Pyridocyclic compounds and preparation methods and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry and relates to pyridocyclic compounds, preparation methods and uses thereof. Specifically, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, which exhibits good anti-tumor activity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and relates to a pyridocyclic compound with TGFβR1 inhibitory activity, a pharmaceutical composition and a medicine kit containing the same, a preparation method and use thereof. Background Art

[0002] Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates various cellular responses, such as cell proliferation, differentiation, migration, and apoptosis. The TGF-β superfamily includes TGF-β1, TGF-β2, TGF-β3, activin, inhibin, bone morphogenetic protein, etc. TGF-β signals through two highly conserved single transmembrane serine / threonine kinases, TGFβR1 and TGFβR2 (ACS Med. Chem. Lett., 2018, 9, 1117).

[0003] Smads are important intracellular TGF-β signal transduction and regulatory molecules that can directly transduce TGF-β signals from the cell membrane to the cell nucleus. The TGF-β / Smads signaling pathway plays an important role in the occurrence and development of tumors. In TGF-β / Smads signal transduction, activated TGF-β first binds to TGFβR2 on the cell membrane surface to form a heterodimer complex, which is further recognized and bound by TGFβR1. Activated TGFβR1 further phosphorylates Smad2 / Smad3 proteins, which further bind to Smad4 to form a heterotrimer complex. This complex enters the cell nucleus and synergizes with auxiliary activating / inhibiting factors to regulate the transcription of target genes (Nature, 2003, 425, 577). As long as any link in the TGF-β / Smads signaling pathway changes, it will lead to abnormalities in the signal transduction pathway (PNAS, 2019, 116, 9166).

[0004] The TGF-β signaling pathway is dysregulated in many diseases, including cancer. The TGFβR1 protein level is significantly increased in gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, liver cancer, lung cancer, cervical cancer, and head and neck cancer cell lines and tumor tissues. Activation of the TGF-β signaling pathway induces significant pathological effects in the tumor stroma, including immunosuppression, angiogenesis, and connective tissue hyperplasia. In addition, the TGF-β signaling pathway can enhance the invasiveness of tumor cells, promote epithelial cell-mesenchymal transition, and improve the tolerance to tumor epithelial cell therapy (Nat. Neurosci., 2014, 17, 943).

[0005] At present, the development of inhibitors targeting TGFβR1, a key target in the TGF-β signaling pathway, has gradually gained attention in the pharmaceutical industry, and published patent applications include WO 02 / 094833A1, WO 2009 / 150547A1, WO 2017 / 035118A1, WO 2018 / 019106A1, etc. However, there is still an urgent need for new TGFβR1 inhibitors in this field, especially TGFβR1 inhibitors with high activity and high selectivity. Summary of the invention

[0006] Through extensive research, the present invention surprisingly discovered a pyridocyclic compound and a corresponding preparation method thereof. The compound can significantly inhibit the activity of TGFβR1 and has good selectivity between TGFβR1 and TGFβR2. As a TGFβR1 inhibitor, the compound can be used to treat proliferative diseases and apoptosis disorders mediated at least in part by the TGF-β signaling pathway, especially diseases mediated at least in part by TGFβR1, such as cancer, for example, liver cancer.

[0007] In a first aspect, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof:

[0008]

[0009] in,

[0010] R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace;

[0011] R 2 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, cyano, -C(=O)NR a R b 、-C(=O)OR a , 4-8 membered heterocyclic groups and 5-10 membered heteroaryl groups, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more R 5 replace;

[0012] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R 6 replace;

[0013] R 3 Selected from hydrogen and -NR c R d ;

[0014] R c and R d are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, -C(=O)R a , C 6-10 Aryl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0015] R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl is optionally substituted with one or more halogens;

[0016] R 5 Each occurrence is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, hydroxyl, halogen, amino and cyano, the C 1-6 Alkyl, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups;

[0017] R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl or C 3-8 The cycloalkyl group is optionally substituted with one or more hydroxy groups;

[0018] R 7 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0019] X is selected from C 1-6 Alkylene and -NR 8 -;

[0020] Y is selected from -CR 9 R 10 -、-NR 8 -、-O-、-S(=O) m - and -C(=O)-;

[0021] Z is selected from -CR 11 -and-N-;

[0022] R 8 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group and -C(=O)R a , the C 1-6 Alkyl, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, 4-8 membered heterocyclic, amino and C 1-6 Alkylamino;

[0023] R 9 and R 10 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6Alkyl, C 3-8 Cycloalkyl, hydroxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Alkylamino and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylamino or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl and 4-8 membered heterocyclic group; or R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring;

[0024] R 11 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 haloalkyl and cyano; and

[0025] m is selected from 0, 1 and 2.

[0026] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0027] In a third aspect, the present invention provides a medicine kit comprising:

[0028] a) at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof as a first therapeutic agent, or a pharmaceutical composition of the present invention as a first pharmaceutical composition;

[0029] b) optionally at least one additional therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising an additional therapeutic agent as a second pharmaceutical composition; and

[0030] c) optional packaging and / or instructions.

[0031] In a fourth aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a TGFβR1 inhibitor for preventing and / or treating a disease or condition (especially cancer, such as liver cancer) that is at least partially mediated by TGFβR1.

[0032] In a fifth aspect, the present invention provides use of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug, or the pharmaceutical composition of the present invention as a TGFβR1 inhibitor.

[0033] In a sixth aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating a disease or condition (especially cancer, such as liver cancer) at least in part mediated by TGFβR1.

[0034] In the seventh aspect, the present invention provides a method for preventing and / or treating a disease or condition (especially cancer, such as liver cancer) that is at least partially mediated by TGFβR1, comprising administering to an individual in need thereof a preventively and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0035] In an eighth aspect, the present invention provides a method for preparing the compound of the present invention, which is carried out by the following reaction scheme 1, 2 or 3:

[0036] Route 1

[0037]

[0038] in,

[0039] LG1 and LG2 are each independently a leaving group, such as methylthio and halogen, preferably chlorine or bromine;

[0040] W is selected from the group consisting of boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and tri-n-butyltin; and

[0041] R 1 , R 2 , R 3 , X, Y and Z are as defined above;

[0042] Route 2

[0043]

[0044] in,

[0045] LG1 is a leaving group, such as methylthio and halogen, preferably chlorine or bromine;

[0046] R 2 -C(=O)NR a R b ;and

[0047] R 1 , R 3 , X, Y, Z, R a and R b As defined above;

[0048] Route 3

[0049]

[0050] in,

[0051] R 2 -C(=O)NR a R b ;and

[0052] R 1 , R 3 , X, Y, Z, R a and R b As defined above.

[0053] The compounds of the present invention can show a strong inhibitory effect on TGFβR1, IC 50 Most of the values ​​can reach below 100 nM, and some even reach below 10 nM. At the same time, they show a weak inhibitory effect on TGFβR2, so they can be used as efficient and highly selective TGFβR1 inhibitors. The compounds of the present invention have anti-tumor activity, less toxic side effects and drug interactions, mild synthesis methods, simple and easy operation, and are suitable for industrial mass production. DETAILED DESCRIPTION

[0054] Before further describing the present invention, it should be understood that the present invention is not limited to the particular embodiments described herein. It should also be understood that the terminology used herein is only for describing but not limiting the particular embodiments.

[0055] definition

[0056] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0057] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0058] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (e.g. 1 to 3) suitable substituents such as halogen.

[0059] As used herein, the term "alkylene" refers to a straight or branched divalent alkyl group.

[0060] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15, for example 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. For example, as used herein, the term "C 3-8 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 8 ring carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0061] As used herein, the term "alkoxy" means an "alkyl" group, as defined above, attached to the parent molecular moiety through an oxygen atom, such as C 1-6 Alkoxy, C 1-3 Alkoxy. C 1-6Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0062] As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0063] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms, including but not limited to -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The haloalkyl group herein is optionally substituted with one or more (such as 1 to 3) substituents described herein.

[0064] As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) groups selected from C(=O), O, S, S(=O), S(=O)2, N, and NR (R represents a hydrogen atom or a substituent, such as, but not limited to, an alkyl or cycloalkyl group). The heterocyclic group may be saturated or unsaturated. Saturated heterocyclic groups may be referred to as heterocycloalkyls, such as 3-8 membered heterocycloalkyls, 5-6 membered heterocycloalkyls, and the like. Unless otherwise specifically indicated in the specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more multicyclic ring system, which may include a fused ring system, a paracyclic system, a bridged ring system, or a spirocyclic system. In particular, a 3-8 membered heterocyclyl is a group having 3-8 carbon atoms and heteroatoms in the ring, for example, it has 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 or 5 to 6 carbon atoms and heteroatoms (referred to as 4 to 8-membered, 4 to 7-membered, 4 to 6-membered, 5 to 8-membered, 5 to 7-membered and 5 to 6-membered heterocyclyl, respectively), such as but not limited to oxiranyl, aziridinyl, azetidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, azepine alkyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, etc.; and their annular derivatives, benzo derivatives, heteroaryl derivatives, or spiro derivatives, etc.

[0065] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. Common aryl groups include (but are not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, etc. For example, the term "C 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0066] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in each case, may additionally be benzo-fused. For example, as used herein, the term "5-10 membered heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 10 ring atoms and comprising at least one heteroatom which may be identical or different (the heteroatom being, for example, N, O or S). Examples of 5-10 membered heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. The heteroaryl group is optionally substituted with one or more (such as one to three) suitable substituents (e.g., halogen, C 1-6 alkyl, etc.) substituted.

[0067] As used herein, the term "alkylamino" refers to a group in which one hydrogen on the amino group is replaced by an alkyl group. For example, as used herein, the term "C 1-6 "Alkylamino" means that one of the hydrogen atoms of the amino group is replaced by a C 1-6 Alkyl substituted groups can be represented by C 1-6 Alkyl-NH-.

[0068] As used herein, the term "hydroxyalkyl" refers to a group in which one hydrogen on an alkyl group is replaced by a hydroxy group. For example, as used herein, the term "hydroxyC 1-6 "Alkyl" refers to C 1-6 A group in which one hydrogen on an alkyl group is replaced by a hydroxyl group can be represented by -C 1-6 Alkyl-OH.

[0069] As used herein, the term "hydroxy" refers to -OH.

[0070] As used herein, the term "cyano" refers to -CN.

[0071] As used herein, the term "amino" refers to -NH2.

[0072] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) atoms (e.g., hydrogen atoms) or groups of atoms (e.g., triflate groups) on the specified group are replaced by other atoms or groups of atoms, provided that the specified group meets the valence requirements in the current case and forms a stable compound after substitution. Combinations of substituents and / or variables are allowed only when the combination can form a stable compound. If a substituent is described as "optionally substituted by...", the substituent can be unsubstituted or substituted. If a first substituent is described as optionally substituted by one or more of the second substituent list, one or more hydrogen atoms in the first substituent can be replaced individually or independently by one or more of the second substituent list, or not replaced.

[0073] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0074] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0075] The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients constituting the formulation and / or the mammal to be treated therewith.

[0076] The term "pharmaceutically acceptable salts" generally includes (but is not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases. Such salts are also called acid addition salts or base addition salts.

[0077] The term "pharmaceutically acceptable ester" generally includes, but is not limited to, esters of the compounds of the present invention with pharmaceutically acceptable carboxylic acids or sulfonic acids, such esters are also known as carboxylates or sulfonates.

[0078] The term "isomers" refers to compounds that have the same number of atoms and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0079] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of a racemate. However, if desired, such compounds can be prepared or separated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or single stereoisomer-enriched (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%) mixtures. As described below, a single stereoisomer of a compound is prepared synthetically from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolution agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0080] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0081] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by many known methods by those skilled in the art. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. In addition, well-known techniques can be used to detect, classify and identify polymorphs, which include (but are not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM), etc.

[0082] The term "solvate" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetoneates, etc.

[0083] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure. For example, the nitrogen atom at position 1 in the parent nucleus of the compound of formula I can form a corresponding nitrogen oxide.

[0084] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with an isotope atom thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0085] The term "metabolite" refers to a derivative compound formed after metabolism of a compound of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th ed.)[M], McGraw-Hill International Editions, 1996.

[0086] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after administration to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0087] The term "independently" means that at least two groups (or ring systems) with the same or similar value ranges in the structure may have the same or different meanings in specific circumstances. For example, substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl. Similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.

[0088] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0089] Compound

[0090] One object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof,

[0091]

[0092] in,

[0093] R 1 Selected from C 6-10Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace;

[0094] R 2 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, cyano, -C(=O)NR a R b 、-C(=O)OR a , 4-8 membered heterocyclic groups and 5-10 membered heteroaryl groups, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more R 5 replace;

[0095] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R 6 replace;

[0096] R 3 Selected from hydrogen and -NR c R d ;

[0097] R c and R d are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, -C(=O)R a , C 6-10 Aryl and 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace;

[0098] R4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl is optionally substituted with one or more halogens;

[0099] R 5 Each occurrence is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, hydroxyl, halogen, amino and cyano, the C 1-6 Alkyl, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group;

[0100] R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl or C 3-8 The cycloalkyl group is optionally substituted with one or more hydroxy groups;

[0101] R 7 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0102] X is selected from C 1-6 Alkylene and -NR 8 -;

[0103] Y is selected from -CR 9 R 10 -、-NR 8 -、-O-、-S(=O)m - and -C(=O)-;

[0104] Z is selected from -CR 11 -and-N-;

[0105] R 8 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group and -C(=O)R a , the C 1-6 Alkyl, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, 4-8 membered heterocyclic, amino and C 1-6 Alkylamino;

[0106] R 9 and R 10 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Alkylamino and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylamino or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl and 4-8 membered heterocyclic group; or R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring;

[0107] R 11 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 haloalkyl and cyano; and

[0108] m is selected from 0, 1 and 2.

[0109] According to some embodiments of the present invention, R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl.

[0110] According to some embodiments of the present invention, R4 is independently selected at each occurrence from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0111] According to some embodiments of the present invention, R 4 is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

[0112] According to some embodiments of the present invention, R 1 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 4 replace.

[0113] According to some embodiments of the present invention, R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 According to some embodiments of the present invention, R 1 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 4 Replacement, where R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl.

[0114] In some embodiments of the present invention, R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 Replacement, where R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl.

[0115] In some embodiments of the present invention, R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more (e.g. 1 or 2) R 4 Replacement, where R 4 is independently selected at each occurrence from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0116] In some embodiments of the present invention, R 1 is selected from phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted by one or more (e.g. 1 or 2) R 4Replacement, where R 4 is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

[0117] In some embodiments of the present invention, R 1 Selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0118] According to some embodiments of the present invention, R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl and 4-8 membered heterocyclic groups.

[0119] According to some embodiments of the present invention, R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0120] According to some embodiments of the present invention, R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl and hydroxyl C 3-6 Cycloalkyl.

[0121] According to some embodiments of the present invention, R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group are optionally substituted by one or more R 6 replace; or

[0122] R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring.

[0123] According to some embodiments of the present invention, R a and R b are independently selected at each occurrence from hydrogen, C 1-6Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more R 6 replace.

[0124] According to some embodiments of the present invention, R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl is optionally substituted by one or more R 6 replace.

[0125] According to some embodiments of the present invention, R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0126] According to some embodiments of the present invention, R 5 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, 4-8 membered heterocyclic group C 1-6 Alkyl, 4-8 membered heterocyclic group, hydroxyl and amino group.

[0127] According to some embodiments of the present invention, R 5 Each time it occurs, it is independently C 1-6 alkyl.

[0128] According to some embodiments of the present invention, R 5 Each occurrence is independently methyl.

[0129] According to some embodiments of the present invention, R 2 Selected from hydrogen, halogen, cyano, -C(=O)NR a R b , 4-8 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by one or more R 5 replace.

[0130] According to some embodiments of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by one or more R 5 replace.

[0131] According to some embodiments of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and optionally C 1-6 Alkyl-substituted 5-6 membered heteroaryl.

[0132] According to some embodiments of the present invention, R 2 Selected from hydrogen, halogen, cyano, -C(=O)NR a R b , 4-8 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by one or more R 5 Replace, where

[0133] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups are optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R 6 replace;

[0134] R 5 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, 4-8 membered heterocyclic group C 1-6 Alkyl, 4-8 membered heterocyclyl, hydroxyl and amino; and

[0135] R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl and 4-8 membered heterocyclic groups.

[0136] In some embodiments of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by one or more R 5 Replace, where

[0137] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0138] R 5 Each time it occurs, it is independently C 1-6 Alkyl; and

[0139] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0140] In some embodiments of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by C 1-6 Alkyl substituted, wherein

[0141] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl is optionally substituted by one or more R 6 replace; and

[0142] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0143] In some embodiments of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and optionally C 1-6 Alkyl substituted thiazolyl.

[0144] In some embodiments of the present invention, R 2 is selected from hydrogen, cyano, -C(=O)NH2, -C(=O)N(H)CH3, The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0145] According to some embodiments of the present invention, R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more selected from hydroxy and C 1-6 Alkyl radicals are substituted.

[0146] According to some embodiments of the present invention, R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 5-6 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0147] According to some embodiments of the present invention, R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 Alkyl, C 1-6 The alkoxy or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0148] According to some embodiments of the present invention, R c and R d are independently selected at each occurrence from hydrogen, C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace.

[0149] According to some embodiments of the present invention, R c and R d Each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R 7 replace.

[0150] According to some embodiments of the present invention, R c and R d Each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted by one or more R 7 replace.

[0151] According to some embodiments of the present invention, R c and R d is independently selected at each occurrence from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted with one or more groups each independently selected from: C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 The alkyl or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0152] According to some embodiments of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0153] R c and R d are independently selected at each occurrence from hydrogen, C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R7 replace; and

[0154] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more selected from hydroxy and C 1-6 Alkyl radicals are substituted.

[0155] In some embodiments of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0156] R c and R d Each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R 7 replace; and

[0157] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 5-6 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0158] In some embodiments of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0159] R c and R d Each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted by one or more R 7 replace; and

[0160] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 Alkyl, C 1-6 The alkoxy or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0161] In some embodiments of the present invention, R 3 Selected from hydrogen, The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0162] According to some embodiments of the present invention, R 8 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, the C 1-6 Alkyl and C 3-8 The cycloalkyl group is optionally substituted by one or more groups selected from the group consisting of hydroxy, C 1-6 Alkoxy or amino.

[0163] According to some embodiments of the present invention, R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.

[0164] According to some embodiments of the present invention, R 8 Each occurrence is independently selected from hydrogen, methyl and ethyl.

[0165] According to some embodiments of the present invention, X is selected from C 1-6 Alkylene and -NH-.

[0166] In some embodiments of the present invention, X is selected from -CH2-, -CH2CH2-, and -NH-.

[0167] According to some embodiments of the present invention, R 9 and R 10 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl and amino C 1-6 Alkyl; or

[0168] R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring.

[0169] According to some embodiments of the present invention, R 9 and R 10 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.

[0170] In some embodiments of the present invention, R 9 and R 10 Each occurrence is independently selected from hydrogen, methyl and ethyl.

[0171] According to some embodiments of the invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-.

[0172] According to some embodiments of the invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-.

[0173] According to some embodiments of the invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-, wherein

[0174] R 9 and R 10 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl and amino C 1-6 Alkyl; or

[0175] R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring.

[0176] In some embodiments of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-, wherein

[0177] R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl;

[0178] R 9 and R 10is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or

[0179] R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring.

[0180] In some embodiments of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0181] R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl;

[0182] R 9 and R 10 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.

[0183] In some embodiments of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0184] R 8 is independently selected at each occurrence from hydrogen, methyl and ethyl;

[0185] R 9 and R 10 Each occurrence is independently selected from hydrogen, methyl and ethyl.

[0186] In some embodiments of the present invention, Y is selected from -CH2-, -CH(CH3)-, -N(CH3)-, -O- and -C(=O)-.

[0187] According to some embodiments of the invention, Z is selected from -CH- and -N-.

[0188] The present invention encompasses compounds of formula I obtained by any combination of the above preferred groups.

[0189] According to some embodiments of the present invention, the compound of the present invention is a compound of formula II-1:

[0190]

[0191] in,

[0192] R 1 , R 2 , R 3, X and Y are as defined above.

[0193] According to some embodiments of the present invention, the compound of the present invention is a compound of formula II-2:

[0194]

[0195] in,

[0196] R 1 , R 2 , R 3 , X and Y are as defined above.

[0197] According to some embodiments of the present invention, the compound of the present invention is a compound of formula III-1:

[0198]

[0199] in,

[0200] R 1 , R 2 , R 3 and Y are as defined above.

[0201] According to some embodiments of the present invention, the compound of the present invention is a compound of formula III-2:

[0202]

[0203] in,

[0204] R 1 , R 2 , R 3 and Y are as defined above.

[0205] According to some embodiments of the present invention, the compound of the present invention is a compound of formula III-3:

[0206]

[0207] in,

[0208] R 1 , R 2 , R 3 and X are as defined above.

[0209] According to some embodiments of the present invention, the compound of the present invention is a compound of formula III-4:

[0210]

[0211] in,

[0212] R 1 , R2 , R 3 and Y are as defined above.

[0213] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 1 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 4 Replacement, R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-8 Cycloalkyl.

[0214] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 Replacement, R 4 is independently selected at each occurrence from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0215] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 1 is selected from phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted by one or more (e.g. 1 or 2) R 4 Replacement, where R 4 is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

[0216] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 1 Selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0217] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 2 Selected from hydrogen, halogen, cyano, -C(=O)NR a R b, 4-8 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by one or more R 5 Replace, where

[0218] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R 6 replace;

[0219] R 5 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, 4-8 membered heterocyclic group C 1-6 Alkyl, 4-8 membered heterocyclyl, hydroxyl and amino; and

[0220] R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkylamino, C 3-6 Cycloalkyl, hydroxyl C 3-6 Cycloalkyl and 4-8 membered heterocyclic groups.

[0221] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by one or more R 5 Replace, where

[0222] R a and Rb are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more R 6 Replace; or R a , R b Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0223] R 5 Each time it occurs, it is independently C 1-6 Alkyl; and

[0224] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0225] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by C 1-6 Alkyl substituted, wherein

[0226] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl is optionally substituted by one or more R 6 replace; and

[0227] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl.

[0228] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 2Selected from hydrogen, cyano, -C(=O)NR a R b and optionally C 1-6 Alkyl substituted thiazolyl.

[0229] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 2 is selected from hydrogen, cyano, -C(=O)NH2, -C(=O)N(H)CH3, The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0230] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0231] R c and R d are independently selected at each occurrence from hydrogen, C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7 replace; and

[0232] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more selected from hydroxy and C 1-6 Alkyl radicals are substituted.

[0233] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0234] R c and R d Each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R 7 replace; and

[0235] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 5-6 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0236] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 3 Selected from hydrogen and -NR c R d ,in,

[0237] R c and R d Each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted by one or more R 7 replace; and

[0238] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 Alkyl, C 1-6 The alkoxy or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radicals are substituted.

[0239] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 of the present invention, R 3 Selected from hydrogen, The wavy line Indicates the point of attachment of the group to the rest of the molecule.

[0240] In some embodiments of the present invention, in the compounds of formula II-1, II-2 and III-3 of the present invention, X is selected from C 1-6 Alkylene and -NH-.

[0241] In some embodiments of the present invention, in the compounds of formula II-1, II-2 and III-3 of the present invention, X is selected from -CH2-, -CH2CH2- and -NH-.

[0242] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-.

[0243] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-, wherein

[0244] R 9 and R 10 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy and 4-8 membered heterocyclic group, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 The alkoxy or 4-8 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl and amino C 1-6 Alkyl; or

[0245] R 9 , R 10 Together with the carbon atoms to which they are attached, they form a 3-6 membered ring.

[0246] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O-, -S- and -C(=O)-, wherein

[0247] R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl;

[0248] R 9 and R 10 is independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or

[0249] R 9 , R 10Together with the carbon atoms to which they are attached, they form a 3-6 membered ring.

[0250] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0251] R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl;

[0252] R 9 and R 10 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.

[0253] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0254] R 8 is independently selected at each occurrence from hydrogen, methyl and ethyl;

[0255] R 9 and R 10 Each occurrence is independently selected from hydrogen, methyl and ethyl.

[0256] In some embodiments of the present invention, in the compounds of formula II-1, II-2, III-1, III-2 and III-4 of the present invention, Y is selected from -CH2-, -CH(CH3)-, -N(CH3)-, -O- and -C(=O)-.

[0257] In some embodiments of the present invention, in the compound of formula III-3 of the present invention, wherein,

[0258] R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 Replacement, R 4 is independently selected at each occurrence from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0259] R 2 Selected from hydrogen, cyano, -C(=O)NRa R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by C 1-6 Alkyl substituted, wherein

[0260] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl is optionally substituted by one or more R 6 replace; and

[0261] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl;

[0262] R 3 Selected from hydrogen and -NR c R d ,in,

[0263] R c and R d Each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R 7 replace; and

[0264] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 The alkoxy or 5-6 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0265] X is selected from C 1-6 Alkylene and -NH-.

[0266] In some embodiments of the present invention, in the compound of formula III-3 of the present invention, wherein,

[0267] R 1 is selected from phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted by one or more (e.g. 1 or 2) R 4 Replacement, where R 4is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl;

[0268] R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and optionally C 1-6 Alkyl substituted thiazolyl;

[0269] R 3 Selected from hydrogen and -NR c R d ,in,

[0270] R c and R d Each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted by one or more R 7 replace; and

[0271] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 Alkyl, C 1-6 The alkoxy or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0272] X is selected from C 1-6 Alkylene and -NH-.

[0273] In some embodiments of the present invention, in the compound of formula III-3 of the present invention, wherein,

[0274] R 1 Selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0275] R 2 is selected from hydrogen, cyano, -C(=O)NH2, -C(=O)N(H)CH3, The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0276] R 3 Selected from hydrogen, The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0277] X is selected from -CH2-, -CH2CH2- and -NH-.

[0278] In some embodiments of the present invention, in the compounds of formula III-1, III-2 and III-4 of the present invention, wherein,

[0279] R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 Replacement, R 4 is independently selected at each occurrence from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0280] R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by C 1-6 Alkyl substituted, wherein

[0281] R a and R b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl and piperidinyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, azetidinyl or piperidinyl is optionally substituted by one or more R 6 replace; and

[0282] R 6 Each occurrence is independently selected from hydroxyl, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 Cycloalkyl and hydroxy C 3-6 Cycloalkyl;

[0283] R 3 Selected from hydrogen and -NR c R d ,in,

[0284] R c and R d Each occurrence is independently selected from hydrogen, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R 7 replace; and

[0285] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6The alkoxy or 5-6 membered heterocyclic group is optionally substituted by one or more selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0286] Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0287] R 8 is independently selected at each occurrence from hydrogen and C 1-6 alkyl;

[0288] R 9 and R 10 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.

[0289] In some embodiments of the present invention, in the compounds of formula III-1, III-2 and III-4 of the present invention, wherein,

[0290] R 1 is selected from phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted by one or more (e.g. 1 or 2) R 4 Replacement, where R 4 is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl;

[0291] R 2 Selected from hydrogen, cyano, -C(=O)NR a R b and optionally C 1-6 Alkyl substituted thiazolyl;

[0292] R 3 Selected from hydrogen and -NR c R d ,in,

[0293] R c and R d Each occurrence is independently selected from hydrogen, phenyl and pyridyl, said phenyl or pyridyl being optionally substituted by one or more R 7 replace; and

[0294] R 7 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and piperazinyl, the C 1-6 Alkyl, C 1-6 The alkoxy or piperazinyl group is optionally selected from hydroxyl and C 1-6 Alkyl radical substitution;

[0295] Y is selected from -CR 9 R 10 -、-NR 8 -, -O- and -C(=O)-, wherein

[0296] R 8 is independently selected at each occurrence from hydrogen, methyl and ethyl;

[0297] R 9 and R 10 Each occurrence is independently selected from hydrogen, methyl and ethyl.

[0298] In some embodiments of the present invention, among the compounds III-1, III-2 and III-4 of the present invention, wherein,

[0299] R 1 Selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0300] R 2 is selected from hydrogen, cyano, -C(=O)NH2, -C(=O)N(H)CH3, The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0301] R 3 Selected from hydrogen, The wavy line Indicates the point of attachment of the group to the rest of the molecule;

[0302] Y is selected from -CH2-, -CH(CH3)-, -N(CH3)-, -O- and -C(=O)-.

[0303] The present invention encompasses compounds of formula II-1, II-2, III-1, III-2, III-3 and III-4 obtained by any combination of the above preferred groups.

[0304] According to some embodiments of the invention, the compound of the invention is selected from:

[0305]

[0306]

[0307]

[0308]

[0309] Preparation methodAnother object of the present invention is to provide a method for preparing the compound of the present invention, which is carried out by the following reaction scheme 1, 2 or 3:

[0310] Route 1

[0311]

[0312] in,

[0313] LG1 and LG2 are each independently a leaving group, such as methylthio and halogen, preferably chlorine or bromine;

[0314] W is selected from the group consisting of boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and tri-n-butyltin; and R 1 , R 2 , R 3 , X, Y and Z are as defined above.

[0315] Step 1-1: Compound SM1 and compound SM2 undergo coupling reaction to obtain compound IM1

[0316] In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent or a mixed solution of an organic solvent and water. The organic solvent can be selected from halogenated hydrocarbons (such as DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, t-BuOH, DMF, AN, ethers (such as DME, THF, Diox), aromatic hydrocarbons (such as TL, XY) and any combination thereof, preferably TL or Diox.

[0317] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable catalyst, preferably a palladium catalyst, such as Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, Pd(PPh3)2Cl2 dichloromethane complex, PdCl2(Amphos)2 and Pd(dppf)Cl2, preferably Pd(dppf)Cl2 or Pd(PPh3)4.

[0318] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable ligand, which can be selected from PPh3, BINAP, P(o-tol)3, TCHP and X-PHOS, preferably PPh3 or X-PHOS.

[0319] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base. The organic base can be selected from DIPEA, TEA, t-BuOK and Py, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3 and NaOH, preferably K2CO3 or Cs2CO3.

[0320] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-200°C, preferably 50-150°C.

[0321] Step 1-2: Compound IM1 undergoes Buchwald reaction with compound SM3 to obtain a compound of formula I

[0322] In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water. The organic solvent can be selected from halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, t-BuOH, DMF, AN, ethers (e.g., DME, THF, Diox), aromatic hydrocarbons (e.g., TL, XY) and any combination thereof, preferably TL or Diox.

[0323] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable catalyst, preferably a palladium catalyst, such as Pd(PPh3)4, Pd(OAc)2 and Pd2(dba)3, preferably Pd(OAc)2 and Pd2(dba)3.

[0324] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable ligand, which can be selected from PPh3, BINAP, P(o-tol)3, TCHP, Xant-PHOS and X-PHOS, preferably Xant-PHOS or BINAP.

[0325] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, wherein the organic base can be selected from DIPEA, TEA, t-BuOK and Py, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3 and NaOH, preferably K3PO4 or Cs2CO3.

[0326] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-200°C, preferably 50-150°C.

[0327] Route 2

[0328]

[0329] in,

[0330] LG1 is a leaving group, such as methylthio and halogen, preferably chlorine or bromine;

[0331] R 2 -C(=O)NR a R b ;and

[0332] R 1 , R 3 , X, Y, Z, R a and R b As defined above.

[0333] Step 2-1: Compound IM1 undergoes Buchwald reaction with compound SM4 to obtain compound IM2

[0334] In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water. The organic solvent can be selected from halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), MeOH, EtOH, t-BuOH, DMF, AN, ethers (e.g., DME, THF, Diox), aromatic hydrocarbons (e.g., TL, XY) and any combination thereof, preferably TL or Diox.

[0335] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable catalyst, preferably a palladium catalyst, such as Pd(PPh3)4, Pd(OAc)2 and Pd2(dba)3, preferably Pd(OAc)2 and Pd2(dba)3.

[0336] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable ligand, which can be selected from PPh3, BINAP, P(o-tol)3, TCHP, Xant-PHOS and X-PHOS, preferably Xant-PHOS or BINAP.

[0337] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, wherein the organic base can be selected from DIPEA, TEA, t-BuOK and Py, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3 and NaOH, preferably K3PO4 or Cs2CO3.

[0338] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-200°C, preferably 50-150°C.

[0339] Step 2-2: Compound IM2 undergoes amine ester exchange reaction with compound SM5 to obtain a compound of formula I

[0340] In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water. The organic solvent can be selected from halogenated hydrocarbons (e.g., DCM, TCM, 1,2-DCE, etc.), DMSO, NMP, DMF, ethers (e.g., DME, THF, Diox) and any combination thereof, preferably DMSO or DMF.

[0341] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-200°C, preferably 50-150°C.

[0342] Route 3

[0343]

[0344] in,

[0345] R 2 -C(=O)NR a R b ;and

[0346] R 1 , R 3 , X, Y, Z, R a and R b As defined above.

[0347] Step 3-1: Compound IM2 is hydrolyzed to obtain compound IM3

[0348] In some embodiments of the present invention, the reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water. The organic solvent can be selected from alcohols (e.g., MeOH, EtOH, n-BuOH, etc.), THF, AcOH, Diox and any combination thereof, preferably THF, EtOH or a mixed solvent thereof and water.

[0349] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, which may be selected from NaOH, KOH and LiOH, preferably NaOH.

[0350] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-100°C, preferably 25-100°C.

[0351] Step 3-2: Compound IM3 and compound SM5 undergo condensation reaction to obtain a compound of formula I

[0352] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable condensing agent, which can be selected from SOCl2, (COCl)2, POCl3, PCl3, PCl5, ECF, IPCF, HATU, HBTU, EEDQ, DEPC, DCC, DIC, EDC, T3P, BOP, PyAOP and PyBOP, preferably HATU.

[0353] In some embodiments of the present invention, the reaction is carried out in the presence of a suitable base, including an organic base or an inorganic base, wherein the organic base can be selected from DIPEA, TEA, t-BuOK and Py, and the inorganic base can be selected from K3PO4, NaH, K2CO3, Na2CO3, Cs2CO3 and NaOH, preferably DIPEA, K2CO3 or t-BuOK.

[0354] In some embodiments of the present invention, the reaction is carried out at a suitable temperature, which is 0-200°C, preferably 25-120°C.

[0355] Pharmaceutical compositions and kits

[0356] Another object of the present invention is to provide a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0357] Another object of the present invention is to provide a medicine box, comprising:

[0358] a) at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof as a first therapeutic agent, or a pharmaceutical composition of the present invention as a first pharmaceutical composition;

[0359] b) optionally at least one additional therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising an additional therapeutic agent as a second pharmaceutical composition; and

[0360] c) optional packaging and / or instructions.

[0361] The term "pharmaceutically acceptable carrier" refers to an excipient with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0362] Pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable approach, for example, by parenteral, local, intravenous, oral, subcutaneous, intraarterial, intradermal, percutaneous, rectal, intracranial, intraperitoneal, intranasal, intramuscular approach or as inhalant administration.

[0363] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0364] When administered orally, the pharmaceutical composition of the present invention can be prepared into any oral acceptable preparation form, including (but not limited to) tablets, capsules, aqueous solutions, aqueous suspensions, etc. Among them, the carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added. The carriers used in capsules generally include lactose and dry corn starch. Aqueous suspensions are usually prepared by mixing API with suitable emulsifiers and suspending agents. Optionally, some sweeteners, aromatics, colorants, etc. can also be added to the above oral preparations.

[0365] The pharmaceutical composition of the present invention can also be administered in the form of sterile injections.

[0366] The pharmaceutical composition of the present invention may contain 0.01 mg to 1000 mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof.

[0367] In some embodiments, the present invention provides a method for preparing a pharmaceutical composition or pharmaceutical formulation of the present invention, the method comprising combining at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopically labeled, metabolite or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0368] The kit of the present invention may contain 0.01 mg to 1000 mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof.

[0369] In some embodiments, the present invention provides a method for preparing a kit of the present invention, comprising combining at least one compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopically labeled, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, optionally with at least one other therapeutic agent, or a pharmaceutical composition comprising the other therapeutic agent, packaging and / or instructions.

[0370] Treatments and uses

[0371] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, which is used as a TGFβR1 inhibitor (especially a TGFβR1 selective inhibitor) for preventing and / or treating a disease or condition (especially cancer, such as liver cancer) that is at least partially mediated by TGFβR1.

[0372] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use as a TGFβR1 inhibitor.

[0373] Another object of the present invention is to provide the use of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating a disease or condition (especially cancer, such as liver cancer) at least partially mediated by TGFβR1.

[0374] Another object of the present invention is to provide a method for preventing and / or treating diseases or conditions (especially cancer, such as liver cancer) that are at least partially mediated by TGFβR1, which comprises administering to an individual in need thereof a preventively and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0375] The term "disease or condition mediated at least in part by TGFβR1" refers to a disease whose pathogenesis includes at least a part of factors related to TGFβR1, including but not limited to cancer, such as lung cancer, colorectal cancer, multiple myeloma (MM), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), pancreatic cancer, liver cancer, neuroblastoma, breast cancer, ovarian cancer, melanoma, other solid tumors or other blood cancers.

[0376] The term "effective amount" refers to a dose that can induce a biological or medical response in cells, tissues, organs or organisms (eg, individuals) and is sufficient to achieve the desired preventive and / or therapeutic effect.

[0377] The dosage regimen can be adjusted to provide the best desired response. For example, the dosage may be a single dose, divided doses may be administered over time, or the dosage may be proportionally reduced or increased according to actual conditions. It is understood that for any particular individual, the specific dosage regimen should be adjusted according to the needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0378] The dosage of the compound of the present invention will depend on the individual situation, the severity of the disease or illness, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. In general, the effective amount is about 0.001-10000mg / kg subject weight / day. In appropriate cases, the effective amount is about 0.01-1000mg / kg subject weight / day. About 0.01-1000mg / kg subject weight, usually about 0.1-500mg / kg subject weight, can be administered every day, every two days or every three days. An exemplary dosage regimen is once or more per day, or once or more per week, or once or more per month. During multiple administrations, the interval between single doses can generally be daily, weekly, monthly or annual. Alternatively, it can be administered in the form of a sustained-release preparation, in which case a lower frequency of administration is required. The dosage and frequency of administration can be different according to the half-life of the drug in the subject, and can also be different according to whether it is a preventive application or a therapeutic application. In preventive applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time; in therapeutic applications, it is sometimes necessary to administer a relatively high dosage at shorter intervals until the progression of the disease is slowed or stopped, preferably until the individual exhibits partial or complete improvement in disease symptoms, after which preventive applications can be employed.

[0379] The term "treatment" refers to the alleviation or elimination of the targeted disease or condition. If a subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof or a pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement, it indicates that the subject has been successfully "treated". It is understood that treatment includes not only complete treatment, but also failure to achieve complete treatment but achieving some biological or medically relevant results. Specifically, "treat" means that the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of the present invention can achieve at least one of the following effects, for example: (1) preventing the occurrence of disease in animals that may be prone to disease but have not yet experienced or displayed disease pathology or symptoms; (2) inhibiting disease in animals that are experiencing or displaying disease pathology or symptoms (i.e., preventing further development of pathology and / or symptoms); (3) ameliorating disease in animals that are experiencing or displaying disease pathology or symptoms (i.e., reversing pathology and / or symptoms).

[0380] The term "administer" or "dosage" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (such as a pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc., so as to bring the pharmaceutically active ingredient or pharmaceutical composition into contact with the individual or its cells, tissues, organs, biological fluids, etc. Common administration methods include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0381] The term "in need of" refers to the physician's or other health care provider's judgment that an individual needs or will benefit from a preventive and / or therapeutic procedure, which judgment is based on a variety of factors within the physician's or other health care provider's area of ​​expertise.

[0382] The term "individual" (or subject) includes human beings or non-human animals. The individuals of the present invention include individuals (patients) suffering from diseases and / or disorders and normal individuals. The non-human animals in the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc.; and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0383] Example

[0384] In order to make the purpose and technical solution of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with examples. However, it will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0385] The reagents or instruments used in the examples are all conventional products that can be obtained commercially. If no specific conditions are specified, they are carried out according to conventional conditions or conditions recommended by the manufacturer. The term "room temperature" used in the present invention refers to 20°C ± 5°C. When used to modify a certain value or numerical range, the term "about" used in the present invention refers to an acceptable error range for those skilled in the art including the value or numerical range and the value or numerical range, for example, the error range is ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, etc.

[0386] In conventional synthesis methods, examples and intermediate synthesis examples, the meanings of the abbreviations are shown in the following table.

[0387]

[0388]

[0389] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance ( 1 H-NMR) and / or mass spectrometry (MS).

[0390] Nuclear magnetic resonance (NMR) 1 The H-NMR was measured using a Bruker 400 MHz nuclear magnetic resonance instrument, the measuring solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard substance was tetramethylsilane (TMS).

[0391] The abbreviations in the nuclear magnetic resonance (NMR) data in the following examples represent the following meanings:

[0392] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0393] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0394] The mass spectrometry (MS) was performed using an Agilent 6120B mass spectrometer, and the ion source was an electrospray ionization source (ESI).

[0395] The embodiments of the present invention adopt the following method to perform preparative high performance liquid chromatography (Prep-HPLC) purification.

[0396] Method A:

[0397] Column: SunFire Prep C 18 OBD(5μm*19mm*150mm)

[0398] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0399] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10 90 28 2.00 10 90 28 16.00 90 10 28

[0400] Method B:

[0401] Column: SunFire Prep C 18 OBD(5μm*19mm*150mm)

[0402] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0403] Time [min] Mobile phase A[%] Mobile phase B[%] Flow rate [mL / min] 0.00 10 90 28 2.00 10 90 28 20.00 90 10 28

[0404] Method C:

[0405] Chromatographic column: SunFire Prep C18 OBD (5μm*19mm*150mm)

[0406] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0407]

[0408]

[0409] Preparation of compounds

[0410] Example 1: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (Compound 4)

[0411]

[0412] Step 1: Synthesis of 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (Compound 4-2)

[0413] Weigh 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (compound 4-1, 300 mg, 1.60 mmol) and (5-chloro-2-fluorophenyl)boric acid (278.16 mg, 1.60 mmol) and dissolve them in a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL), then add Pd(dppf)Cl2 (116.73 mg, 159.53 μmol) and potassium carbonate (660.45 mg, 4.79 mmol). After the addition is completed, replace the reaction system with nitrogen three times, and under nitrogen protection, heat to 100 ° C and react for 8 hours. The reaction solution was cooled to room temperature, diluted with 50 mL of dichloromethane, washed once with 20 mL of clean water and 20 mL of saturated brine, and then the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain the title compound (358 mg, yield 79.53%).

[0414] MS (ESI): m / z 282.0 [M+H] +

[0415] Step 2: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinate (Compound 4-3)

[0416] 4-Chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (compound 4-2, 110 mg, 389.88 μmol) and methyl 4-aminonicotinate (71.18 mg, 467.85 μmol) were dissolved in 1,4-dioxane (5 mL), palladium acetate (8.75 mg, 38.99 μmol), BINAP (48.55 mg, 77.98 μmol) and cesium carbonate (317.57 mg, 974.69 μmol) were added, and after addition, the reaction system was replaced with nitrogen three times, and the reaction was carried out at 120°C in a microwave for 3 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated to dryness to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the title compound (100 mg, yield 64.47%).

[0417] MS (ESI): m / z 398.1 [M+H] +

[0418] Step 3: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (Compound 4)

[0419] Weigh 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinate (compound 4-3, 21 mg, 52.79 μmol) and 2-aminopropane-1,3-diol (24.05 mg, 263.93 μmol) and dissolve in N,N-dimethylformamide (1 mL), heat to 100°C, and react for 15 hours. After the reaction solution is cooled to room temperature, it is directly purified by preparative high performance liquid chromatography (method A), and the prepared solution is lyophilized to obtain the title compound (6.55 mg, yield 27.15%).

[0420] MS (ESI): m / z 457.1 [M+H] +

[0421] Its structural characterization is as follows:

[0422] 1H NMR (400MHz, DMSO-d6): δ10.56(s,1H),8.86(s,1H),8.49(d,J=8.1Hz,1H),8.41(d, J=5.8Hz,1H),7.96(dd,J=6.7,2.8Hz,1H),7.61(s,1H),7.53(ddd,J=8.8,4.2,2.8H z,1H),7.44–7.34(m,2H),4.72(t,J=5.7Hz,2H),4.00(dq,J=8.0,5.8Hz,1H),3.52( q,J=5.3Hz,4H),3.01(t,J=7.7Hz,2H),2.88(t,J=7.4Hz,2H),2.15(p,J=7.6Hz,2H).

[0423] Example 2: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinamide (Compound 2)

[0424]

[0425] Step 1: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinic acid (Compound 2-1)

[0426] 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinate methyl ester (compound 4-3, 100 mg, 251.36 μmol) was dissolved in methanol (6 mL), sodium hydroxide (30.16 mg, 754.09 μmol) and water (2 mL) were added, and the temperature was raised to 80°C, and the mixture was stirred for 1 hour. After the ethanol was evaporated from the reaction solution under reduced pressure, the pH was adjusted to about 5 with a 1 mol / L hydrochloric acid aqueous solution, and the filtered material was washed with 50 mL of clean water and then dried to obtain the title compound (89 mg, yield 92.25%).

[0427] MS (ESI): m / z 384.1 [M+H] +

[0428] Step 2: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinamide (Compound 2)

[0429] Weigh 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinic acid (Compound 2-1, 35 mg, 91.19 μmol) and ammonium chloride (9.76 mg, 182.39 μmol) and dissolve in N,N-dimethylformamide (3 mL), then add N,N-diisopropylethylamine (47.14 mg, 364.77 μmol) and HATU (41.61 mg, 109.43 μmol), and react at room temperature for 1 hour. Slowly pour the reaction solution into 20 mL of water, filter, rinse the filtered material with 30 mL of clean water and 50 mL of acetonitrile, and then dry to obtain the title compound (21 mg, yield 60.15%).

[0430] MS (ESI): m / z 383.1 [M+H] +

[0431] Its structural characterization is as follows:

[0432] 1 H NMR (400MHz, DMSO-d6): δ10.98(s,1H),8.86(s,1H),8.41(d,J=5.9Hz,2H),7.96(dd,J=6.7,2.8Hz,1H),7.85(s,1H),7.65–7.60( m,1H),7.53(ddd,J=8.8,4.2,2.8Hz,1H),7.43–7.35(m,2H),3.01(t,J=7.7Hz,2H),2.87(t,J=7.4Hz,2H),2.15(p,J=7.6Hz,2H).

[0433] Example 3: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinonitrile (Compound 1)

[0434]

[0435] 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)nicotinamide (Compound 2, 18 mg, 47.02 μmol) was dissolved in phosphorus oxychloride (2 mL), heated to 90°C, and reacted for 5 hours. After the reaction solution was concentrated to dryness to obtain an oily substance under reduced pressure, 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of dichloromethane were added, and then the organic phase was separated and washed with 5 mL of clean water. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (method B), and the prepared solution was lyophilized to obtain the title compound (1.91 mg, yield 8.48%).

[0436] MS (ESI): m / z 365.0 [M+H] +

[0437] Its structural characterization is as follows:

[0438] 1 H NMR (400MHz, DMSO-d6): δ10.02(s,1H),8.90(s,1H),8.54(s,1H),7.95(dd,J=6.6,2.8Hz,1H),7.60(ddd,J=8.8,4. 2,2.8Hz,1H),7.52–7.37(m,2H),7.07(s,1H),3.08(t,J=7.6Hz,2H),2.78(t,J=7.3Hz,2H),2.14(p,J=7.5Hz,2H).

[0439] Example 4: Synthesis of 4-((2-(5-chloro-2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-N-(2-hydroxyethyl)nicotinamide (Compound 43)

[0440]

[0441] Compound 4-3 (20 mg, 0.05 mmol) and 2-aminoethanol (92 mg, 1.50 mmol) were dissolved in DMSO (1.5 mL) and reacted at 100°C for 15 hours. The reaction solution was cooled to room temperature and directly purified by high performance liquid chromatography (method C), and the prepared solution was lyophilized to obtain the title compound (15 mg, yield 69.20%).

[0442] MS (ESI): m / z 427.0 [M+H] +.

[0443] Its structural characterization is as follows:

[0444] 1H NMR (400MHz, DMSO-d6) δ10.6 (s, 1H), 8.89 (t, J = 5.2Hz, 1H), 8.83 (s, 1H), 8.4 1(d,J=6.0Hz,1H),7.95(dd,J=6.8,2.8Hz,1H),7.61(s,1H),7.56–7.49(m,1H ),7.43–7.34(m,2H),4.78(t,J=5.6Hz,1H),3.54(q,J=6.0Hz,2H),3.35(q,J =6.0Hz,2H),3.01(t,J=7.6Hz,2H),2.88(t,J=7.2Hz,2H),2.20–2.09(m,2H).

[0445] Referring to the synthesis methods of Examples 1 to 4, the following compounds were synthesized similarly:

[0446]

[0447]

[0448] Pharmacological activity test

[0449] Test Example 1: In vitro enzyme activity inhibition test (TGFβR1)

[0450] Experimental method: Based on ADP-Glo TM Instructions for the Kinase Assay Kit (Promega) The inhibitory effect of the compounds of the present invention on the TGFβR1 enzyme activity was determined as follows:

[0451] After pre-incubation of TGFβR1 enzyme with different concentrations of test compounds (1000 nM, 100 nM, 10 nM) at 30°C for 30 min, TGFβR1 peptide and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at 30°C for 3 h, ADP-Glo TM Reagent, incubate at room temperature for 90 minutes, then add kinase detection reagent. After incubation at room temperature for 30 minutes, detect the chemiluminescent signal value. The solvent group (DMSO) was used as the negative control, and the buffer group (without TGFβR1 enzyme) was used as the blank control. The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0452] Percent inhibition rate = (1-(chemiluminescent signal value of different concentrations of compounds-chemiluminescent signal value of blank control) / (chemiluminescent signal value of negative control-chemiluminescent signal value of blank control)) × 100%;

[0453] When the percentage inhibition rate was between 30% and 80%, the half inhibitory concentration (IC 50) or range:

[0454] IC 50 =X×(1-percent inhibition rate (%)) / percent inhibition rate (%), wherein: X is the test concentration of the compound.

[0455] The experimental results are shown in Table 1 below:

[0456] Table 1. Inhibitory activity of the compounds of the present invention on TGFβR1

[0457] Example No. <![CDATA[IC for TGFβR1 50 (nM)]]> Embodiment 1 69.19±28.56 Embodiment 2 3.01±1.05 Embodiment 3 70.43±11.68 Embodiment 4 30.42±7.93

[0458] It can be seen from Table 1 that the compounds of the present invention have a significant inhibitory effect on TGFβR1.

[0459] Test Example 2: In vitro enzyme activity inhibition test (TGFβR2)

[0460] Experimental method: Based on ADP-Glo TM Instructions for the Kinase Assay Kit (Promega) The inhibitory effect of the compounds of the present invention on the TGFβR2 enzyme activity was determined as follows:

[0461] After pre-incubation of TGFβR2 enzyme with different concentrations of test compounds (1000nM, 100nM, 10nM) at 30°C for 30min, myelin basic protein (MBP) and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at 30°C for 3h, ADP-Glo TM Reagent, incubate at room temperature for 90 minutes, then add kinase detection reagent. Detect the chemiluminescence signal value after incubation at room temperature for 30 minutes. Take the solvent group (DMSO) as the negative control and the buffer group (without TGFβR2 enzyme) as the blank control, and calculate the percentage inhibition rate of different concentrations of compounds according to the following formula:

[0462] Percent inhibition rate = (1-(chemiluminescent signal value of different concentrations of compounds-chemiluminescent signal value of blank control) / (chemiluminescent signal value of negative control-chemiluminescent signal value of blank control)) × 100%;

[0463] When the percentage inhibition rate was between 30% and 80%, the half inhibitory concentration (IC 50 ) or range:

[0464] IC 50 =X×(1-percent inhibition rate (%)) / percent inhibition rate (%), wherein: X is the test concentration of the compound.

[0465] The experimental results are shown in Table 2 below:

[0466] Table 2. Inhibition rate of the compounds of the present invention on TGFβR2 enzyme activity

[0467] Example No. <![CDATA[IC for TGFβR2 50 (nM)]]> Embodiment 1 >1000

[0468] As can be seen from Table 2, the compounds of the present invention have weak inhibitory activity on TGFβR2.

[0469] It can be seen from Table 1 and Table 2 that the compounds of the present invention have a selective inhibitory effect on TGFβR1.

[0470] Test Example 3: In vitro cell activity inhibition test

[0471] Experimental method: According to Bright-Glo TM Instructions for luciferase assay kit (Promega) The inhibitory effect of the compounds of the present invention on HEK293-SBE cells was determined as follows:

[0472] HEK293-SBE cells (Bps bioscience) were added to a 96-well plate (10% FBS medium MEM medium), 30,000 / well, and cultured overnight at 37°C, 5% CO2. The culture medium was replaced with 0.5% FBS MEM medium, and the test compound diluted in 0.5% FBS MEM medium was added. The highest final concentration of the test compound was 10 μM, and the compound was diluted 4 times, with a total of 9 concentration gradients. After 4-5 hours of culture, 10 μl of TGFβ-1 was added. The final concentration of TGFβ-1 was 0.5 ng / ml. 10 μl of culture medium was added to replace TGFβ as a negative control group. No test compound was added to the blank control, and TGFβ-1 was added. BrightGlo reagent was added to each well, and the chemiluminescent signal value was read on an ELISA reader.

[0473] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0474] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control)) × 100%;

[0475] The percentage inhibition rate of different concentrations of compounds was plotted against the compound concentration, and the curve was fitted according to the four-parameter model to calculate the IC 50 value:

[0476] y=Min+(Max-Min) / (1+(x / IC 50)^(-Hillslope)), where: y is the percentage inhibition rate; Max and Min are the maximum and minimum values ​​of the fitting curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0477] The experimental results are shown in Table 3 below:

[0478] Table 3. Inhibitory effect of the compounds of the present invention on the luciferase reporter gene of HEK293-SBE cells

[0479] Example No. <![CDATA[IC 50 (nM)]]> Embodiment 1 20.87±2.56 Embodiment 2 8.61±0.77 Embodiment 4 20.91±2.25

[0480] As can be seen from Table 3, the compounds of the present invention have a significant inhibitory effect on the TGFβ / Smad signaling pathway of HEK293-SBE cells.

[0481] Test Example 4: Biochemical hERG inhibition test.

[0482] 1. Test system:

[0483] Kit: Predictor TM hERG fluorescence polarization detection kit (ThermoFisher), the kit contains the following components: positive control compound hERG potassium channel blocker E4031; hERG cell membrane; affinity tracer Tracer; and hERG buffer.

[0484] 2. Test parameters:

[0485] hERG concentration: 1×; Tracer concentration: 1 nM; incubation time: 2 h; BMG PHERAstar FS FP.

[0486] 3. Test methods:

[0487] Carry out the test according to the instructions of the kit, the steps are as follows:

[0488] Test group: 10 μM and 1 μM of the test compound were added to the microplate containing hERG cell membrane, and a tracer with high hERG affinity was added to each well. After the microplate was incubated at room temperature for 2 hours, the changes in fluorescence polarization (excitation wavelength: 540 nm; emission wavelength: 590 nm) values ​​were detected using a multifunctional microplate reader.

[0489] Positive control group: 30 μM positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.

[0490] Blank control group: hERG buffer was used instead of the test compound, and no hERG cell membrane was added. The experimental method was the same as that of the test group.

[0491] 4. Data processing:

[0492] According to the data ratio, the percentage inhibition rate (%) of the compound of the present invention on hERG at different concentrations was calculated, and the half inhibitory concentration (IC 50 )’s scope.

[0493] Percent inhibition rate (%) = (1-(fluorescence polarization value of the test compound-fluorescence polarization value of the positive control) / (fluorescence polarization value of the blank control-fluorescence polarization value of the positive control)) × 100%;

[0494] 5. Experimental results:

[0495] The above method was used to determine the inhibition of hERG by the compounds. The results are shown in Table 4 below.

[0496] Table 4. hERG inhibition test results of the compounds of the present invention

[0497] Example No. <![CDATA[IC 50 (μM)]]> Embodiment 1 >10

[0498] The test results show that the compound of the present invention has low affinity to hERG and competes with the affinity tracer Tracer with an IC 50 All of them were greater than 10 μM, indicating that the compounds of the present invention have a lower risk of cardiac toxicity associated with hERG ion channels.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace; R 2 Selected from cyano and -C(=O)NR a R b ; R a and R b is independently selected at each occurrence from hydrogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R 6 replace; R 3 Selected from hydrogen; R 4 is independently selected at each occurrence from deuterium, halogen and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogens; R 6 Each occurrence is independently selected from halogen, hydroxyl, C 1-6 Alkyl and amino groups; X is selected from -CH2; Y is selected from -CH2-; Z is selected from -CH-.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from deuterium, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Each occurrence is independently selected from halogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is independently selected at each occurrence from fluoro, chloro, methyl, trifluoromethyl, difluoromethyl and monofluoromethyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 4 replace.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl, the phenyl group is optionally substituted by one or more R 4 replace.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl, pyridyl and pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is optionally substituted by one or more R 4 replace.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl, pyridinyl and pyrazolyl, wherein the phenyl, pyridinyl or pyrazolyl is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl, said phenyl being optionally substituted with one or more halogens.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from The wavy line Indicates the point of attachment of the group to the rest of the molecule.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 12. The compound according to any one of claims 1 to 4 or 6 to 11 or a pharmaceutically acceptable salt thereof, wherein: R 6 Each occurrence is independently selected from hydroxy.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or 6 to 11, wherein: R 2 Selected from cyano, -C(=O)NH2, -C(=O)N(H)CH3, The wavy line Indicates the point of attachment of the group to the rest of the molecule.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

16. A kit comprising: a) at least one compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as a first therapeutic agent, or a pharmaceutical composition according to claim 15 as a first pharmaceutical composition; b) optionally at least one additional therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising an additional therapeutic agent as a second pharmaceutical composition; and c) optional packaging and / or instructions.

17. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating a disease or condition mediated at least in part by TGFβR1.

18. The use of claim 17, wherein the disease or condition mediated at least in part by TGF[beta]R1 is selected from cancer.

19. The use of claim 18, wherein the disease or condition mediated at least in part by TGFβR1 is selected from liver cancer.

20. A method for preparing a compound according to any one of claims 1 to 14, which is carried out by the following reaction scheme 1, 2 or 3: Route 1 LG1 and LG2 are each independently a leaving group; W is selected from the group consisting of boronic acid, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and tri-n-butyltin; and R 1 , R 2 , R 3 , X, Y and Z are as defined in any one of claims 1 to 14; Route 2 in, LG1 is the leaving group; R 2 -C(=O)NR a R b ;and R 1 , R 3 , X, Y, Z, R a and R b As defined in any one of claims 1 to 14; Route 3 in, R 2 -C(=O)NR a R b ;and R 1 , R 3 , X, Y, Z, R a and R b As defined in any one of claims 1 to 14.

21. The method of claim 20, wherein LG1 and LG2 are each independently methylthio and halogen.

22. The method of claim 20, wherein LG1 and LG2 are each independently chlorine or bromine.

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