Hz,1H),7.25-7.15(m,1H),6.68-6.62(m,1H),6.56(d,J=2.7Hz,1H),4.67(s,0.7H),4.54(s,1.3H),4.05-3.85(m,3H),2.85-2.65(m,2H),2.61-2.50(m,1H),2.23(s,2H),2.01(s,1H),1.70-1.40(m,4H),1.40-1.32(m,9H),0.71-0.62(m,2H),0.48-0.40(m,2H).

And step 3: n- ((6- (7- (4- (3-cyclopropylureido) -2-fluorophenoxy) thieno [3,2-b ] pyridin-2-yl) pyridin-3-yl) methyl) -N- (piperidin-4-yl) acetamide (609)

To a suspension of 608(0.314g, 0.465mmol) in ethyl acetate (6mL) was added 1N HCl-ethyl acetate (2.0mL, 2.0mmol) at room temperature. The reaction mixture was stirred overnight, then concentrated and co-evaporated with ethyl acetate. The residue was purified by flash chromatography using a high pressure flash column (Yamazen Co.) (DCM/MeOH: 96/4 to 80/20) packed with amino silica gel to give the title compound 609(0.193g, 72% yield) as a white amorphous solid. ¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.71(s,1H),8.54-8.46(m,2H),8.34(s,0.3H),8.30(s,0.7H),8.26(d,J=8.1Hz,0.3H),8.18(d,J=8.1Hz,0.7H),7.82-7.69(m,2H),7.38(t,J=9.0Hz,1H),7.25-7.15(m,1H),6.68-6.62(m,1H),6.57(d,J=3.0Hz,1H),4.66(s,0.7H),4.54(s,1.3H),3.90-3.75(m,1H),3.00-2.90(m,2H),2.61-2.40(m,3H),2.20(s,2H),1.99(s,1H),1.65-1.40(m,4H),0.71-0.62(m,2H),0.48-0.40(m,2H).

Compound 611 (example 503) was prepared in one step in analogy to compound 115-a (example 80-a, scheme 29) via an amide coupling reaction of compound 49 (scheme 15) with 1-hydroxycyclopropanecarboxylic acid. In analogy to compound 31 (example 17, scheme 13), compound 612 (example 504) was obtained in two steps. Compound 613 (example 504) was prepared via amide coupling of compound 343 (example 200, scheme 71) with 2[2- (2-methoxyethoxy) ethoxy ] acetic acid.

TABLE 59 characterization of Compounds 611 to 613 (examples 503 to 505)

Pharmaceutical composition

In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compositions of the present invention may be formulated by any method well known in the art and may be prepared for administration by any route including, but not limited to: parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal routes of administration. In some embodiments, the compositions of the present invention are administered intravenously in a hospital setting. In some embodiments, administration may be by the oral route.

The characteristics of the carrier, excipient or diluent will depend on the route of administration. The term "pharmaceutically acceptable" as used herein refers to a non-toxic substance that is compatible with a biological system, e.g., a cell, cell culture, tissue, or organism, and does not interfere with the utility of the biological activity of the active ingredient. Thus, the compositions of the present invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's pharmaceutical Sciences,18th Edition, ed.a. gennaro, Mack Publishing co., Easton, Pa., 1990.

The active compound is included in a pharmaceutically acceptable carrier, excipient or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient without causing serious toxic effects to the patient being treated. The effective dosage range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated as above using the weight of the derivative or by other methods known to those skilled in the art.

Inhibition of VEGF receptor signaling

In some embodiments, the invention provides a method of inhibiting VEGF receptor signaling in a cell, the method comprising contacting a cell in need of inhibition of VEGF receptor signaling with an inhibitor of VEGF receptor signaling of the invention. Because the compounds of the present invention inhibit VEGF receptor signaling, they are useful research tools for studying the role of VEGF receptor signaling in biological processes in vitro.

In some embodiments, inhibiting VEGF receptor signaling results in inhibition of cell proliferation in the contacted cell.

Detection examples

Inhibition of VEGF Activity

The compounds of the invention were tested using the following protocol.

Detection example 1

In vitro receptor tyrosine kinase assay (VEGF receptor KDR)

The assay measures the ability of a compound to inhibit the enzymatic activity of a recombinant human VEGF receptor.

A1.6-kb cDNA corresponding to the catalytic domain of VEGFR2(KDR) (Genbank accession No. AF035121, amino acids 806 to 1356) was cloned into the Pst I site of pDEST20 Gateway vector (Invitrogen) to generate a GST-tagged form of the enzyme. Using this structure, recombinant baculoviruses were generated using the Bac-to-BacTM system according to the manufacturer's instructions (Invitrogen).

When Sf9 cells (Spodoptera frugiperda) were infected with the recombinant baculovirus construct, GST-VEGFR2806-1356 protein was expressed. Briefly, Sf9 cells grown in suspension and maintained in serum-free medium (Sf 900II supplemented with gentamicin) were infected with the above-mentioned viruses at an infection rate (MOI) of 0.1 at 27 ℃ with agitation at 120rpm on a rotary shaker over a 72 hour period, at a cell density of about 2x10⁶Individual cells/ml, infected cells were harvested by centrifugation at 398g for 15 minutes. The cell pellet was frozen at-80 ℃ until purification.

All steps described in the cell extraction and purification method were performed at 4 ℃. Frozen Sf9 cell pellets infected with GST-VEGFR2806-1356 recombinant baculovirus were thawed and gently resuspended in buffer A (PBS supplemented with 1. mu.g/ml pepstatin, 2. mu.g/ml antipeptidase and leupeptin (leupeptin), 50. mu.g/ml PMSF, 50. mu.g/ml TLCK and 10. mu.ME 64 and 0.5mM DTT (pH 7.3)) using 3ml buffer per gram of cells. The suspension was homogenized by a Dounce homogenizer (Douncehomogenized) and 1% Triton X-100 was added to the homogenate, after which it was centrifuged at 22500g for 30 min at 4 ℃. The supernatant (cell extract) was used as starting material for the purification of GST-VEGFR 2806-1356.

The supernatant was loaded onto a GST agarose column (Sigma) equilibrated in PBS (pH 7.3). After washing with 4 Column Volumes (CV) of PBS (pH 7.3) +1% Triton X-100 and 4CV of buffer B (50mM Tris pH 8.0, 20% glycerol and 100mM NaCl), bound proteins were eluted stepwise with 5CV of buffer B supplemented with 5mM DTT and 15mM glutathione. GST-VEGFR2806-1356 enriched fractions from this chromatography step, i.e. fractions with high o.d.280, were mixed based on u.v. detection. The final GST-VEGFR2806-1356 protein formulation concentration is about 0.7mg/ml, with a purity approaching 70%. Purified GST-VEGFR2806-1356 protein material was aliquoted and frozen at-80 ℃ prior to use in enzyme assays.

Inhibition of VEGFR/KDR was measured in the DELFIATM assay (Perkin Elmer). The substrate poly (Glu4, Tyr) was immobilized on a black high binding polystyrene 96-well plate. The coated plates were washed and stored at 4 ℃. During the assay, the enzyme was preincubated with inhibitor and Mg-ATP on ice for 4 minutes in polypropylene 96-well plates, followed by transfer to coated plates. The kinase reaction then takes place at 30 ℃ for 10 to 30 minutes. For VEGFR/KDR, the ATP concentration in the assay was 0.6. mu.M (2X Km). The enzyme concentration was 5 nM. After incubation, the kinase reaction was quenched with EDTA and the plates were washed. The phosphorylated product was detected by incubation with europium-labeled anti-phosphotyrosine MoAb. After washing the plates, bound moabs were detected by time-resolved fluorescence analysis in a Gemini SpectraMax reader (molecular devices). Evaluating a range of concentrations of a compound, and determining IC ₅₀Value (concentration of compound at which enzyme activity is 50% inhibited). The results are shown in table 60. In the table, "a" indicates IC₅₀A value of less than 50 nanomolar; "b" indicates IC₅₀Value ≥ 50<100 nanomolar, "c" indicates IC₅₀Value ≥ 100<250 nanomolar; and "d" indicates IC₅₀The value is more than or equal to 250 nanomoles.

Watch 60

Compound numbering	VEGFR IC50μM
		116	a
85	a
		88	a
113	a
		92	a
3	a
		114	a
105	a
		115	a
201	a
		50	a
25	a
		51	a
106	a
		8	b
119	c
		89	a
86	a
		120	c
117	a
		14	d
92-A	a
		7	a
90	a
		123	a
127	a
		129	a
130	a
		128	a
9	a
		93	a

Compound numbering	VEGFR IC50μM
		10	a
20	a
		19	a
193	a
		21	a
194	a
		137	a
117-A	b
		39	a
4	a
		5	a
205	b
		43	a
140	a
		115-A	a
195	a
		49	a
52	a
		54	a
53	a
		66	a
55	a
		108	a
141	a
		142	a
67	a
		225	a
143	a
		72	a
44	a
		110	a
259-A	a
		217	a
109	a
		218	a
45	a
		36	a
73	a
		35	a
212	a
		169	a
70	a
		298	a
299	a
		111	a

Compound numbering	VEGFR IC50μM
		161-B	a
40	b
		161-A	a
222	a
		29	c
223	c
		253	a
37	c
		224	a
254-A	a
		235	a
31	c
		171	a
227	a
		183	a
185	a
		34	a
187	a
		288	a
38	a
		228	a
41	a
		229	a
46	a
		236	a
168	a
		170	a
256	a
		50-A	a
258	a
		13	b
239	a
		237	a
172	a
		42	b
154	a
		230	a
231	a
		58	a
59	a
		60	a
232	a
		155	a
62	a
		63	a

Compound numbering	VEGFR IC50μM
		61	a
266	a
		48	a
178	a
		267	a
283	a
		259	a
273	d
		76	a
157	a
		190	a
238	a
		274	a
240	a
		275	a
77	a
		82	a
241	a
		173	a
276	b
		79	a
80	a
		247	a
254	a
		83	a
189	a
		255	b
233	a
		56	a
257	a
		271-A	b
81	a
		244	a
180	a
		161	a
57	a
		54-A	a
54-E	a
		166	a
84	a
		54-F	a
54-G	a
		277	c
54-B	a
		310	a

Compound numbering	VEGFR IC50μM
		295	a
311	a
		315	a
316	a
		54-D	A
68	a
		293	a
323	a
		324	a
325	a
		326	a
327	a
		328	a
329	a
		330	a
331	a
		332	a
333	a
		334	a
335	a
		339	a
340	a
		341	a
343	a
		344	a
345	a
		346	a
347	a
		348	a
349	a
		350	a
351	a
		352	a
353	a
		354	a
355	a
		357	a
358	a
		363	a
364	a
		365	a
367	b
		368	a
369	a
		372	a

Compound numbering	VEGFR IC50μM
		373	a
375	a
		376	a
377	a
		378	a
379	a
		380	a
381	a
		382	a
383	a
		384	a
385	a
		386	a
387	a
		388	a
389	a
		390	a
391	a
		392	a
394	a
		395	a
396	a
		397	a
399	a
		400	a
401	a
		402	a
405	a
		406	a
407	a
		408	a
409	a
		410	a
411	a
		412	a
413	a
		414	a
416	a
		417	a
418	a
		420	a
421	a
		422	a
423	a
		424	a

Compound numbering	VEGFR IC50μM
		426	a
427	a
		428	a
429	d
		434	a
440	d
		441	a
442	a
		443	d
444	a
		445	a
446	a
		447	a
448	c
		449	a
450	a
		451	d
452	a
		453	a
454	a
		455	c
456	a
		457	b
458	b
		460	a
462	a
		465	b
466	a
		467	a
468	a
		471	b
472	b
		473	a
475	a
		476	a
477	a
		478	a
480	a
		481	a
482	a
		483	a
484	a
		485	a
486	a
		487	a

Compound numbering	VEGFR IC50μM
		488	a
489	a
		490	a
491	a
		492	a
493	a
		494	a
495	a
		496	a
497	a
		498	a
499	a
		500	a
502	a
		503	b
504	a
		505	b
506	a
		507	a
508	a
		509	a
510	a
		511	a
512	a
		515	a
516	a
		518	a
519	a
		520	a
521	a
		522	a
524	a
		526	a
527	a
		528	a
529	a
		530	a
531	a
		532	a
533	a
		535	a
536	a
		537	a
538	a
		539	a

Compound numbering	VEGFR IC50μM
		540	a
543	a
		544	a
545	a
		546	a
547	a
		548	d
549	a
		550	a
551	a
		552	a
556	a
		557	a
558	a
		559	a
562	a
		570	a
574	a
		575	a
576	a
		580	a
581	a
		582	a
583	a
		584	a
588	a
		589	a
596	a
		599	a
609	a
		342-A	a
461	a
		462	a
469	a
		463	c

Detection example 2

VEGF-dependent Erk phosphorylation

Cells and growth factors: HUVEC cells were purchased from Cambrex Bio Science Walkersville, Inc and cultured according to the vendor's instructions. Cloning of VEGF against baculovirus expressing Sf9 cells Using Gateway cloning technology (Invitrogen)₁₆₅The full-length coding sequence of (1). VEGF was purified from conditioned medium using a NaCl gradient elution from a HiTrap heparin column (GE Healthcare Life Sciences) followed by an imidazole gradient elution from a HiTrap chelating column (GE Healthcare Life Sciences)₁₆₅Then the buffer was stored in PBS supplemented with 0.1% BSA and the filters were sterilized.

Cell detection: cells were seeded at 8000 cells/well in 96-well plates and grown for 48 hours. Followed by Cells were grown overnight in serum-free and growth factor-free medium and exposed to compound dilutions for 1.5 hours. After 15 min incubation in culture medium, VEGF was added₁₆₅(150ng/mL) cells were placed in ice-cold lysis buffer (50mM HEPES, pH7.4, 150mM NaCl, 1.5mM MgCl) containing 1mM 4- (2 aminoethyl) benzenesulfonyl fluoride hydrochloride, 200. mu.M sodium orthovanadate, 1mM sodium fluoride, 10. mu.g/mL leupeptin, 10. mu.g/mL antipeptidase, 1. mu.g/mL pepstatin, and 50. mu.g/mL p-toluoyl-L-lysine sodium chloromethyl ketone hydrochloride₂1% Triton X-100, 10% glycerol) and treated according to Western blot analysis (Western blots) to detect ERKl/2(T202/Y204) phosphate resistance (Cell Signaling Technologies).

Western blot analysis: lysed samples from one treatment well were separated on 5 to 20% SDS-PAGE gels and blot analysis was performed using an Immobilon polyvinylidene fluoride membrane (Amersham) according to the manufacturer's instructions. Blots were washed with Tris-buffered saline containing 0.1% Tween 20 detergent (TBST) and probed for antibodies against Thr202/Tyr204-ERK (cell signaling technologies). Chemiluminescence detection (Amersham, ECL plus) was performed according to the manufacturer's instructions using imaging and densitometry analysis with a Storm densitometer (GE Healthcare;800PMT, 100nM resolution). Preparation of IC Using 4-parameter fitting model Using values over a range of dilutions ₅₀Curve line. These curves were calculated using GraFit 5.0 software.

Detection example 3

In vivo solid tumor disease model

This test measures the ability of a compound to inhibit the growth of a solid tumor.

In the flank of female athymic CD1 mice (Charles River Inc.), lxl 06U 87, a431 or SKLMS cells were injected subcutaneously per mouse to form tumor xenografts. Once formed, the tumors were serially passaged subcutaneously in nude mouse hosts. Tumor fragments from these host animals were used in subsequent compound evaluation experiments. For compound evaluation experiments, surgical implantationApproximately 30mg of tumor fragments from donor tumors were implanted subcutaneously into female nude mice weighing approximately 20 g. When the tumor size is about 100mm³(about 7 to 10 days after implantation), animals were randomized and divided into treatment and control groups. Each group contained 6 to 8 tumor bearing mice, each mouse ear tagged and individually tracked throughout the experiment.

Mice were weighed and tumors were measured by caliper three times a week starting on day 1. These tumor measurements were converted to tumor volumes by the well-known formula (L + W/4)34/3 π. When the control tumor size reached about 1500mm³When necessary, the experiment was terminated. In this model, the mean change in tumor volume of compound-treated groups/mean change in tumor volume of control groups (untreated or vehicle-treated) x 100(Δ T/Δ C) was subtracted by 100 to give the percent tumor growth inhibition (% TGI) for each test compound. Animals were monitored for body weight twice weekly for up to 3 weeks, except for tumor volume.

Detection example 4

In vivo Choroidal Neovascularization (CNV) model

This test measures the ability of a compound to inhibit CNV progression. CNV is the leading cause of severe vision loss in patients with age-related macular degeneration (AMD).

Male Brown-Norway rats (Brown-Norway Rat) (Japan clearco., Ltd.) were used in these studies.

Rats were anesthetized by intraperitoneal injection of pentobarbital (pentobarbital) and the right pupil dilated with 0.5% tropicamide (tropicamide) and 0.5% phenylephrine hydrochloride. A slit lamp delivery system using a green laser light condenser (Nidex inc., JapAn), and a system using Healon^TMMicroscope slides of (AMO Inc) were used as contact lenses, and the right eye received 6 laser burns between retinal vessels. The laser power was 100 or 200mW for 0.1 second and the spot diameter was 100 μm. Upon laser firing, blister generation was observed, which indicates Bruch's membrane rupture, which is important for the occurrence of CNV.

After laser irradiation (day 0), rats were grouped based on their body weight using SAS software (SAS institute Japan, R8.1). After anesthetizing the animals and dilating the right pupil (as mentioned above), on day 3, the right eye of the animals received the compound or vehicle at a dose of 10 or 3nmol per eye (10 μ L per eye). Prior to injection, the compounds are dissolved or suspended in CBS, PBS or other suitable vehicle.

On day 10, animals were anesthetized with ether and high molecular weight Fluorescein Isothiocyanate (FITC) -dextran (SIGMA, 2xl 0) was injected via tail vein⁶MW) (20 mg per rat). Approximately 30 minutes after FITC-dextran injection, animals were euthanized by ether or carbon dioxide, and the eyes were removed and fixed with 10% formalin (formaline) neutral buffer solution. After being fixed for 1 hour, the cornea, lens and retina were removed from the eyeball, and RPE-choroid-scleral plate specimens were obtained. These slab specimens were mounted in 50% glycerol on a microscope slide, and the laser-burned portions were photographed using a fluorescence microscope (Nikon, excitation filter: 465-. The CNV area was obtained by measuring the high fluorescence area observed on the photographs using the Scion image.

The mean CNV area of 6 burns was used as the individual CNV area value, and the mean CNV area of the compound-treated group was compared with the vehicle-treated group. Results for some compounds of the invention are shown in table 61 and are indicated as percent inhibition of CNV progression ("a" indicates greater than or equal to 60% inhibition and "B" indicates 240% to <60% inhibition).

Watch 61

Detection example 4

VEGF-induced retinal vascular permeability in rabbits

Materials and methods

This test measures the ability of a compound to inhibit VEGF-induced retinal vascular permeability. Vascular permeability is responsible for severe vision loss in patients with age-related macular degeneration (AMD). Male Dutch rabbits (Dutch rabbitt) (approximately 2kg, Kitayama LABES co., LTD, Nagano, Japan) were anesthetized with pentobarbital and topically with 0.4% oxybuprocaine hydrochloride. After dilating the pupil with 0.5% tropicamide eye drops, the test substance or vehicle was injected into the vitreous cavity. Intravitreal injection of recombinant human VEGF 48 hours before measurement of vitrescein concentration₁₆₅(500ng; Sigma-Aldrich Co., St Louis, Mo.). Rabbits were anesthetized with pentobarbital and sequentially injected with sodium fluorescein (2mg/kg) via the auricular vein. The pupil was dilated with 0.5% tropicamide eye drops and the ocular fluorescein content was measured 30 minutes after fluorescein injection using FM-2Fluorotron Master (Ocumetrics, Mountain View, CA). The fluorescein concentration in the vitreous was obtained at a data point 0.25mm from the posterior end along the optical axis. Vitreous fluorescence concentration is considered to be fluorescein leakage from retinal vascular structures. The mean fluorescence peaks of the test substance-treated group were compared with those of the vehicle-treated group.

Claims (35)

1. A compound having the formula (I)

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from arylHeteroaryl, cycloalkyl or heterocyclic ring system, C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)⁶)-C(O)-、(R⁶)(R⁶) N-C (O) -O-heterocyclyl-C (O) -, PivO-heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -N (R)⁶) heterocyclyl-C (O) -, (C)₁-C₆Alkyl (Box) N-heterocyclyl-C (O) -, HO-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -O-heterocyclyl-C (O) -, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C (O) -and (R)⁶)(R⁶) N-heterocyclyl-C (O) -wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more independently selected R³⁸Substitution;

m is an optionally substituted fused heterocyclic moiety;

z is selected from-O-, -S (O)_0-2-and-NR⁵-, wherein R⁵Selected from H, optionally substituted C₁-C₅Alkyl, optionally substituted (C)₁-C₅) Acyl and C₁-C₆alkyl-O-C (O), wherein C₁-C₆Alkyl is optionally substituted;

ar is a group of the formula C,

Wherein the content of the first and second substances,

A⁴、A⁵、A⁶and A⁷Independently selected from N and-CH-, with the proviso that A⁴、A⁵、A⁶And A⁷Up to two of which may be N, wherein Ar is optionally substituted; and

g is a group B-L-T, wherein

B is selected from the group consisting of a covalent bond, -N (R)¹³)-、-N(SO₂R¹³)-、-O-、-S(O)_0-2and-C (= O) -;

l is selected from the group consisting of a covalent bond, -C (= S) N (R)¹³)-、-C(=NR¹⁴)N(R¹³)-、-SO₂N(R¹³)-、-SO₂-、-C(=O)N(R¹³)-、-N(R¹³)-、-C(=O)C_1-2alkyl-N (R)¹³)-、-N(R¹³)C_1-2alkyl-C (= O) -, -C (= O) C_0-1alkyl-C (= O) N (R)¹³)-、-C_0-4Alkylene, -C (= O) C_0-1alkyl-C (= O) OR³-、-C(=NR¹⁴)-C_0-1alkyl-C (= O) -, -C (= O) -C_0-1alkyl-C (= O) -and optionally substituted 4 to 6 membered heterocyclyl containing 1 to 3 ring heteroatoms including at least one nitrogen, wherein the alkyl and alkylene groups are optionally substituted; and

t is selected from-H, -R¹³、-C_0-4Alkyl, -CO_0-4alkyl-Q, -O-C_0-4alkyl-Q, -C_0-4alkyl-O-Q, -N (R)¹³)C_0-4alkyl-Q, -SO₂C_0-4alkyl-Q, -C (= O) C_0-4alkyl-Q, -C_0-4alkyl-N (R)¹³) Q and-C (= O) N (R)¹³)-C_0-4alkyl-Q, wherein each C_0-4Alkyl is optionally substituted;

wherein

R³⁸Is selected from C₂-C₆Alkynyl-heterocyclyl, H (O) C-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_il-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_il-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C ₁-C₆alkyl-heterocyclyl-CH₂-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, F-heterocyclyl-C₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, R³⁷-C₁-C₆alkyl-O-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-O-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-O-aryl-N (R)⁶)-C₁-C₆Alkyl-, (by one or more C)₁-C₆Alkyl substituted heteroaryl) -N (R)⁶)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆alkyl-aryl-N (R)⁶)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆alkyl-C (O) -aryl-N (R)⁶)-C₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-O-aryl-N (R)⁶)-C₁-C₆Alkyl-, (R)⁶)₂N-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆Alkyl radical C (O) -O-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-S (O)₂-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, (optionally substituted by one or more C) ₁-C₆Alkyl-substituted heterocyclyl) -C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -C₁-C₆Alkyl-, heterocyclyl-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -C₁-C₆alkyl-heteroaryl-N (R)⁶)-C(O)-C₁-C₆Alkyl-, (C)₁-C₆Alkyl radical)₂N-heterocyclyl-C (O) -C₁-C₆Alkyl-, heteroaryl-C₁-C₆alkyl-N (R)⁶)-C(O)-C₁-C₆Alkyl-, (Boc) (H) N-heterocyclyl-C (O) -C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, Boc-heterocyclyl-C (O) -C₁-C₆Alkyl-, Ac-O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, (Boc) (H) N-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, NH₂-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (H) N-C (O) -heterocyclyl-C (O) -C₁-C₆Alkyl-, NH₂-heterocyclyl-C (O) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-O-C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -N (R)⁶) -heterocyclyl-C (O) -, (R)⁶)(R⁶) N-heterocyclyl-C (O) -, (R)⁶)(R⁶) N-heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-O-C₁-C₆Alkyl-, C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C (O) -, (R)⁶)(R⁶) N-C (O) -heterocyclyl-O-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-O-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, halogen-C ₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, halogen-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-N (R)⁶) -heterocyclyl-C₁-C₆Alkyl-, R³⁷-O-C(O)-C₁-C₆alkyl-N (R)⁶)-C(O)-N(R⁶) -heterocyclyl-C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (H) N-C (O) -heterocyclyl-N [ C ]₁-C₆alkyl-C (O) -OH]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C (O) -heterocyclyl-C₁-C₆Alkyl-, HO-C (O) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -CO) -heterocyclyl-C₁-C₆Alkyl-, (C)₁-C₆Alkyl) (C₁-C₆Alkyl) N-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) - [ (C)₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) - [ (C)₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, R³⁷O-C₁-C₆Alkyl- [ (C)₁-C₆Alkyl) (C₁-C₆Alkyl) heterocyclic group]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N (R)⁶)-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N [ C (O) -NH-C₁-C₆Alkyl radical]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆alkyl-N [ C (O) -C₁-C₆Alkyl radical]-C₁-C₆Alkyl-, C₁-C₆alkyl-O-C₁-C₆Alkyl- [ C (O) -C₁-C₆alkyl-OH]-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, spiro-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -spiro-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-C ₁-C₆Alkyl-, heterocyclyl-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₂-C₆alkenyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C₂-C₈alkenyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶)-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, heterocyclyl-C (O) -, (R)⁶)(R⁶) N-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, C₂-C₆alkenyl-C (O) -O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶) N-C (O) -heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆Alkyl-heterocyclesradical-C₁-C₆Alkyl- (heterocyclyl) -, R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -N (R)⁶)-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-(CH₂)_n[(CH₂)_iO]_xC₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, HO-heterocyclyl-C₁-C₆Alkyl-, R³⁷O-cycloalkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-and R³⁷O-(CH₂)_n[(CH₂)_iO]_x-C₁-C₆alkyl-C (O) -N (R)⁶) -heterocyclyl-C₁-C₆An alkyl group;

a is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R³⁷O)(R^37aO)P(O)O-C₁-C₆alkyl-C (O) -, -C (= NR)³⁷) -H and-C₁-C₆alkyl-CF₃；

Each R is⁶Independently is H or C₁-C₆An alkyl group;

R³⁷Selected from H, C₁-C₆Alkyl and C₃-C₁₀A cycloalkyl group;

R^37aselected from H, C₁-C₆Alkyl and C₃-C₁₀A cycloalkyl group;

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

il is 2 or 3;

jl is an integer from 0 to 4, or 1 or 2;

n is an integer of 0 to 4;

R³⁹selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n2(C₆-C₁₀Aryl), - (CH)₂)_n2(C₅-C₁₀Heteroaryl), (CH)₂)_n2(5-to 10-membered heterocyclic group), - (CH)₂)_n2O(CH₂)_i2OR³⁷And- (CH)₂)_n2OR³⁷Wherein R is as defined above³⁹Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

R⁹selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n3(C₆-C₁₀Aryl), - (CH)₂)_n3(C₅-C₁₀Heteroaryl), - (CH)₂)_n3(5-to 10-membered heterocyclic group), - (CH)₂)_n3O(CH₂)_i3OR³⁷And- (CH)₂)_n3OR³⁷Wherein R is as defined above⁹Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

R¹⁰selected from H, -OH, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl, - (CH)₂)_n4(C₆-C₁₀Aryl), - (CH)₂)_n4(C₅-C₁₀Heteroaryl), - (CH)₂)_n4(5-to 10-membered heterocyclic group), - (CH)₂)_n4O(CH₂)_i4OR³⁷And- (CH)₂)_n4OR³⁷Wherein R is as defined above¹⁰Said alkyl, aryl, heteroaryl and heterocyclyl portions of groups are optionally substituted;

n2 is an integer from 0 to 6;

i2 is an integer from 2 to 6;

n3 is an integer from 0 to 6;

i3 is an integer from 2 to 6;

n4 is an integer from 0 to 6;

i4 is an integer from 2 to 6;

R²independently at each occurrence is selected from-H, halogen, trihalomethyl, -CN, -NO ₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_nAryl, -O (CH)₂)_nHeteroaryl, - (CH)₂)_0-5(aryl), - (CH)₂)_0-5(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Wherein T is²Selected from-OH, -OMe, -OEt, -NH₂、-NHMe、-NMe₂-NHEt and-NEt₂And wherein said aryl, heteroaryl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl is optionally substituted; and

q is an integer of 0 to 4;

R¹³selected from-H, -CN, -NO₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³、-C(O)SR³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_n5Aryl, -O (CH₂)_n5Heteroaryl, - (CH)₂)_n5(aryl), - (CH)₂)_n5(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Optionally substituted C₁-C₄Alkylcarbonyl and a saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic radical, wherein T²Selected from-OH, -OMe, -OEt, -NH₂、-NHMe、-NMe₂-NHEt and-NEt₂And wherein said aryl, heteroaryl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl is optionally substituted;

two R¹³Together with the atoms to which they are attached may be combined to form optionally substituted 1 to 4R⁶⁰Substituted heteroalicyclic wherein the heteroalicyclic may have up to 4 ring heteroatoms and the heteroalicyclic may be fused to aryl or heteroaryl, in which case the aryl or heteroaryl is further optionally substituted with 1 to 4-R⁶⁰Substitution;

n5 is an integer from 0 to 6;

R⁶⁰selected from-H, halogen, trihalomethyl, -CN, -NO ₂、-NH₂、-OR³、-NR³R⁴、-S(O)_0-2R³、-SO₂NR³R³、-CO₂R³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)CO₂R³、-C(O)R³Optionally substituted (C)₁-C₆) Alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl;

when attached to a non-aromatic carbon, two R⁶⁰May be oxo;

each R is³Independently selected from-H and R⁴；

R⁴Is selected from (C)₁-C₆) Alkyl, aryl, lower arylalkyl, heterocyclyl and lower heterocyclyl-alkyl, each of which is optionally substitutedInstead of, or

R³And R⁴Together with the common nitrogen to which they are attached form an optionally substituted 5-to 7-membered heterocyclyl, which optionally contains at least one other ring heteroatom selected from N, O, S and P;

R¹⁴is selected from-H, -NO₂、-NH₂、-N(R³)R⁴、-CN、-OR³Optionally substituted (C)₁-C₆) Alkyl, optionally substituted heteroalicyclic-alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic,

q is a 3-to 10-membered ring system optionally substituted with zero, one or more R²⁰Substitution;

R²⁰selected from-H, halogen, trihalomethyl, -CN, -NO₂、-NH₂、-OR³、-OCF₃、-NR³R⁴、-S(O)_0-2R³、-S(O)₂NR³R³、-C(O)OR³、-C(O)NR³R³、-N(R³)SO₂R³、-N(R³)C(O)R³、-N(R³)C(O)OR³、-C(O)R³、-C(O)SR³、C₁-C₄Alkoxy radical, C₁-C₄Alkylthio, -O (CH)₂)_n6Aryl, -O (CH)₂)_n6Heteroaryl, - (CH)₂)_n6(aryl), - (CH)₂)_n6(heteroaryl) C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -CH₂(CH₂)_0-4-T²Optionally substituted C₁-C₄Alkylcarbonyl group, C₁-C₄Alkoxy, optionally substituted by C₁-C₄Alkoxy-substituted C₁-C₄Alkyl-substituted amino, - (CH) ₂)_n6P(=O)(C₁-C₆Alkyl radical)₂Saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic radicals, -SiMe₃and-SbF₅(ii) a And

n6 is an integer from 0 to 6.

2. A compound having formula (Ia),

wherein D, M, Z, Ar and G are as defined for formula (I), except that

R³⁸Is selected from (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, (optionally substituted 7-or 8-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted spiro-heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted bridged bicyclic ring system) -C₁-C₆Alkyl-, (substituted piperazine) -C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, C₁-C₆alkyl-S (O)_0-2-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R³⁷S(O)_0-2aryl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, R³⁷O-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, R^37aO-C(O)-C₁-C₆alkyl-N (R)³⁷)-C(O)-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R¹¹-C₁-C₆alkyl-C (O) -piperazine-C₁-C₆Alkyl-, C₀-C₆Alkyl- (5 or 6 membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, (5-10 membered optionally substituted heterocyclyl) -C₁-C₆alkyl-O- (oxo-substituted 5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (5-10 membered optionally substituted heterocyclyl) -C ₁-C₆alkyl-N (R)¹) - (oxo-substituted 5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (5-10 membered optionally substituted heterocyclyl) -C₁-C₆alkyl-S (O)_0-2- (oxo-substituted 5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (R)²³)(R²⁴)P(O)-C₁-C₆alkyl-C (O) -, (R)²³)(R²⁴)(O)P-C₁-C₆alkyl-N (R)³⁷)-C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C(H)(R²⁸)-、R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, R²⁹O-C(O)-C(H)(C(O)-OR^29a)-O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-and (substituted piperidine) -C₁-C₆Alkyl-;

wherein

R¹Is H or C₁-C₆An alkyl group;

R¹¹is-OH, -O-C₁-C₆Alkyl, optionally substituted 5-to 10-membered heterocyclyl or-O- (amino acid);

R²³selected from H, -OH, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, aryl, -O-aryl, cycloalkyl, -O-cycloalkyl, heteroaryl, -O-heteroaryl, 5-to 10-membered heterocyclyl, -O- (5-to 10-membered heterocyclyl), -C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl, -O-C₁-C₆Alkyl-heteroaryl, -C₁-C₆Alkyl-cycloalkyl, -O-C₁-C₆Alkyl-cycloalkyl, -C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) and-O-C₁-C₆Alkyl- (5 to 10 membered heterocyclyl);

R²⁴selected from H, -OH, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, aryl, -O-aryl, cycloalkyl, -O-cycloalkyl, heteroaryl, -O-heteroaryl, 5-to 10-membered heterocyclyl, -O- (5-to 10-membered heterocyclyl), -C₁-C₆Alkyl-aryl, -O-C₁-C₆Alkyl-aryl, -C₁-C₆Alkyl-heteroaryl, -O-C₁-C₆Alkyl-heteroaryl, -C ₁-C₆Alkyl-cycloalkyl, -O-C₁-C₆Alkyl-cycloalkyl, -C₁-C₆Alkyl- (5-to 10-membered heterocyclyl) and-O-C₁-C₆Alkyl- (5 to 10 membered heterocyclyl);

R²⁸selected from H, -CF₃、-CHF₂、-CH₂F. CN, optionally substituted C₁-C₆Alkyl and C₃-C₆A cycloalkyl group;

R²⁹selected from H, C₁-C₆Alkyl and cation; and

R^29aselected from H, C₁-C₆Alkyl groups and cations.

3. A compound having formula (II) or formula (III),

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine, wherein said pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine are substituted with one R³⁸Substituted, or D is unsubstituted tetrahydropyridine;

R³⁸is selected from R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-, (oxo-substituted heterocyclyl) -C₁-C₂Alkyl- (wherein the oxo-substituted heterocyclyl is further optionally substituted by-N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac) and-OH), R³⁷O-(CH₂)_n-O-(CH₂)_n1C(O)-N(R⁴⁰)-CH₂-、C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, (heterocyclyl) -C (O) - (wherein heterocyclyl is optionally substituted by C₁-C₆Alkyl substituted), C₁-C₆alkyl-S (O)²-(CH₂)₂-N(A)-CH₂-、C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, HO-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -, (C) ₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)₂)_1-6-、C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)³⁹)-C(O)-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷-O-C (O) -heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, C₁-C₆alkyl-SO₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, (HO-substituted C)₁-C₆alkyl-N (R)³⁹)-C(O)-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-, heterocyclyl radical-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆Alkyl-, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-, (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-, C₀-C₆Alkyl- (5 or 6 membered heterocyclyl) -C₁-C₆alkyl-piperazine-C₁-C₆Alkyl-, H (O) C-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-;

whereinWhen D is imidazole, said imidazole is further optionally substituted with C₁-C₆Alkyl substitution;

R³⁷Is H, C₁-C₆An alkyl group;

R^37ais H, C₁-C₆An alkyl group;

a is H, Ac, -C (O) -CH₂-OMe、-C(O)-CH(NH₂)-C(CH₃)₃、-C(O)-C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (O) -H, -C (O) -C₁-C₆Alkyl, -C₁-C₆alkyl-O-C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -, C₁-C₆Alkyl and-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)-C(O)-OBn；

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

i1 is 2 or 3;

j 1 is an integer from 0 to 4, alternatively 1 or 2;

n is an integer of 0 to 4;

n1 is an integer from 0 to 4;

R³⁹is H, C₁-C₆An alkyl group, a carboxyl group,

R⁴⁰is C₁-C₆alkyl-OR⁴¹；

R⁴¹Is H, C₁-C₆An alkyl group;

R⁹is H, C₁-C₆An alkyl group;

R¹⁰is H, C₁-C₆An alkyl group;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

R²is H or F;

R^2ah, F, Cl;

g is selected from

R¹³Is H or C₁-C₆An alkyl group; and is

Each R is²⁰Independently selected from H, halogen, -PO (C)₁-C₆Alkyl radical)₂、-S(O)₂-C₁-C₆Alkyl) and-C (O) -NH₂。

4. The compound of claim 3, having formula (IV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is selected from the group consisting of pyridine, phenyl, imidazole and heterocycle-C ≡ C-, wherein said pyridine, phenyl and imidazole are each substituted with one R³⁸Substitution;

R³⁸is selected from R³⁷O-(CH₂)₂-N(A)-CH₂- (e.g. R)³⁷O-(CH₂)₂-N(A)-CH₂-, (oxo-substituted heterocyclyl) -C₁-C₆Alkyl- (e.g. alkyl)) And (heterocyclyl) -C (O) - (e.g. C)),

Wherein when D is imidazole, said imidazole is further optionally substituted with C₁-C₆Alkyl (e.g. -CH)₃) Substitution;

R³⁷is H or C₁-C₆An alkyl group;

a is H or Ac;

R²is F;

R^2ais H; and

each R is²⁰Independently selected from H, -PO (C)₁-C₆Alkyl radical)₂(e.g., -PO (Me)₂)、-S(O)₂-C₁-C₆Alkyl) (e.g., -S (O)₂Me) and-C (O) -NH₂。

5. The compound of claim 3, having formula (VI):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is selected from pyridine, phenyl, imidazole, pyrazole and tetrahydropyridine, each substituted by one R³⁸Substituted, or D is unsubstituted tetrahydropyridine;

R³⁸is selected from R³⁷O-(CH₂)₂-N(A)-(CH₂)_1-2-、R³⁷O-(CH₂)_n-O-(CH₂)_n1C(O)-N(R⁴⁰)-CH₂-、C₁-C₆Alkyl-heterocyclyl- (CH)₂)_1-2-, (oxo-substituted heterocyclyl) -C₁-C₆Alkyl- (wherein the oxo-substituted heterocyclyl is further optionally substituted with a substituent selected from the group consisting of-N (R)⁹)(R¹⁰)、C₁-C₆Alkyl, -N (R)³⁷) (Ac), -OH and (heterocyclyl) -C (O) -, wherein the heterocyclyl is optionally substituted with C ₁-C₆Alkyl substituted), C₁-C₆alkyl-S (O)₂-(CH₂)₂-N(A)-CH₂-、C₀-C₆Alkyl-heterocyclyl- (CH)₂)_1-3-, HO-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-CH₂-、(C₁-C₆Alkyl) -C (O) -heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl- (CH)_1-6-、C₀-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)³⁹)-C(O)-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰) N-heterocyclyl-C (O) -, R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R₃₇-O-C(O)-C₁-C₆alkyl-heterocyclyl-C (O) -, HOOC-C₁-C₆alkyl-N (A) -CH₂-、(HOOC)(NR⁹R¹⁰)-C₁-C₆alkyl-N (A) -CH₂-、R³⁷-O-C (O) -heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₀-C₆alkyl-heterocyclyl-C (O) -, C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-, cycloalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -, C₁-C₆alkyl-SO₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆alkyl-heterocyclyl-CH₂-, (HO-substituted C)₁-C₆Alkyl) -N (R)³⁹)-C(O)-、NC-C₁-C₆alkyl-heterocyclyl-CH₂-, heterocyclyl radical-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、C₁-C₆alkyl-S (O)₂-heterocyclyl-CH₂-, heteroaryl-C₁-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-C₁-C₆Alkyl-, N (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-, (optionally substituted 8-to 10-membered fused heterocyclyl) -C₁-C₆Alkyl-and (difluoro-substituted heterocyclyl) -C₁-C₆Alkyl-;

wherein when D is imidazole, the imidazole is further optionally substituted with C₁-C₆Alkyl substitution;

R³⁷Is H, C₁-C₆An alkyl group;

R^37ais H, C₁-C₆An alkyl group;

a is H, Ac, -C (O) -CH₂-OMe、-C(O)-CH(NH₂)-C(CH₃)₃、-C(O)-(CH₂)_n-N(R³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)-C(O)-N(R³⁹)-C₁-C₆Alkyl and substituted benzeneC(O)-H、-C(O)-C₁-C₆Alkyl, -C₁-C₆alkyl-O-C₁-C₆Alkyl, -C (O) -C₁-C₆alkyl-OH, -C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(=NH)-H、-C(O)-(CH₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -cycloalkyl, -C (O) -N (R)⁹)(R¹⁰)、(R²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -and C₁-C₆An alkyl group, a carboxyl group,

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

i1 is 2 or 3;

j1 is an integer from 0 to 4, alternatively 1 or 2;

n is an integer of 0 to 4;

n1 is an integer from 0 to 4;

R³⁹is H or C₁-C₆An alkyl group;

R⁴⁰is-C₁-C₆alkyl-OR⁴¹；

R⁴¹Is H or C₁-C₆An alkyl group;

R⁹is H or C₁-C₆An alkyl group;

R¹⁰is H or C₁-C₆An alkyl group;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

R²is H or F; and

R^2ah, F or Cl.

6. The compound of claim 3, having formula (VII):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is pyridine or imidazole, wherein said pyridine and imidazole are substituted by one R ³⁸Substitution;

R³⁸selected from (oxo-substituted heterocyclyl) -C₁-C₆Alkyl-, (heterocyclyl) -C (O) -, C₁-C₆Alkyl radical, R³⁷O-(CH₂)₂-N(A)-CH₂-, heterocyclyl radical-C₁-C₆alkyl-N (R)³⁹) -C (O) -, heterocyclyl-CH₂-；

Wherein when D is imidazole, the imidazole is further optionally substituted with C₁-C₆Alkyl (e.g. -CH)₃) Substitution;

R³⁷is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl or-C (O) -C₁-C₆An alkyl group;

R³⁹is H or C₁-C₆An alkyl group;

R²is F; and

R^2ais H.

7. The compound of claim 3, having formula (VIII):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-CH₂-, e.g. MeO- (CH)₂)₂-N(A)-CH₂-；

A is H or-C (O) -C₁-C₆Alkyl radicals, e.g. C (O) -CH₃；

R¹³Is H or C₁-C₆An alkyl group;

R³⁷is C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

R²⁰is H or F.

8. The compound of claim 3, having formula (IX):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸Is R³⁷O-(CH₂)₂-N(A)-CH₂-, e.g. MeO- (CH)₂)₂-N(A)-CH₂-；

A is H or-C (O) -C₁-C₆An alkyl group;

R³⁷is H or C₁-C₆An alkyl group; and

R²is F.

9. The compound of claim 3, having formula (X):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(A)-(CH₂)_j1-、R³⁷O-C(O)-C₀-C₆alkyl-heterocyclyl-CH₂-、R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-(CH₂)_i1-N(R³⁹)-C(O)-、R³⁷-O-C(O)-C ₁-C₆alkyl-heterocyclyl-C (O) -, (R)⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C(O)-C₁-C₆alkyl-heterocyclyl-CH₂-、(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-heterocyclyl-CH₂-、F₃C-C₁-C₆alkyl-heterocyclyl-CH₂-、N(R⁹)(R¹⁰)N-C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-and C₁-C₆alkyl-C (O) -O-C₁-C₆alkyl-C (O) - (5-to 10-membered heterocyclyl) -C₁-C₆Alkyl-;

R³⁷is H or C₁-C₆An alkyl group;

a is selected from-C (O) -C₁-C₆alkyl-N (R)³⁹)-C(O)-C₁-C₆alkyl-N (R)⁹)(R¹⁰)、-C(O)-N(R³⁹)-C₁-C₆Alkyl, -C (= NR)³⁷)-C₁-C₆Alkyl, -C (O) - (CH)₂)_n-S(O)₂-C₁-C₆Alkyl, -C (O) -N (R)⁹)(R¹⁰) And (R)²³)(R²⁴)P(O)O-C₁-C₆alkyl-C (O) -;

n is an integer of 0 to 4;

R³⁹is H or C₁-C₆An alkyl group;

R⁹is H or C₁-C₆An alkyl group;

R¹⁰is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H or F;

R²³is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, and-O- (5-to 10-membered heterocyclyl);

R²⁴is selected from-OH, C₁-C₆Alkoxy, -O-aryl, -O-cycloalkyl, -O-heteroaryl, -O- (5-to 10-membered heterocyclyl);

j is an integer from 0 to 4, or an integer from 0 to 2;

i is 2 or 3;

x is an integer from 0 to 6, alternatively 2 or 3;

i1 is 2 or 3;

j1 is an integer from 0 to 4, alternatively 1 or 2; and

g is

10. The compound of claim 9, wherein R³⁸Further comprises C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-heterocyclyl-C (O) -, or-C (O) -piperidine-piperazine-CH₃。

11. The compound of claim 3, having formula (XI):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

wherein

D is a group R³⁸Substituted and further substituted by C₁-C₆Alkyl substituted imidazoles;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, aryl, heteroaryl, and heteroaryl,

R³⁹Is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

12. The compound of claim 3, having formula (XII):

wherein

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸Substituted phenyl;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C ₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, -C (O) -N (R)³⁹) -a cycloalkyl group;

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

13. The compound of claim 3, having formula (XIII)

Including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸Substituted and further substituted by C₁-C₆Alkyl substituted imidazoles;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, aryl, heteroaryl, and heteroaryl,

R³⁹Is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

14. The compound of claim 3, having formula (XIV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸Substituted tetrahydropyridines;

R³⁸is R³⁷O-C(O)-C₁-C₆alkyl-C (O) -, R³⁷-O-C₁-C₆alkyl-O-C₁-C₆alkyl-C (O) -;

R³⁷is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

15. The compound of claim 3, having formula (XV):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is a quilt R³⁸A substituted pyrazole;

R³⁸is a ringalkyl-N (R)³⁹)-C(O)-O-C₁-C₆Alkyl-, R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-；

A is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is F;

R^2ais H; and

g is

16. The compound of claim 3, having formula (XVI):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-CH₂；

A is selected from H, -C (O) -C₁-C₆Alkyl, -C (O) -N (R)³⁹)-C₁-C₆Alkyl and-C (O) -C₁-C₆alkyl-OH;

R³⁷is H, C₁-C₆An alkyl group;

R³⁹is H, C₁-C₆An alkyl group; and

R²is H.

17. The compound of claim 3, having formula (XVII):

including the N-oxides, hydrates, solvates, pharmaceutically acceptable salts of tautomers, prodrugs and complexes thereof, as well as the racemates and racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a quilt R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-、

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆An alkyl group, a carboxyl group,

R³⁹is H or C₁-C₆An alkyl group;

R²is H; and

g is

18. The compound of claim 3, having formula (XVIII):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

D is pyridine or imidazole, each R³⁸And wherein the imidazole is further substituted by-C₁-C₆Alkyl radicals, e.g. -CH₃Substitution;

R³⁸is R³⁷O-(CH₂)_1-6-N(A)-(CH₂)_1-4-or R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-CH₂-；

R³⁷Is H or C₁-C₆An alkyl group;

a is-C (O) -N (R)³⁹)-C₁-C₆Alkyl, -C (O) -H,

R³⁹is H or C₁-C₆An alkyl group;

R²is H or F;

R^2ais H or F; and

g is

19. A compound having the formula (XIX):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, racemic and non-racemic mixtures, diastereomers and enantiomers thereof, wherein,

d is a group R³⁸A substituted pyridine;

R³⁸is R³⁷O-(CH₂)₂-N(A)-(CH₂)₂-；

R³⁷Is C₁-C₆An alkyl group;

a is H or C₁-C₆An alkyl group, a carboxyl group,

R²is F;

R^2ais H; and

g is

20. A compound selected from

Including the N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, as well as racemic and non-racemic mixtures, diastereomers and enantiomers thereof.

21. The compound of claim 1 or 2, wherein G is

22. The compound of any one of claims 1, 2 and 21, whereinIs composed of

23. The compound of any one of claims 1, 2, 21, and 22, wherein Ar isWherein Ar is optionally substituted.

24. The compound of any one of claims 1, 2, and 21-23, wherein D is pyridyl, imidazolyl, or triazolyl, each of which is substituted with one R ³⁸And (4) substitution.

25. The compound of any one of claims 1, 2, and 21-24, wherein R³⁸Is selected from R³⁷O-C(O)-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-, C₁-C₆alkyl-heterocyclyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-C (O) -heterocyclyl-C₁-C₆Alkyl-, R³⁷O-C₁-C₆alkyl-heterocyclyl-C₁-C₆Alkyl-and R³⁷O-(CH₂)_j-[(CH₂)_iO]_x-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C₁-C₆Alkyl-, wherein each of said alkyl and heterocyclyl is optionally substituted.

26. The compound of any one of claims 1, 2, and 21-25, wherein D is substituted with one R³⁸A substituted pyridyl group.

27. The compound of any one of claims 1, 2, and 21-26, wherein R³⁸Through C₁-C₆When alkyl is attached to D, the C₁-C₆Alkyl is-CH₂-。

28. The compound of any one of claims 1, 2, and 21-23, wherein D is selected from C₁-C₆alkyl-heterocyclyl-C (O) -, C₁-C₆alkyl-heterocyclyl-C₁-C₆alkyl-N (R)⁶)-C(O)-、(R⁶)(R⁶) N-C (O) -O-heterocyclyl-C (O) -, PivO-heterocyclyl-C (O) -, C₁-C₆alkyl-O-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -N (R)⁶) heterocyclyl-C (O) -, (C)₁-C₆Alkyl (Box) N-heterocyclyl-C (O) -, HO-C (O) -heterocyclyl-C (O) -, C₁-C₆alkyl-C (O) -O-heterocyclyl-C (O) -, (R)⁶)(R⁶)N-C₁-C₆alkyl-N (R)⁶) -C (O) -heterocyclyl-C (O) -, C ₁-C₆alkyl-heterocyclyl-C (O) -and (R)⁶)(R⁶) N-heterocyclyl-c (o) -wherein both the alkyl and heterocyclyl are optionally substituted.

29. The compound of any one of claims 1, 2, and 21-28, wherein R⁶Is H.

30. A composition comprising a compound of any one of claims 1-29.

31. A method of inhibiting kinase activity comprising contacting the kinase with a compound of any one of claims 1-29, or a composition thereof.

32. A method of inhibiting angiogenesis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-29, or a composition thereof.

33. A method of treating a disease in response to inhibiting kinase activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-29, or a composition thereof.

34. A method of treating a cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-29, or a composition thereof.

35. A therapeutic method for treating an ophthalmic disease, condition, or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-29, or a composition thereof.