p53-Y220C selective small molecule reactivator compound, pharmaceutical composition and use thereof

Abstract

The present invention provides compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, which have good p53-Y220C mutant activating activity and can be used in the manufacture of drugs for the treatment of neoplastic diseases containing the p53-Y220C mutant protein and for similar disorders or diseases. [Formula 1] TIFF2026522396000314.tif34170

Description

[Technical Field]

[0001] This invention relates to the patent application number 202310767412.7, titled "Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof" filed with the China National Intellectual Property Administration on June 27, 2023; the patent application number 202310972386.1, titled "Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof" filed with the China National Intellectual Property Administration on August 3, 2023; and the patent application number 202311158861.8, titled "Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof" filed with the China National Intellectual Property Administration on September 8, 2023. This invention claims priority over the prior applications filed with the China National Intellectual Property Administration on October 23, patent application number 202311378644.X, titled "p53-Y220C Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof", filed with the China National Intellectual Property Administration on November 22, 2023, patent application number 202311566589.7, titled "p53-Y220C Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof", and filed with the China National Intellectual Property Administration on February 6, 2024, patent application number 202410171815.X, titled "p53-Y220C Selective Small Molecule Reactivator Compound, Pharmaceutical Composition and Use thereof". The above prior applications are incorporated into this invention in their entirety by reference.

[0002] The present invention belongs to the field of pharmaceutical compounds, and more specifically, relates to p53-Y220C selective small molecule reactivator compounds, pharmaceutical compositions, and their use. [Background technology]

[0003] Tumors are a collection of related diseases characterized by the uncontrolled proliferation of tumor cells and their potential to metastasize to various parts of the body. Tumor cell proliferation is inseparable from proto-oncogenes and tumor suppressor genes; gene mutations can lead to abnormal activation or suppression of both, further promoting uncontrolled cell division. TP53 is a well-known tumor suppressor gene, often called the "guardian of the genome." TP53 belongs to the p53-like transcription factor family and includes three members: TP53, TP63, and TP73 genes, which encode three proteins: p53, p63, and p73, respectively. They are structurally similar, with nearly identical DNA-binding domains that bind to similar DNA-specific sequences and can regulate the transcription of the same gene and several different genes. The C-terminal domains differ in size, sequence, and function, regulating DNA binding and transcription, and mediating protein interactions. The N-terminal sequences encode at least two different transcriptional activation domains. Similar to p53, p63 is also an important transcription factor that responds to DNA damage by inducing apoptosis, acting on the skull, face, limbs, and central nervous system, and is involved in the production and regeneration of squamous epithelial cells throughout the body. p73 is required for the production of ciliated epithelial cells and acts on male germ cells, the immune system, the auditory system, the trachea, lungs, and the central nervous system, among others.

[0004] The tumor suppressor p53 is primarily distributed in the cytoplasm and acts as a sensor of cellular stress, responding to various cellular stresses including ultraviolet radiation, hypoxia, oncogene activation, and DNA damage. When activated, p53 binds to specific DNA sequences in the form of tetramers, mediating downstream gene transcription and suppressing cancer progression through various inhibitory mechanisms, including cell cycle regulation, apoptosis, senescence, stem cell differentiation, metabolism (decreased glucose synthesis), ROS and mitochondrial activity, and DNA damage repair. p53 can activate proteins involved in the above pathways, such as Fas / Apol, KILLER / DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21. Furthermore, p53 can inhibit the transcription of various genes, including c-MYC, Cyclin B, VEGF, RAD51, and hTERT.

[0005] Due to its crucial role in tumor suppression, the TP53 gene is the most frequently mutated gene in human cancers, with p53 mutations present in approximately 50% of malignant tumors. In contrast to mutations in other tumor suppressor genes such as RB1, APC, and PTEN, most TP53 mutations are missense mutations, accounting for 75% of cases. Missense mutations are mostly located in the DNA-binding domain of p53, resulting in misfolding of the protein sequence necessary for DNA recognition and binding. p53 can be mutated at many amino acid sites, including Vall43, Hisl68, Argl75, Tyr220, Gly245, Arg248, Arg299, Phe270, Arg273, and Arg282. Correspondingly, examples of p53 mutations that can suppress wild-type p53 activity include R175H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 mutations not only distort the structure of the DNA binding site but can also disrupt its thermodynamic stability. After mutation, TP53 loses the tumor suppressor transcriptional activity of wild-type p53 in the form of homozygous deletion, and in the form of heterozygous deletion, it exhibits dominant-negative effects and gain-of-function effects, such as increased binding of p63 and p73, thereby promoting tumor development and progression. Therefore, mutated p53 proteins can be considered heterogeneous proteins, exhibiting different degrees of loss of normal tumor suppressor function and acquisition of oncogenic properties (GOF).

[0006] Although different p53 mutants exhibit varying activity, TP53 missense mutants can be considered proto-oncogenes, promoting tumor metastasis and poor prognosis due to drug resistance, making them therapeutic targets for drug development. Among these, the oncogenic p53 Y220C mutant exhibits a typical structure particularly suitable for the development of small molecule stabilizers. This is the ninth most common p53 missense mutant found in cancer, representing approximately 100,000 new cancer cases worldwide each year. The mutation of Tyr220 to Cys forms a narrow hydrophobic crack on the surface of the p53 DBD, thereby reducing its thermal stability by 4 kcal / mol. While wild-type p53 is moderately stable and melts and denatures at 44°C, the Y220C mutant protein rapidly unfolds and denatures from its folded state under physiological body temperature conditions, effectively removing the p53 wild-type tumor suppressor signal and promoting tumor development. Importantly, the hydrophobic cracks caused by the Y220C mutation are detached from the surface of the p53 protein, which is involved in DNA recognition or protein-protein interaction, allowing for the development of small molecule drugs without interfering with its binding to native DNA substrates. The Y220C mutant is a temperature-sensitive mutant, binding to DNA at relatively low temperatures and denaturing at body temperature. When a small molecule compound selectively binds to the p53-Y220C mutant, the compound can stabilize the Y220C mutant, reduce the likelihood of p53 protein denaturation at body temperature, convert p53 from an unfolded state to a folded state, and restore the wild-type structure and transcriptional activity of p53.

[0007] The research results indicate that while some small molecules, such as PK083, PK7088, PK5196, and PC14586, can bind to the hydrophobic cracks of the Y220C mutant, their high concentrations make it impossible to rule out whether or not they are off-target. Therefore, there is still a need to develop superior small molecules that bind more specifically to the Y220C mutant, better restore the structure and transcriptional activity of p53 wild-type, and more effectively inhibit tumors. [Overview of the Initiative]

[0008] To solve the problems existing in the prior art, the present invention provides a compound represented by formula (I) and its racemates, stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, [Chemical Formula] wherein R1 and R2 are the same or different and independently of each other are H, halogen, C 3-14 , 3-12 , 1-12 , a , 6-10 , , 6-10 , 1-12 , a1 alkyl group, C 1-12 alkoxy group, R3 is selected from H, C 1-12 alkyl group, R4 is H, halogen, cyano group, C 1-12 alkyl group, C 2-12 alkenyl group, C 2-12 alkynyl group, C 1-12 alkoxy group, C 3-12 cycloalkyl group, halo C 1-12 alkyl group, halo C 1-12 alkoxy group, halo C 3-12 cycloalkyl group, cyano C 1-12 alkyl group, cyano C 1-12 alkoxy group, W is C 2-6 alkenylene group, C 2-6 alkynylene group, C 3-14 cycloalkylene group, C 6-10 arylene group, 5- to 10-membered heteroarylene group, Ring A is C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-10 aryl group, 5- to 10-membered heteroaryl group, R a is H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more R a1 substituted C 1-12 alkyl group, C 1-12 alkoxy group, C 3-12 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-10 aryl group, 5- to 10-membered heteroaryl group, -C(O)N(Ra11 )(R a12 ), -N(R a13 )(R a14 ), -S(O)2-R a15 -S(O)(=NR a16 )(R a17 ), -P(O)(R a18 )(R a19 ) are selected from each R a1 These are identical or different, independently of each other, H, OH, CN, halogen, unsubstituted, or selectively one, two or more R a2 C is replaced by 1-12 Alkyl alkyl group, C 1-12 Alkoxy group, C 3-12 Cycloalkyl group, 3-14 member heterocyclyl group, C 6-10 Aryl group, 5-10 membered heteroaryl group, -NH2, -S(O)2-C 1-12 Selected from alkyl groups, each R a2 These are the same or different, and independently of each other, H, OH, NH2, CN, halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups, R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 H and C are the same or different, and are independent of each other. 1-12 Alkyl alkyl group, C 3-7 Selected from cycloalkyl groups and 3-8 membered heterocyclyl groups, m is selected from 0, 1, 2, 3, 4, and 5. Z is either nonexistent, or NH, S, O, C 1-6 Alkylene group, C 1-6 Selected from alkylene-NH, Ring E is a 3-14 member heterocyclyl group, C 3-12 Selected from cycloalkyl groups, R e is H, halogen, unsubstituted, or selectively one, two or more R e1 C is replaced by 1-12 Alkyl, halo C 1-12Alkyl groups, deuterated C 1-12 Alkyl alkyl group, C 1-12 Alkoxy group, C 3-12 Cycloalkyl group, 3-14 member heterocyclyl group, C 1-12 Alkyl-NH-, (C 1-12 Selected from alkyl)2-N-, each R e1 These are the same or different, and independently of each other, H, OH, NH2, CN, halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups, or two R groups bonded to the same carbon atom e Each atom is bonded to C 3-12 A cycloalkane ring, a 3-14 membered heterocycle, or two R atoms bonded to different carbon atoms e Each atom forms a 3-14 member heteroring with the atom it is bonded to, and p is selected from 0, 1, 2, 3, 4, and 5. X1, X2, and X3 are identical or different, independently selected from CH or N, and at least two of X1, X2, and X3 are CH. R x H, CN, halogen, C 1-12 Alkyl alkyl group, C 1-12 Selected from alkoxy groups, n is selected from 0, 1, 2, or 3. Y is selected from C(O), C(O)NH, C(S), and SO2.

[0009] According to some embodiments, R1, R2, and R3 are the same or different, and H and C are independent of each other. 1-6 Selected from alkyl groups.

[0010] According to some embodiments, R1, R2, and R3 are all H.

[0011] According to some embodiments, R4 is C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, Halo C 1-6 Alkyl alkyl, cyano C 1-6 Selected from alkyl groups, According to some embodiments, R4 is C 1-6Alkyl group, halo C 1-6 Alkyl group, cyano C 1-6 Selected from an alkyl group, According to some embodiments, R4 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, a cyanomethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group.

[0012] According to some embodiments, R4 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyanomethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group.

[0013] According to some embodiments, W is C 2-4 An alkenylene group, C 2-4 An alkynylene group, C 3-6 A cycloalkylene group, C 6-10 Selected from an arylene group, a 5- to 6-membered heteroarylene group, According to some embodiments, W is

Chemical formula

[0014] According to some embodiments, ring A is selected from a phenyl group, a 5- to 6-membered heteroaryl group, an 8- to 9-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, C 3-6 Selected from a membered cycloalkyl group, According to some embodiments, ring A is selected from a phenyl group, a 5- to 6-membered heteroaryl group, an 8- to 9-membered heteroaryl group, an 8- to 9-membered heterocyclyl group, C 3-6 Selected from a membered cycloalkyl group, According to some embodiments, ring A is

Chemical formula

[0015] According to some embodiments, R ais H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more Rs a1 substituted C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, 4-7 member heterocyclyl group, phenyl group, 5-6 member heteroaryl group, -C(O)(NHC 1-6 alkyl), -S(O)2-C 1-6 alkyl group, -S(O)(=NH)(C 1-6 alkyl), -S(O)(NC 1-6 alkyl)(C 1-6 alkyl), -P(O)(C 1-6 alkyl)(C 1-6 alkyl), -NH2, each R a1 is the same or different and independently of one another is H, OH, CN, halogen, C 1-6 alkyl group, haloC 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, 5-6 member heterocyclyl group, phenyl group, 5-6 member heteroaryl group, cyanoC 1-6 alkyl group, cyanoC 1-6 alkoxy group, C 1-6 alkyl group-NH-, (C 1-6 alkyl)2-N-, -S(O)2-C 1-6 alkyl group, C 1-6 alkyl group-O-C 1-6 alkyl group, hydroxyC 1-6 alkyl group, selected from According to some embodiments, R a is H, F, Cl, CN, oxo (=O), OH, unsubstituted or optionally substituted with one, two or more Rs a1 methyl group, ethyl group, propyl group, isopropyl group, tert-butyl, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methoxy group, isopropoxy group, propoxy group, phenyl group, pyridyl group, benzyl group, piperidinyl group,

Chemical formula

[0016] According to some embodiments, [ka] teeth, [ka] Selected from.

[0017] According to some embodiments, Z is either absent or selected from NH, S, O, CH2, and CH2NH.

[0018] According to some embodiments, ring E is selected from a 5- to 9-member heterocyclyl group or a C 5-6 cycloalkyl group, According to some embodiments, ring E is selected from a 6- to 9-member heterocyclyl group or a C 5-6 cycloalkyl group, According to some embodiments, ring E is

Chemical formula

[0019] According to some embodiments, ring E is

Chemical formula

[0020] According to some embodiments, R e is H, halogen, a C e1 alkyl group which is unsubstituted or selectively substituted with one, two or more R 1-6 groups, a halo C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a 4- to 9-member heterocyclyl group, (C 1-6 alkyl)2-N-, and each R e1 is the same or different and independently selected from OH, halogen, a C 1-3 alkyl group, a C 1-3 alkoxy group, or two R e together with the atoms to which each is attached form a C 3-6 cycloalkane ring, According to some embodiments, R e is H, halogen, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a 5- to 6-member heterocyclyl group, (C 1-6Selected from alkyl)2-N- or two R e Each atom is bonded to C 3-6 Forming a cycloalkane ring, According to some embodiments, R e H, F, Cl, methyl group, deuterated methyl group (CD3), trifluoromethyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, dimethylamino group, [ka] Selected from, or two R atoms bonded to the same carbon atom e Each atom, along with the atom to which it is bonded, forms a cyclopropane ring. [ka] or two R atoms bonded to different carbon atoms e Each atom, along with the atoms to which it is bonded [ka] It forms.

[0021] According to some embodiments, R e H, F, Cl, methyl group, deuterated methyl group (CD3), trifluoromethyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, dimethylamino group, [ka] Selected from, or two R atoms bonded to the same carbon atom e Each atom, along with the atom to which it is bonded, forms a cyclopropane ring. [ka] or two R atoms bonded to different carbon atoms e Each atom, along with the atoms to which it is bonded [ka] It forms.

[0022] According to some embodiments, X1, X2, and X3 are all CH, or one of X1, X2, and X3 is N. According to some embodiments, R x H, CN, halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups, According to some embodiments, R x The group is selected from H, F, Cl, CN, methoxy group, and methyl group.

[0023] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, ring A, ring E, X1, X2, X3, Y, R1, R2, R3, R4, R a , R e , R x m, n, and p have the definitions set forth herein.

[0024] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, ring A, ring E, X1, X2, X3, Y, R1, R2, R3, R4, R a , R e , R x m, n, and p have the definitions set forth herein.

[0025] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, R a , R x m and n have the definitions set forth herein.

[0026] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, rings A, R a , R x m and n have the definitions set forth herein.

[0027] According to some embodiments, the compound represented by formula (I) has the structure shown below, [ka] In the formula, R a , R e The terms have the definitions set forth herein.

[0028] According to some embodiments, exemplary and non-limiting specific examples of the compound represented by formula (I) and its racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof are as follows:

[0029] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0030] The present invention further provides a method for producing a compound represented by formula (I), comprising one step of reacting compound 1 and compound 2 to obtain a compound represented by formula (I). [ka] In the formula, ring A, ring E, X1, X2, X3, W, Y, Z, R1, R2, R3, R4, R a , R e , R x m, n, and p have the definitions set forth herein.

[0031] The present invention further provides a pharmaceutical composition comprising at least one of the following: a therapeutically effective amount of the compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

[0032] According to embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable auxiliary materials.

[0033] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more other therapeutic agents.

[0034] The present invention further provides a method for treating a neoplastic disease, comprising administering to a patient at least one of the compounds represented by formula (I), racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, in a preventive or therapeutically effective amount.

[0035] According to embodiments of the present invention, the tumor is a tumor containing the p53-Y220C mutant.

[0036] The present invention further provides a method for treating neoplastic diseases, comprising administering a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition to a patient.

[0037] In some embodiments, the patient includes mammals, preferably humans.

[0038] The present invention further provides at least one of the compounds represented by formula (I), racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for treating neoplastic diseases.

[0039] The present invention further provides the use in the manufacture of drugs of at least one of the compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof.

[0040] According to embodiments of the present invention, the use may be in the manufacture of drugs that combat tumors containing the p53-Y220C mutant, for example, in the manufacture of p53-Y220C reactivator drugs.

[0041] According to embodiments of the present invention, tumors containing the p53-Y220C mutant include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendiceal cancer, astrocytoma, basal cell tumor, cholangiocarcinoma, bladder cancer, bone cancer, brain tumors such as cerebellar astrocytoma, cerebral astrocytoma / glioblastoma, ependymal cell tumor, neuromedulloblastoma, supratentorial blastoma, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt lymphoma, cancer of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, Childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid diseases, colon cancer, cutaneous T-cell lymphoma, fibrinogenic round cell tumor, endometrial cancer, ependymal cell tumor, esophageal cancer, Ewing's sarcoma, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, glioma, hairy cell leukemia, head and neck cancer, cardiac tumor, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip cancer and oral cancer, liposarcoma, liver cancer, lung cancer, such as non-small cell lung cancer and small cell lung cancer. Lymphoma, leukemia, macroglobulinemia, malignant fibrous histiocytoma / osteosarcoma, medulloblastoma, melanoma, mesothelioma, primary metastatic squamous cell carcinoma, oral cancer, multiple endocrine neoplasia, myelodysplastic syndrome, myeloid leukemia, nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, pancreatic cancer, carcinoid tumor, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, penile cancer, pharyngeal cancer, chromophilic cell tumor, pineal stellate cell tumor This includes cystomas, pineal germ cell tumors, pituitary adenomas, pleuroblastomas, plasmacytomas, primary central nervous system islet cell carcinomas, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, non-epithelial malignancies, skin cancer, cutaneous Merkel cell tumors, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, T-cell lymphoma, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, gestational trophoblastoma, cancer of unknown primary origin, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor. [Effects of the Invention]

[0042] The compounds of the present invention have excellent p53-Y220C mutant activating activity and can effectively restore the activity of the p53-Y220C mutant protein. They can be used in the treatment of neoplastic diseases containing the p53-Y220C mutant protein and in the manufacture of drugs for similar disorders or diseases. Furthermore, the novel structural compounds obtained by the structural optimization of the present invention exhibit superior antitumor effects against multiple tumor models, improved pharmacokinetic properties, and safety compared to compounds in the prior art.

[0043] The definitions and explanations of the terms are as follows:

[0044] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, and can be arbitrarily combined and linked to one another. Such combined and linked definitions of groups and the structures of compounds should be understood to be within the scope described in the specification and / or claims of this application.

[0045] Unless otherwise stated, the numerical ranges described herein and in the claims correspond to descriptions of at least each specific integer value within that range. For example, the numerical range "1 to 14" corresponds to descriptions of each integer value within the numerical range "1 to 14," namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0046] In the definition of the general formula of this application, the term “selective” (or “selectively”) means that it is substituted with zero, one or more substituents. For example, “selectively substituted with one, two or more Rs” means that it is possible to choose not to be substituted with R (unsubstituted) or to be substituted with one, two or more Rs.

[0047] "More than" refers to 3 or more, such as 3, 4, 5, 6, 7, 8, 9, or 10.

[0048] "C 1-12 The term "alkyl group" refers to linear and branched alkyl groups having 1 to 12 carbon atoms, and "C 1-8 The term "alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 The term "alkyl group" should be understood to refer to linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0049] "C 2~12 The term "alkenyl group" should be understood to mean a linear or branched monovalent hydrocarbon group having 1 to 12 carbon atoms, containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C 2-8 It has an alkenyl group, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 It has an alkenyl group and two or three carbon atoms (i.e., C 2-3It has an alkenyl group. If the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-buto-2-enyl, (Z)-buto-2-enyl, (E)-buto-1-enyl, (Z)-buto-1-enyl, pento-4-enyl, (E)-pento-3-enyl, (Z)-pento-3-enyl, (E)-pento-2-enyl, (Z)-pento-2-enyl, (E)-pento-1-enyl Nyl, (Z)-pento-1-enyl, hexa-5-enyl, (E)-hexa-4-enyl, (Z)-hexa-4-enyl, (E)-hexa-3-enyl, (Z)-hexa-3-enyl, (E)-hexa-2-enyl, (Z)-hexa-2-enyl, (E)-hexa-1-enyl, (Z)-hexa-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbuto-3-enyl, 2-methylbuto-3-enyl, 1-methylbuto-3-enyl, 3-methylbuto-2-enyl, (E)-2-methylbuto-2-enyl, (Z)-2-methylbuto-2-enyl, (E)-1-methylbuto-2-enyl, (Z)-1-methylbuto These are to-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylpropane-2-enyl, 1-ethylpropane-1-enyl, 1-propyl vinyl, and 1-isopropyl vinyl.

[0050] "C 2-12 The "alkynyl group" preferably contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, for example, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C 2~8 An alkynyl group), having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C 2~6"Alkynyl group"), having 2 or 3 carbon atoms ("C 2~3 An "alkynyl group" should be understood to mean a linear or branched monovalent hydrocarbon group having 1 to 12 carbon atoms. Examples of such alkynyl groups include ethynyl, propa-1-inyl, propa-2-inyl, buta-1-inyl, buta-2-inyl, buta-3-inyl, penta-1-inyl, penta-2-inyl, penta-3-inyl, penta-4-inyl, hexa-1-inyl, hexa-2-inyl, hexa-3-inyl, hexa-4-inyl, hexa-5-inyl, 1-methylpropa-2-inyl, 2-methylbuta-3-inyl, 1-methylbuta-3-inyl, 1-methylbuta-2-inyl, 3-methylbuta-1-inyl, 1-ethylpropa-2-inyl, 3-methylpenta-4-inyl, 2-methylpenta- These are ethylpenta-4-inyl, 1-methylpenta-4-inyl, 2-methylpenta-3-inyl, 1-methylpenta-3-inyl, 4-methylpenta-2-inyl, 1-methylpenta-2-inyl, 4-methylpenta-1-inyl, 3-methylpenta-1-inyl, 2-ethylbuta-3-inyl, 1-ethylbuta-3-inyl, 1-ethylbuta-2-inyl, 1-propylpropa-2-inyl, 1-isopropylpropa-2-inyl, 2,2-dimethylbuta-3-inyl, 1,1-dimethylbuta-3-inyl, 1,1-dimethylbuta-2-inyl, or 3,3-dimethylbuta-1-inyl. In particular, the alkynyl group is ethynyl, propa-1-inyl, or propa-2-inyl.

[0051] "C 3-12 The term "cycloalkyl group" should be understood to mean a saturated monovalent monocyclic, bicyclic (e.g., fused ring, bridging ring, spiro ring) hydrocarbon ring or tricycloalkane, which has 3 to 12 carbon atoms, preferably "C 3-10 "Cycloalkyl group", more preferably "C 3-8 It is a "cycloalkyl group". 3-12 The term "cycloalkyl group" should be understood to mean a saturated monovalent monocyclic, bicyclic (e.g., bridging ring, spiro ring) hydrocarbon ring or tricycloalkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.3-12 The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or a bicyclic hydrocarbon group, such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, dicyclo[2.1.1]hexyl, dicyclo[2.2.1]heptyl, dicyclo[2.2.1]heptenyl, 6,6-dimethyldicyclo[3.1.1]heptyl, 2,6,6-trimethyldicyclo[3.1.1]heptyl, dicyclo[2.2.2]octanyl, 2,7-diazaspiro[3,5]nonanyl, or 2,6-diazaspiro[3,4]octanyl; or a tricyclic hydrocarbon group, such as adamantane.

[0052] "C 6-14 The term "aryl group" should be understood to mean a monocyclic, bicyclic, or tricyclic hydrocarbon ring of the Aromatic or partially Aromatic genus, preferably having 6 to 14 carbon atoms, which may be a single aromatic ring or multiple aromatic rings fused together, preferably "C 6-10 It may also be an "aryl group". 6-14 The term "aryl group" preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6~14 "aryl group"), especially a ring having 6 carbon atoms ("C6 aryl group"), for example phenyl or biphenyl, or a ring having 9 carbon atoms ("C9 aryl group"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl group"), for example, tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 "aryl group"), for example, a fluorenyl group, or a ring having 14 carbon atoms ("C" 14 The term "aryl group" should be understood to mean, for example, an anthracenyl group. 6-20If an aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution position is not limited and may be ortho, para, or meta, for example.

[0053] The term “5-14 membered heteroaryl group” should be understood to include monovalent monocyclic, bicyclic (e.g., fused ring, bridging ring, spiro ring), or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as “5-10 membered heteroaryl group”. The term “5-14 membered heteroaryl group” should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, each of which may be benzo-fused. “Hyperaryl group” further refers to a group in which a heteroaromatic ring is fused to one or more aryl groups, alicyclic, or heterocyclyl rings, wherein the bonded groups or points are on the heteroaromatic ring. Non-restrictive examples include 1-,2-,3-,5-,6-,7- or 8-indolidinyl, 1-,3-,4-,5-,6- or 7-isoindolyl, 2-,3-,4-,5-,6- or 7-indolyl, 2-,3-,4-,5-,6- or 7-indazolyl, 2-,4-,5-,6-,7- or 8-prinyl, 1-,2-,3-,4-, 6-,7-,8- or 9-quinolidinyl, 2-,3-,4-,5-,6-,7- or 8-quinolinyl, 1-,3-,4-,5-,6-,7- or 8-isoquinolinyl, 1-,4-,5-,6-,7- or 8-phthalazinyl, 2-,3-,4-,5- or 6-naphthilidinyl, 2-,3-,5-,6-,7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-sinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazole, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolin, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridine, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridine, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-,8- or 9-phenoxazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazine, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinoline, 2-, 3-, 4- or thieno[2,3-b]furan, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 1 1-7H-pyrazino[2,3-c]carbazole, 2-3-,5-,6- or 7-2H-flo[3,2-b]-pyranyl, 2-,3-,4-,5-,7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-3- or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-,4- or 54H-imidazo[4,5-d]thiazolyl, 3-,5- or 8-pyrazino[2,3-d]pyridazinyl, 2-,3-,5- or 6-Imidazo[2,1-b]thiazolyl, 1-,3-,6-,7-,8- or 9-Flo[3,4-c]sinnorinyl, 1-,2-,3-,4-,5-,6-,8-,9-,10 or 11-4H-Pyrido[2,3-c]carbazolyl, 2-,3-,6- or 7-Imidazo[1,2-b][1,2,4]triazinyl, 7-Benzo[b]thienyl, 2-,4-,5-,6- or 7-Benzoxazolyl, 2-,4-,5-,6- Examples include 7-benzimidazolyl, 2-,4-,4-,5-,6- or 7-benzothiazolyl, 1-,2-,4-,5-,6-,7-,8- or 9-benzoxapinyl, 2-4-,5-,6-,7- or 8-benzoxazinyl, and 1-,2-,3-,5-,6-,7-,8-,9-,10- or 11-4H-pyrrolo[1,2-b][2]benzoazapinyl. Typical condensed heteroaryl groups include 2-,3-,4-,5-,6-,7-, or 8-quinolinyl, 1-,3-,4-,5-,6-,7-, or 8-isoquinolinyl, 2-,3-,4-,5-,6-, or 7-indolyl, 2-,3-,4-,5-,6-, or 7-benzo[b]thienyl, 2-,4-,5-,6-, or 7-benzoxazolyl, 2-,4-,5-,6-, or 7-benzimidazolyl, and 2-,4-,5-,6-, or 7-benzothiazolyl,The invention is not limited to these examples. When the 5-14 membered heteroaryl is bonded to other groups to constitute the compound of the present invention, the carbon atoms on the 5-14 membered heteroaryl ring may be bonded to other groups, or the heteroatoms on the 5-14 membered heteroaryl ring may be bonded to other groups. If the 5-14 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution position is not limited; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring may be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring may be substituted.

[0054] The term "carbocyclic ring" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon rings (e.g., monocyclic rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and cyclononane rings, or bicyclic rings including spiro, condensed, or bridging systems (e.g., bicyclo[11.1]pentane, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, or bicyclo[5.2.0]nonane, sulfenyl, etc.) which are selectively substituted with one or more (e.g., 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclic ring" refers to a carbocyclic ring having 3, 4, 5, or 6 ring-forming carbon atoms.

[0055] Unless otherwise defined, the term “3-14 membered heterocyclyl group” refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., condensed, bridging, spiro), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, for example, 1, 2, 3, 4, 5 or more heteroatoms, of which N and S can be selectively oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2-. Preferably, the heterocyclyl group may be selected from “3-10 membered heterocyclyl groups”. The term "3-10 membered heterocyclyl group" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S, and N. The heterocyclyl group may be bonded to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclyl group may include condensed or bridged rings and spiro rings. In particular, the heterocyclyl group may include, but is not limited to, four-membered rings such as azetidinyl and oxetanyl, five-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl, six-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or seven-membered rings such as diazepanyl. Selectively, the heterocyclyl group may be benzo-condensed. The heterocyclyl group may be a bicyclic ring, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, but is not limited to these.The heterocyclyl group may be partially unsaturated, meaning it may contain one or more double bonds, such as dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydroxazolyl, or 4H-[1,4]thiadinyl, but is not limited to these. It may also be benzo-condensed, such as dihydroisoquinolinyl, but is not limited to these. When the 3-14 membered heterocyclyl group is bonded to another group to constitute a compound of the present invention, the carbon atoms on the 3-14 membered heterocyclyl group may be bonded to the other group, or the heteroatoms on the 3-14 membered heterocyclyl group may be bonded to the other group. For example, if the 3-14 membered heterocyclyl group is selected from piperazinyl groups, the nitrogen atoms on the piperazinyl group may be bonded to the other group. When a 3-14 membered heterocyclyl group is selected from a piperidinyl group, the nitrogen atom on the piperidinyl ring and the carbon atom at its para position may be bonded to other groups.

[0056] The term "spiro ring" refers to a ring system in which two rings share a single ring-forming atom.

[0057] The term "condensed ring" refers to a ring system in which two rings share two ring-forming atoms.

[0058] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0059] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0060] "Halo" refers to substitution with one or more halogens.

[0061] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, and the definition of an alkyl group is as described above.

[0062] The term "oxo" refers to a substituent that has been substituted with an oxo group (=O) formed after the oxidation of a carbon, nitrogen, or sulfur atom in the substituent.

[0063] The term "alkylamino group" refers to -NH-(alkyl) or -N-(alkyl)2, and the definition of alkyl is as described above. Non-limiting examples of alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0064] A "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, and alkyl groups are defined as described above. Non-exclusive examples of hydroxyalkyl groups include methylol group, hydroxyethyl group, hydroxypropyl group, hydroxymethylpropyl group, or dihydroxypropyl group.

[0065] The term "alkyloxy group" refers to -O-(alkyl), and the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0066] The terms "alkylene oxy group" and "oxyalkylene group" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chain or branched-chain saturated divalent hydrocarbon group. The definition of the number of carbon atoms in "alkylene" is the same as the definition for "alkyl" above. As will be understood by those skilled in the art, alkylene oxy groups and oxyalkylene groups can be bonded to the rest of the molecule containing them in any direction; that is, they are interchangeable.

[0067] The term "nitrogen oxide" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds.

[0068] Unless otherwise stated, heterocyclyl groups, heterocyclylene groups, heteroaryl groups, or heteroarylene groups include all possible isomeric forms thereof, e.g., positional isomers. Thus, some exemplary and non-limiting examples may include forms in which the group is substituted at one, two or more positions, such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if any), or bonded to another group, and include thienyl or thienylene groups containing pyridine-2-yl, pyridine-2-ylidene, pyridine-3-yl, pyridine-3-ylidene, pyridine-4-yl and pyridine-4-ylidene, thiophene-2-yl, thiophene-2-ylidene, thiophene-3-yl and thiophene-3-ylidene, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl and pyrazole-5-yl.

[0069] The compounds of this disclosure may exist in different tautomer forms, and all such forms are encompassed within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers that exist in equilibrium and can be converted from one isomer form to another. This includes all possible tautomers, i.e., those existing in the form of a single isomer or a mixture of any proportions of such tautomers. Non-limiting examples include keto-enols, imine-enamines, lactam-lactims, and the like.

[0070] A wavy line intersecting a chemical bond. [ka] This is used to indicate the position where a group bonds with other atoms in the structure. For example, [ka] This indicates the bond to the 3-position of the pyridyl group. When the bond position of the group is not fixed, taking the pyridyl group as an example, [ka] This can be expressed in this way, indicating that it can bind to any possible position on the pyridyl group. Also, [ka] This indicates that the group can be bonded to any bondable position on the heteroaromatic ring, for example, to any of the four carbon atoms on the pyridine ring to the right of the heteroaryl group, or to a carbon atom on the pyrazole ring to the left. Unless otherwise stated, any similar expressions in this application shall be interpreted in the same way as above.

[0071] In the chemical structure of the compound of the present invention, [ka] This indicates an unspecified placement. [ka] This indicates an absolute configuration, meaning that when stereoisomers exist in the chemical structure, a bond is formed. [ka] teeth [ka] It may be, or [ka] The two arrangements may be included simultaneously.

[0072] In the present invention, references to compounds include isotope-labeled compounds, which are identical to those shown in formula I, but in which one or more atoms are substituted with atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes of compounds that can be incorporated into the present invention include isotopes of H, C, N, O, S, F, and Cl, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Contains Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, or pharmaceutically acceptable salts of the said compounds or prodrugs are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, radioisotopes ( 3 H and 14 Compounds incorporating tritium (i.e., C) can be used to measure the distribution of drugs and / or substrate tissues. 3 H) and carbon-14 (i.e.) 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, relatively heavy isotopes (deuterium, i.e.) 2 Replacing with H or D, etc., can provide certain therapeutic benefits resulting from higher metabolic stability (e.g., increased half-life in the body or reduced dose requirements), and is therefore preferable in some cases. The hydrogen appearing in the substituents of the present invention does not separately list the terms deuterium or tritium, nor does it exclude deuterium or tritium, and deuterium or tritium may be included as well.

[0073] As those skilled in the art will understand, the compounds represented by formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form intramolecular salts.

[0074] The compounds of the present invention can exist in the form of solvates (e.g., hydrates), and the compounds of the present invention contain a polar solvent, particularly, water, methanol, or ethanol, as a component of the crystal lattice of the compound. The amount of the polar solvent, particularly water, can be in stoichiometric or non-stoichiometric ratios.

[0075] The compounds of the present invention may be chiral depending on their molecular structure and can therefore exist in various enantiomer forms. Accordingly, these compounds may exist in racemic or optically active forms. The compounds of the present invention include isomers or mixtures thereof, or racemics, in which each chiral carbon is in an R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomer compounds by chemical or physical methods well known to those skilled in the art, or can be used in synthesis in this form. In the case of racemicamines, diastereomers are prepared from a mixture by reaction with an optically active resolving reagent. Examples of suitable resolving reagents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or the R and S forms of various optically active camphorsulfonic acids. Enantiomers can also be advantageously resolved by chromatography using optically active resolution reagents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized metachlorate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0076] The corresponding stable isomers can be isolated by known methods, such as extraction, filtration, or column chromatography.

[0077] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0078] The term “therapeutic dose” means the amount of an active compound or drug that elicits a biological or medical response sought by researchers, veterinarians, physicians, or other clinicians in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder, or condition in an individual that has a disease, disorder, or condition but has not yet experienced or developed the disease or symptoms of the disease; (2) inhibition of disease: for example, inhibiting a disease, disorder, or condition (i.e., preventing further progression of the disease and / or symptoms) in an individual that has experienced or developed the disease or symptoms of the disease, disorder, or condition; (3) mitigation of disease: for example, mitigating a disease, disorder, or condition (i.e., reversing the disease and / or symptoms) in an individual that has experienced or developed the disease or symptoms of the disease, disorder, or condition. [Brief explanation of the drawing]

[0079] [Figure 1] This is the tumor growth curve of experimental animals in the NUGC-3 human gastric cancer subcutaneous transplant tumor model. [Figure 2] This is the tumor growth curve of experimental animals in a female NOD / SCID model of human lung cancer LU5269 subcutaneous xenograft. [Modes for carrying out the invention]

[0080] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and interpretive of the present invention and should not be interpreted as limiting the scope of protection of the present invention. All technologies realized based on the above-described aspects of the present invention fall within the scope of protection of the present invention.

[0081] Unless otherwise specified, the raw materials and reagents used in the following examples are either commercially available or can be prepared by known methods.

[0082] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography (LC-MS). The NMR chemical shift (δ) is expressed in parts per million (ppm). A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), or deuterated chloroform (CDCl3) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0083] For liquid chromatography-LC-MS measurements, an Agilent 1200 Infinity Series mass spectrometer was used. For HPLC measurements, an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6mm chromatography column) were used.

[0084] For thin-layer chromatography, silica gel plates such as Yantai Huanghai HSGF254 or Qingdao Marine Chemical GF254 silica gel plates are used. The silica gel plates used for TLC are 0.15 mm to 0.20 mm in size, while those used for the separation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm in size. For column chromatography, silica gel of 200 to 300 mesh size from Yantai Huanghai is generally used as the support.

[0085] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0086] Example 1 [ka]

[0087] Step 1: Synthesis of Compound 001-2 In a reaction flask, acetonitrile (4.72 g, 114.872 mmol, 3.4 eq) and tetrahydrofuran (150 mL) solution were added, and n-butyllithium (44 mL) was added dropwise at -78°C, stirring continuously for 1 hour. Then, 2,6-dichloropyridine (compound 001-1, 5 g, 33.786 mmol, 1 eq) in a tetrahydrofuran solution (50 mL) was added dropwise, and the reaction was continued at -78°C for 2 hours. The temperature was then raised to room temperature and the reaction was continued for 30 minutes. After the reaction was complete, water was added to quench the mixture, and the organic phase was extracted with ethyl acetate (3 × 300 mL). The organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 001-2 (4.66 g, 89.49%).

[0088] 1 H NMR(400MHz,DMSO-d6)δ 7.92(t,J=7.8Hz,1H),7.52(dd,J=8.0,0.7Hz,1H),7.45(dd,J=7.6,0.7Hz,1H),4.26(s,2H).

[0089] Step 2: Synthesis of Compound 001-3 2-(6-chloropyridine-2-yl)acetonitrile (compound 001-2, 5g, 32.770 mmol, 1eq) was added to a reaction flask and dissolved in dichloromethane (100 mL). A solution of 2-[(aminooxy)sulfanyl]-1,3,5-trimethylbenzene (14.11g, 65.546 mmol, 2.00eq) in dichloromethane (70 mL) was added at 0°C, and the mixture was stirred for 2 hours at 0°C. After the reaction was complete, diethyl ether was added, and the solvent was further rotated to obtain crude product 001-3 (7g, 40.65%), which was used directly in the next step.

[0090] Step 3: Synthesis of Compounds 001-4 1-amino-2-chloro-6-(cyanomethyl)pyridine-1-onium-2,4,6-trimethylbenzenesulfonate (compound 001-3, 8 g, 21.748 mmol, 1 eq) was added to a reaction flask and dissolved with methanol (80.0 mL). Potassium carbonate (6.01 g, 43.496 mmol, 2.00 eq) was added under ice bath, and the mixture was further heated to room temperature and reacted overnight. After the reaction was complete, the solvent was rotated dry, water was added, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound 001-4 (1.7 g, 39.64%).

[0091] 1 H NMR(400MHz,DMSO-d6)δ 7.28(dd,J=8.8,1.2Hz,1H),7.01(dd,J=8.8,7.3Hz,1H),6.75(dd,J=7.3,1.2Hz,1H),5.80(s,1H),5.57(s,2H).

[0092] Step 4: Synthesis of Compounds 001-5 7-chloropyrazolo[1,5-a]pyridine-2-amine (compound 001-4, 1.4 g, 8.353 mmol, 1 eq), 4-dimethylaminopyridine (102.05 mg, 0.835 mmol, 0.1 eq), and di-tert-butyldicarbonate (2.01 g, 9.188 mmol, 1.1 eq) were added sequentially to a reaction flask, dissolved with 1,4-dioxane (20 mL), and reacted at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 001-5 (634 mg, 22.68%). LCMS:(ESI,m / z):267.85 [M+H] + .

[0093] Step 5: Synthesis of Compounds 001-6 N,N-dimethylformamide (344.03 mg, 4.706 mmol, 2 eq) and tetrahydrofuran (13 mL) were added to a reaction flask, phosphorus oxychloride (1.08 g, 7.059 mmol, 3 eq) was added at 0°C, and the mixture was reacted for 30 minutes. Then, tert-butyl (7-chloropyrido[1,5-a]pyridine-2-yl)carbamate (compound 001-5, 630 mg, 2.353 mmol, 1 eq) was added, and the mixture was heated to 40°C and reacted for 30 minutes. After the reaction was complete, saturated sodium carbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to directly obtain compound 001-6 (791 mg, 90.93%). LCMS:(ESI,m / z):296.00 [M+H] + .

[0094] Step 6: Synthesis of Compounds 001-7 (7-chloro-3-formylpyrido[1,5-a]pyridine-2-yl)carbamate tert-butyl (compound 001-6, 740 mg, 2.502 mmol, 1 eq) was added to a reaction flask, dissolved with dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and reacted at room temperature for 30 minutes. After the reaction was complete, the solvent was directly rotated to obtain crude product 001-7 (800 mg, 138.92%), which was used directly in the next step. LCMS:(ESI,m / z):196.00 [M+H] + .

[0095] Step 7: Synthesis of Compounds 001-8 2-amino-7-chloropyrazolo[1,5-a]pyridine-3-formaldehyde (compound 001-7,490 mg, 2.505 mmol, 1 eq) and p-toluenesulfonic acid hydrate (1.43 g, 7.515 mmol, 3 eq) were added to a reaction flask and dissolved with acetonitrile (8 mL). In another flask, sodium nitrite (345.66 mg, 5.010 mmol, 2 eq) and potassium iodide (1.04 g, 6.262 mmol, 2.5 eq) were added and dissolved with water (2 mL). This mixed aqueous solution was then added dropwise to the acetonitrile solution and the mixture was allowed to react overnight at room temperature. After the reaction was complete, saturated sodium thiosulfate aqueous solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 001-8 (180 mg, 23.21%).

[0096] 1 H NMR(400MHz,DMSO-d6)δ 9.76(s,1H),8.22(dd,J=8.7,1.2Hz,1H),7.73(dd,J=8.7,7.5Hz,1H),7.54(dd,J=7.6,1.2Hz,1H).

[0097] Step 8: Synthesis of Compounds 001-9 7-chloro-2-iodopyrazolo[1,5-a]pyridine-3-formaldehyde (compound 001-8, 160 mg, 0.522 mmol, 1 eq) and (triphenylphosphonium) difluoroacetic acid intramolecular salt (372.01 mg, 1.044 mmol, 2 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (8.0 mL), and reacted at 60°C for 2 hours. Then, tetrabutylammonium fluoride solution (1 M tetrahydrofuran solution, 1.566 mL, 1.566 mmol, 3.00 eq) was added and the reaction was continued for 1 hour. After the reaction was complete, ethyl acetate was added to dilute the mixture, water was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 001-9 (57 mg, 29.98%).

[0098] 1 H NMR(400MHz,DMSO-d6)δ 7.85-7.82(m,1H),7.38(dd,J=8.9,7.3Hz,1H),7.25(dd,J=7.3,1.1Hz,1H),3.78(q,J=11.0Hz,2H).

[0099] Step 9: Synthesis of Compounds 001-10 Under nitrogen gas protection at 50°C, 7-chloro-2-iodo-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine (compound 001-9, 400 mg, 1.110 mmol, 1 eq), N-Boc-aminopropine (189.42 mg, 1.221 mmol, 1.1 eq), cuprous iodide (21.13 mg, 0.111 mmol, 0.1 eq), tetrakistriphenylphosphine palladium (128.22 mg, 0.111 mmol, 0.1 eq), and diisopropylamine (1.12 g) were added. Dissolve 11,100 mmol, 10 eq) in tetrahydrofuran (6 mL), stir, and react for 1 hour. After the reaction is complete, quench the reaction mixture with water at room temperature, extract with ethyl acetate (3 × 30 mL), combine the organic phases, backwash with saturated sodium chloride (2 × 20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:9) to obtain compound 001-10 (400 mg, 92.96%). LCMS:(ESI,m / z):387.95 [M+H] + .

[0100] Step 10: Synthesis of Compounds 001-11 Under nitrogen gas protection, {3-[7-chloro-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]propa-2-in-1-yl}carbamate tert-butyl (compound 001-10, 380 mg, 0.980 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidine-4-amine dihydrochloride (240.92 mg, 1.176 mmol, 1.2 eq), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (82 Compounds 001-11 (380 mg, 80.20%) were dissolved in 1,4-dioxane (4 mL) and stirred at 120°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and the reaction mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 001-11 (380 mg, 80.20%). LCMS:(ESI,m / z):483.90 [M+H] + .

[0101] Step 11: Synthesis of Compounds 001-12 At room temperature, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-2-yl)propa-2-in-1-yl]carbamate tert-butyl (compound 001-11, 100 mg, 0.207 mmol, 1 eq) was added to a reaction flask, dissolved with methanol (2 mL), and 4 M HCl / 1,4-dioxane (2 mL) was added dropwise at 0°C. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, the resulting residue was concentrated under vacuum to obtain compound 001-12. LCMS:(ESI,m / z):383.85 [M+H] + .

[0102] Step 12: Synthesis of 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 001) At room temperature, add N-hydroxybenzotriazole (22.21 mg, 0.164 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.51 mg, 0.164 mmol, 1.5 eq), N,N-diisopropylethylamine (42.49 mg, 0.329 mmol, 3 eq), and N,N-dimethylformamide (3 mL) to a reaction flask, stir for 5 minutes, and then 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine disate Add the acid salt (compound 001-12, 50 mg, 0.110 mmol, 1 eq) and 1-tert-butyl-1H-pyrazole-4-carboxylic acid (22.12 mg, 0.156 mmol, 1.32 eq), stir at room temperature, and react for 2 hours. After the reaction is complete, extract the reaction mixture with ethyl acetate (3 × 30 mL), combine the organic phases, backwash with saturated sodium chloride solution (3 × 30 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; Mobile phase A: Water (0.1% ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Elution gradient: 32% to 55% in 10 minutes; Detection wavelength: UV 254nm / 220nm; Retention time (minutes): 9.73), yielded 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide of compound 001 (19.18mg, 27.23%).

[0103] LCMS:(ESI,m / z):534.25 [M+H] + . 1H NMR(400MHz,DMSO)δ 8.62(t,J=5.5Hz,1H),8.32(s,1H),7.90(s,1H),7.28(t,J=8.2Hz,1H),7.02(d,J=8.7H z,1H),6.32(d,J=7.6Hz,1H),6.22(d,J=9.0Hz,1H),4.93(s,0.5H),4.81(s,0.5H),4.3 4(d,J=5.5Hz,2H),3.94-3.68(m,3H),3.05(t,J=10.9Hz,1H),2.78(d,J=11.3Hz,1H),2 .38-2.23(m,1H),2.20(s,3H),2.13(t,J=10.6Hz,1H),1.99-1.80(m,2H),1.53(s,9H).

[0104] Example 2 [ka]

[0105] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl)-1-propyl]-1H-pyrazole-4-carboxamide (compound 003) At room temperature, stir and incubate a 1 mL solution of 1-isopropyl-1H-pyrazole-4-carboxylic acid (16.2 mg, 0.106 mmol, 1.2 eq), N,N-diisopropylethylamine (56.65 mg, 0.440 mmol, 5 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (40 mg, 0.106 mmol, 1.2 eq) in N,N-dimethylformamide for 30 minutes. The mixture was then mixed with 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 40 mg, 0.104 mmol, 1 eq), stirred, and allowed to react for 2 hours. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire C18 5μm, 30mm × 150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 27% to 54% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.48), yielding compound 003, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl)-1-propyl]-1H-pyrazole-4-carboxamide (16.65 mg, 36.45%).

[0106] LCMS:(ESI,m / z):520.15 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.65(t,J=5.5Hz,1H),8.26(s,1H),7.89(s,1H),7.29(t,J=8.23Hz,1H),7.03(d,J=8.7Hz,1H),6.32( d,J=7.6Hz,1H),6.25(d,J=9.0Hz,1H),4.95(s,0.5H),4.82(s,0.5H),4.51(hept,J=6.7Hz,1H),4.32( d,J=5.6Hz,2H),3.94-3.83(m,1H),3.76(q,J=11.1Hz,2H),3.08(t,J=11.0Hz,1H),2.81(d,J=11.4Hz, 1H),2.40-2.25(m,1H),2.22(s,3H),2.17(t,J=10.8Hz,1H),2.02-1.80(m,2H),1.42(d,J=6.7Hz,6H).

[0107] Example 3 [ka]

[0108] Step 1: Synthesis of 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 004) Under nitrogen gas protection, at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 40 mg, 0.088 mmol, 1 eq) and 1-ethyl-1H-pyrazole-4-carboxylic acid (18.43 mg, 0.132 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (0.8 mL) and N,N-diisopropylethylamine (56.65 mg, 0.440 mL) were added. Add 1.5 eq of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50.00 mg, 0.132 mmol, 1.5 eq) and continue stirring for 1 hour. After the reaction is complete, add methanol (1.0 mL) to quench the mixture, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 31% B to 54% B in 10 min; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 8.63), yielded compound 004, 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (21.27 mg, 47.61%).

[0109] LCMS:(ESI,m / z):506.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.65(t,J=5.6Hz,1H),8.22(d,J=0.7Hz,1H),7.89(d,J=0.7Hz,1H),7.28(dd,J=8.7,7.6Hz,1H),7.03(d ,J=8.7Hz,1H),6.32(d,J=7.3Hz,1H),6.23(d,J=9.1Hz,1H),4.87(d,J=49.6Hz,1H),4.33(d,J=5.6Hz,2H ),4.15(q,J=7.3Hz,2H),3.92-3.81(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=10.9Hz,1H),2.78(d,J=1 1.3Hz,1H),2.37-2.22(m,1H),2.20(s,3H),2.18-2.10(m,1H),1.99-1.70(m,2H),1.37(t,J=7.3Hz,3H).

[0110] Example 4 [ka]

[0111] Step 1: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 005) Under nitrogen gas protection, 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (14.29 mg, 0.094 mmol, 1.2 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.5 mg, 0.117 mmol, 1.5 eq), 1-hydroxy-benzotriazole (15.86 mg, 0.117 mmol, 1.5 eq), and N,N-diisopropylethylamine (50.57 mg, 0.390 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl) was added. Add )-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.078 mmol, 1 eq), stir at room temperature and react for 1 hour. After the reaction is complete, add water to the reaction mixture, extract with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 33% B to 60% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.95), yielded compound 005, 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (17.74 mg, 43.63%).

[0112] LCMS:(ESI,m / z):517.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.63(t,J=5.6Hz,1H),8.26(s,1H),7.86(s,1H),7.28(dd,J=8.7,7.6Hz,1H),7.03(d,J= 8.6Hz,1H),6.32(d,J=7.5Hz,1H),6.23(d,J=9.0Hz,1H),4.88(d,J=49.2Hz,1H),4.33(d ,J=5.6Hz,2H),3.87-3.70(m,4H),3.06(t,J=11.3Hz,1H),2.79(d,J=11.4Hz,1H),2.39- 2.23(m,1H),2.21(s,3H),2.15(t,J=10.5Hz,1H),1.99-1.80(m,2H),1.09-0.92(m,4H).

[0113] Example 5 [ka]

[0114] Step 1: Synthesis of Compound 006-2 In a reaction flask, ethyl 1H-pyrazole-4-carboxylate (compound 006-1, 1 g, 7.136 mmol, 1 eq), cyclobutyl bromide (1.93 g, 14.272 mmol, 2 eq), and cesium carbonate (6.97 g, 21.408 mmol, 3 eq) were added and dissolved with N,N-dimethylformamide (10 mL). The mixture was reacted at 80°C for 3 hours. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined. The mixture was backwashed with saturated sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 006-2 (1.5 g, 97.40%). LCMS:(ESI,m / z):195.10 [M+H] + .

[0115] Step 2: Synthesis of Compound 006-3 1-Cyclobutyl-1H-pyrazole-4-carboxylate ethyl (compound 006-2, 200 mg, 1.030 mmol, 1 eq) was added to a reaction flask and dissolved in ethanol (2 mL). Sodium hydroxide (10 M, 2 mL, 10 mmol, 10 eq) was then added, and the mixture was reacted at 50°C for 2 hours. After the reaction was complete, the solvent was rotated dry, water was added, and the pH was adjusted to 2 with 1 M aqueous hydrogen chloride solution. The reaction mixture was extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 006-3 (190 mg).

[0116] Step 3: Synthesis of 1-cyclobutyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 006) In the reaction flask, 1-cyclobutyl-1H-pyrazole-4-carboxylic acid (compound 006-3, 30 mg, 0.181 mmol, 1 eq) and 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 69.21 mg) were added. (g, 0.181 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (102.96 mg, 0.271 mmol, 1.5 eq), and N,N-diisopropylethylamine (116.66 mg, 0.905 mmol, 5 eq) were added and dissolved with N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to quench the mixture, and the reaction mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: XBridge BEH C18 OBD Prep Column 130, 5μm, 30mm × 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), B: acetonitrile; flow rate: 60 mL / min; gradient: from 36% B to 56% B in 10 minutes; wavelength: UV 254 nm / 220 nm; retention time (minutes): 9.2), yielding compound 006, 1-cyclobutyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide.

[0117] LCMS:(ESI,m / z):531.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.64(t,J=5.6Hz,1H),8.29(s,1H),7.91(s,1H),7.28(t,J=8.2Hz,1H),7.02(d, J=8.7Hz,1H),6.32(d,J=7.6Hz,1H),6.22(d,J=9.1Hz,1H),4.95-4.79(m,2H),4. 33(d,J=5.5Hz,2H),3.91-3.69(m,3H),3.05(t,J=11.0Hz,1H),2.78(d,J=11.5Hz ,1H),2.49-2.29(m,5H),2.20(s,3H),2.13(t,J=10.8Hz,1H),1.96-1.72(m,4H).

[0118] Example 6 [ka]

[0119] Step 1: Synthesis of Compound 007-1 Under nitrogen gas protection, ethyl 1H-pyrazole-4-carboxylate (compound 006-1,500 mg, 3.568 mmol, 1 eq), bromocyclopentane (1063.43 mg, 7.136 mmol, 2 eqs), and cesium carbonate (3487.38 mg, 10.704 mmol, 3 eqs) were added to a reaction flask, dissolved with N,N-dimethylformamide (5 mL), and the mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 20:1) to obtain compound 007-1 (450 mg, 57.29%). LCMS:(ESI,m / z):209.05 [M+H] + .

[0120] Step 2: Synthesis of Compound 007-2 Under nitrogen gas protection, 1-cyclopentyl-1H-pyrazole-4-carboxylate ethyl (compound 007-1, 200 mg, 0.960 mmol, 1 eq) and lithium hydroxide (115.00 mg, 4.800 mmol, 5 eq) were added to a reaction flask. Tetrahydrofuran (1 mL) / water (1 mL) / anhydrous methanol (1 mL) were added to dissolve the compounds, and the mixture was heated to 50°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was neutralized to pH=7 with 1 mol / L hydrochloric acid aqueous solution. The mixture was concentrated under reduced pressure. 10 mL of tetrahydrofuran was added to the resulting residue and stirred for 5 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 007-2 (95 mg, 54.29%). LCMS:(ESI,m / z):181.00 [M+H] + .

[0121] Step 3: Synthesis of 1-cyclopentyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 007) Under nitrogen gas protection, add 1-cyclopentyl-1H-pyrazole-4-carboxylic acid (compound 007-2, 14.1 mg, 0.078 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg, 0.078 mmol, 1.5 eq), 1-hydroxy-benzotriazole (10.6 mg, 0.078 mmol, 1.5 eq), and N,N-diisopropylethylamine (33.7 mg, 0.260 mmol, 5 eq) to a reaction flask, add N,N-dimethylformamide (2 mL) to dissolve, stir at room temperature for 10 minutes, and then add 2-(3-aminopropyl Add P-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.052 mmol, 1 eq), react for 1 hour, extract with ethyl acetate (2 × 20 mL) after reaction, combine organic phases, backwash with saturated sodium chloride solution (3 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (XBridge BEH C18 OBD Prep Column 130Å, 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 34% B to 60% B in 10 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.02), yielding compound 007, 1-cyclopentyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (7.1 mg, 24.37%).

[0122] LCMS:(ESI,m / z):545.90 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.62(t,J=5.6Hz,1H),8.25(s,1H),7.88(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.8Hz,1H) ,6.32(dd,J=7.3Hz,1H),6.22(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.77-4.66(m,1H),4.33(d,J =5.6Hz,2H),3.93-3.81(m,1H),3.75(q,J=11.1Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.6Hz, 1H),2.37-2.29(m,1H),2.26-2.15(m,4H),2.15-2.04(m,3H),1.96-1.70(m,6H),1.69-1.57(m,2H).

[0123] Example 7 [ka]

[0124] Step 1: Synthesis of Compound 009-1 Under nitrogen gas protection, ethyl 1H-pyrazole-4-carboxylate (compound 006-1,500 mg, 3.568 mmol, 1 eq), 3-bromooxetane (977.41 mg, 7.136 mmol, 2 eq), and cesium carbonate (3487.38 mg, 10.704 mmol, 3 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (5 mL), and the mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 18:1) to obtain compound 009-1 (480 mg, 64.25%). LCMS:(ESI,m / z):197.00 [M+H] + .

[0125] Step 2: Synthesis of Compound 009-2 Under nitrogen gas protection, 1-(oxetan-3-yl)-1H-pyrazole-4-carboxylate ethyl (compound 009-1, 200 mg, 0.960 mmol, 1 eq) and lithium hydroxide (115.00 mg, 4.800 mmol, 5 eq) were added to a reaction flask. Tetrahydrofuran (1 mL) / water (1 mL) / anhydrous methanol (1 mL) were added to dissolve the compounds, and the temperature was raised to 50°C and stirred for 1 hour. After the reaction was complete, the pH was neutralized to 7 with 1 mol / L hydrochloric acid aqueous solution, and the mixture was concentrated under reduced pressure. 10 mL of tetrahydrofuran was added to the resulting residue and stirred for 5 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 009-2 (95 mg, 54.29%). LCMS:(ESI,m / z):169.00 [M+H] + .

[0126] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide (compound 009) Under nitrogen gas protection, the reaction flask was filled with 1-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid (compound 009-2, 13.2 mg, 0.078 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg, 0.078 mmol, 1.5 eq), 1-hydroxy-benzotriazole (10.6 mg, 0.078 mmol, 1.5 eq), and N,N-diisopropylethylamine (33.7 mg, 0.260 mmol, 5 eq). Adding [compound name], dissolve in N,N-dimethylformamide (2 mL), stir at room temperature for 10 minutes, add 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.052 mmol, 1 eq), stir at room temperature and react for 1 hour, and the desired product was found by liquid chromatography. The reaction mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL x 3), and dried with anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire C18 5μm, 30mm × 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 5% B to 29% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.53), yielding compound 009, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide (5.79 mg, 20.80%).

[0127] LCMS:(ESI,m / z):534.05 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.75-8.70(m,1H),8.37(s,1H),8.04(s,1H),7.28(t,J=8.3Hz,1H),7.03(d,J=8.6Hz,1H),6.32 (d,J=7.7Hz,1H),6.23(d,J=8.7Hz,1H),5.61(m,1H),4.92(t,J=7.1Hz,2H),4.87(t,J=6.4Hz,2H ),4.82(s,1H),4.34(d,J=5.4Hz,2H),3.92-3.81(m,1H),3.75(q,J=11.2Hz,2H),3.06(m,1H),2 .80(d,J=11.3Hz,1H),2.41-2.28(m,1H),2.22(d,J=2.1Hz,3H),2.14(m,1H),1.94-1.83(m,2H).

[0128] Example 8 [ka]

[0129] Step 1: Synthesis of Compound 010-1 At room temperature, ethyl 1H-pyrazole-4-carboxylate (compound 006-1, 1 g, 7.136 mmol, 1 eq), potassium isopropenyltrifluoroborate (2.11 g, 14.272 mmol, 2 eq), 2,2'-bipyridine (2.23 g, 14.272 mmol, 2 eq), copper acetate (2.59 g, 14.272 mmol, 2 eq), and sodium carbonate (1.51 g, 14.272 mmol, 2 eq) were added to a reaction flask. Oxygen gas was introduced using a 10 mL solution of dichloroethane, and the mixture was reacted overnight at 70°C. After the reaction was complete, the reaction mixture was quenched with a saturated solution of disodium ethylenediaminetetraacetate, filtered, and the filtrate was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with a saturated sodium chloride solution (3 × 20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 010-1 (900 mg, 69.99%). LCMS:(ESI,m / z):180.95 [M+H] + .

[0130] Step 2: Synthesis of Compound 010-2 Under nitrogen gas protection, at 0°C, diethylzinc (2.74 g, 22.195 mmol, 5 eq) was added to a 10 mL solution of trifluoroacetic acid (2.53 g, 22.195 mmol, 5 eq) in dichloromethane, and the mixture was stirred and reacted for 20 minutes. Then, at 0°C, diiodomethane (11.89 g, 44.390 mmol, 10 eq) was added dropwise, and the mixture was stirred and reacted for 20 minutes. Finally, at 0°C, a 3 mL solution of 1-(propa-1-en-2-yl)-1H-pyrazole-4-carboxylate ethyl (compound 010-1,800 mg, 4.439 mmol, 1 eq) in dichloromethane was added dropwise. The reaction was stirred at 20°C for 16 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate (3 × 30 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire C18 5 μm, 30 mm × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 2% to 55% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 9.73). Compound 010-2 (90 mg, 10.44%) was obtained. LCMS:(ESI,m / z):195.45 [M+H] + .

[0131] Step 3: Synthesis of Compound 010-3 Under nitrogen gas protection at room temperature, a solution of 1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylate ethyl (compound 010-2, 70 mg, 0.360 mmol, 1 eq) and sodium hydroxide (28.83 mg, 0.720 mmol, 2 eq) in ethanol (2 mL) and water (2 mL) was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was diluted with water at room temperature, acidified to pH=5 with 1 mol / L hydrochloric acid solution, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 010-3 (50 mg, 83.49%) without further purification. LCMS:(ESI,m / z):167.40 [M+H] + .

[0132] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide (compound 010) At room temperature, a solution of 1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylic acid (compound 010-3, 10 mg, 0.060 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (27.46 mg, 0.072 mmol, 1.2 eq), and N,N-diisopropylethylamine (38.89 mg, 0.300 mmol, 5 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes, followed by 2-(3-aminopropyl Add rop-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 27.46 mg, 0.060 mmol, 1 eq) and stir, then react for 2 hours. After the reaction is complete, quench the reaction mixture with water, extract with ethyl acetate (3 × 30 mL), combine the organic phases, backwash with saturated sodium chloride solution (3 × 30 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; Mobile phase A: Water (0.1% ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Elution gradient: 35% to 57% in 10 minutes; Detection wavelength: UV 254nm / 220nm; Retention time (minutes): 8.52), yielding compound 010, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide (15.49mg, 48.18%).

[0133] LCMS:(ESI,m / z):532.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.63(t,J=5.5Hz,1H),8.29(s,1H),7.87(s,1H),7.27(t,J=8.0Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d ,J=7.5Hz,1H),6.22(d,J=9.0Hz,1H),4.87(d,J=49.8Hz,1H),4.33(d,J=5.5Hz,2H),3.92-3.80(m,1H) ,3.75(q,11.2Hz,2H),3.05(t,J=10.6Hz,1H),2.78(d,J=11.0Hz,1H),2.36-2.24(m,1H),2.20(s,3H) ,2.13(t,J=10.5Hz,1H),1.99-1.79(m,2H),1.57(s,3H),1.19(q,J=5.3Hz,2H),0.93(q,J=5.2Hz,2H).

[0134] Example 9 [ka]

[0135] Step 1: Synthesis of Compound 012-2 Under nitrogen gas protection, 4-(4-(ethoxycarbonyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate tert-butyl (compound 012-1,300 mg, 0.928 mmol, 1 eq) was added to a reaction flask and dissolved with 1,4-dioxane (4 mL). A solution of 1,4-dioxane in 4 M hydrogen chloride (4 mL) was added, and the mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was basicized to pH=8 with saturated sodium carbonate solution, the mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 012-2 (180 mg, 85.08%). LCMS:(ESI,m / z):224.45 [M+H] + .

[0136] Step 2: Synthesis of Compound 012-3 Under nitrogen gas protection, 1-(piperidine-4-yl)-1H-pyrazole-4-carboxylate ethyl (compound 012-2, 150 mg, 0.672 mmol, 1 eq), sodium borohydride cyanohydride (84.43 mg, 1.344 mmol, 2 eq), 37% aqueous formaldehyde solution (40.34 mg, 1.344 mmol, 2 eq), and acetic acid (0.04 mL, 0.067 mmol, 0.1 eq) were added to a reaction flask, and methanol (5 mL) was added to dissolve the compounds. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, saturated ammonium chloride (10 mL) was added to the reaction mixture at 0°C to quench it, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography under the following conditions: C18 column, mobile phase: water (0.1% ammonium bicarbonate) and acetonitrile, gradient from 10% to 20% over 10 minutes, detection wavelength: UV. The wavelength is 254 nm. Compound 012-3 (50 mg, 30.64%) was obtained. LCMS:(ESI,m / z):238.00 [M+H] + .

[0137] Step 3: Synthesis of Compound 012-4 Under nitrogen gas protection, 1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-carboxylate ethyl (compound 012-3, 50 mg, 0.211 mmol, 1 eq) and lithium hydroxide (10 mg, 0.422 mmol, 2 eq) were added to a reaction flask, dissolved in water (1.0 mL) and tetrahydrofuran (1.0 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain compound 012-4 (45 mg, 94.51%). LCMS:(ESI,m / z):210.05 [M+H] + .

[0138] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-carboxamide (compound 012) Under nitrogen gas protection, add 1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-carboxylic acid (compound 012-4, 13.8 mg, 0.066 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg, 0.078 mmol, 1.5 eq), 1-hydroxy-benzotriazole (10.6 mg, 0.078 mmol, 1.5 eq), and N,N-diisopropylethylamine (33.7 mg, 0.260 mmol, 5 eq) to a reaction flask, dissolve with N,N-dimethylformamide (2 mL), stir at room temperature for 10 minutes, and then 2-(3-aminopropane-1-yl) Add -1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.052 mmol, 1 eq), stir at room temperature and react for 1 hour. After the reaction is complete, add water, extract with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 5% B to 35% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 4.5), the formate salt (2.24 mg, 8.69%) of compound 012, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1-(1-methylpiperidine-4-yl)-1H-pyrazole-4-carboxamide, was obtained.

[0139] 1H NMR(400MHz,Chloroform-d)δ 8.01(s,1H),7.81(s,1H),7.18(t,J=7.8Hz,1H),6.88(d,J=8.7Hz,1H),6.33(t,J=5.5 Hz,1H),6.20(d,J=9.2Hz,1H),5.93(d,J=7.5Hz,1H),4.88(d,J=48.8Hz,1H),4.53(d, J=5.2Hz,1H),4.34-4.23(m,1H),3.70-3.51(m,3H),3.30-3.20(m,1H),2.98(d,J=12. 2Hz,1H),2.57(s,1H),2.53(s,3H),2.37(s,3H),2.34-2.19(m,6H),2.16-2.02(m,3H).

[0140] Example 10 [ka]

[0141] Step 1: Synthesis of Compound 013-1 At 80°C, a solution of ethyl 1H-pyrazole-4-carboxylate (compound 006-1, 400 mg, 2.854 mmol, 1 eq), oxiran-4-yl 4-methylbenzenesulfonic acid (877.92 mg, 3.425 mmol, 1.2 eq), and cesium carbonate (2.789 g, 8.562 mmol, 3 eq) in N,N-dimethylformamide (10 mL) was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was quenched with water at room temperature and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 013-1 (300 mg, 46.87%). LCMS:(ESI,m / z):224.85 [M+H] + . Step 2: Synthesis of Compound 013-2 At 50°C, a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate ethyl (compound 013-1,250 mg, 1.115 mmol, 1 eq) and lithium hydroxide (53.4 mg, 2.230 mmol, 2 eq) in ethanol (3 mL) and water (3 mL) was stirred and reacted for 1 hour. After the reaction was complete, the reaction mixture was diluted with water at room temperature, acidified to pH=5 with 1 M hydrochloric acid solution, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 013-2 (160 mg, 73.15%) without further purification. LCMS:(ESI,m / z):197.05 [M+H] + .

[0142] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (compound 013) At room temperature, a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (compound 013-2, 14.04 mg, 0.071 mmol, 1 eq), N,N-diisopropylethylamine (46.11 mg, 0.355 mmol, 5 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (32.56 mg, 0.085 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes, and then 2-(3-a Minopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 32.56 mg, 0.071 mmol, 1 eq) was added and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; elution gradient: 31% to 61% in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.45), yielding compound 013, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (28.05mg, 70.00%).

[0143] LCMS:(ESI,m / z):562.15 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.67(t,J=5.3Hz,1H),8.29(s,1H),7.92(s,1H),7.29(t,J=8.2Hz,1H),7.03(d,J=8.7Hz,1H),6.32 (d,J=7.6Hz,1H),6.23(d,J=9.0Hz,1H),4.94(s,0.5H),4.81(s,0.5H),4.44(m,1H),4.34(d,J=5.4H z,2H),3.98-3.92(m,2H),3.90-3.82(m,1H),3.75(m,2H),3.54-3.41(m,2H),3.06(t,J=10.6Hz,1H) ,2.78(d,J=10.8Hz,1H),2.37-2.24(m,1H),2.20(s,3H),2.14(t,J=10.7Hz,1H),2.03-1.80(m,6H).

[0144] Example 11 [ka]

[0145] Step 1: Synthesis of Compound 014-2 Under nitrogen gas protection, a solution of methyl 1H-pyrazole-4-carboxylate (compound 014-1,600 mg, 4.758 mmol, 1 eq) and 4-methyltetrahydro-2H-pyran-4-ol (3868.47 mg, 33.306 mmol, 7 eq) in sulfuric acid (269 μL) was stirred and reacted at 90°C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire C18 5 μm, 30 mm × 150 mm; mobile phase A: water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 40 mL / min; elution gradient: 5% to 28% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.08), yielding compound 014-2 (120 mg, 12.00%). LCMS:(ESI,m / z):211.05 [M+H] + .

[0146] Step 2: Synthesis of 3-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 014) At room temperature, a solution of 1-(4-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (compound 014-2, 15.38 mg, 0.073 mmol, 1 eq), N,N-diisopropylethylamine (47.28 mg, 0.365 mmol, 5 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (33.38 mg, 0.088 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes, and then 2- (3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 40.06 mg, 0.088 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; elution gradient: 24% to 50% in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.8), yielding compound 014, 3-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide. LCMS:(ESI,m / z):576.15 [M+H] + .

[0147] 1H NMR(400MHz,DMSO-d6)δ 8.64(t,J=5.6Hz,1H),8.40(s,1H),7.95(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.03(d,J=8.7Hz, 1H),6.32(d,J=7.5Hz,1H),6.22(d,J=9.1Hz,1H),4.87(d,J=49.4Hz,1H),4.35(d,J=5.6Hz,2H) ,3.92-3.64(m,5H),3.45(ddd,J=11.5,8.0,3.2Hz,2H),3.06(t,J=9.7Hz,1H),2.78(d,J=11.6H z,1H),2.37-2.22(m,3H),2.20(s,3H),2.14(td,J=11.5,2.4Hz,1H),1.88(m,4H),1.44(s,3H).

[0148] Example 12 [ka]

[0149] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-phenyl-1H-pyrazole-4-carboxamide (compound 015) Under nitrogen gas protection, 1-phenyl-1H-pyrazole-4-carboxylic acid (14.73 mg, 0.078 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.00 mg, 0.078 mmol, 1.5 eq), 1-hydroxy-benzotriazole (10.57 mg, 0.078 mmol, 1.5 eq), and N,N-diisopropylethylamine (33.71 mg, 0.260 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride was added. (Compound 001-12, 20 mg, 0.052 mmol, 1 eq) was added, stirred, and reacted for 1 hour. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions: (Column specifications: YMC Triart C18 ExRs 5 μm, 30 mm * 150 mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 41% B to 67% B in 10 minutes; Detection wavelength: UV) At 254 nm / 220 nm (retention time: 8.55 minutes), compound 015 was converted to N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-phenyl-1H-pyrazole-4-carboxamide (11.42 mg, 39.47%). LCMS:(ESI,m / z):553.90 [M+H] + .

[0150] 1H NMR(400MHz,DMSO-d6)δ 8.98(s,1H),8.85(t,J=5.5Hz,1H),8.19(s,1H),7.87(d,J=7.9Hz,2H),7.54(t,J=7.9Hz,2H),7.37(t,J= 7.4Hz,1H),7.29(t,J=8.1Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7.6Hz,1H),6.22(d,J=9.0Hz,1H),4. 88(d,J=49.4Hz,1H),4.40(d,J=5.5Hz,2H),3.94-3.82(m,1H),3.77(q,J=11.0Hz,2H),3.06(t,J=11.7Hz ,1H),2.78(d,J=11.6Hz,1H),2.37-2.22(m,1H),2.20(s,3H),2.14(t,J=10.5Hz,1H),1.99-1.81(m,2H).

[0151] Example 13 [ka]

[0152] Step 1: Synthesis of Compound 022-2 4-bromo-1H-pyrazole (compound 022-1, 1 g, 6.804 mmol, 1 eq), methyl 2-bromoisobutyrate (2.46 g, 13.608 mmol, 2 eq), and cesium carbonate (6.65 g, 20.412 mmol, 3 eq) were added sequentially to a reaction flask, dissolved with N,N-dimethylformamide (10 mL), and reacted at 80°C for 5 hours. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 022-2 (1.4 g, 79.11%). LCMS:(ESI,m / z):246.85 [M+H] + .

[0153] Step 2: Synthesis of Compound 022-3 Methyl 2-(4-bromo-1H-pyrazole-1-yl)-2-isobutyrate (compound 022-2, 1.15 g, 4.654 mmol, 1 eq) was added to a reaction flask and dissolved in ethanol (23.0 mL). Sodium borohydride (528.2 mg, 13.962 mmol, 3 eq) was added at 0°C, the temperature was raised to room temperature, and the reaction was continued for 2 hours. Water was added to quench the reaction mixture, the reaction mixture was extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 022-3 (1 g, 93.17%). LCMS:(ESI,m / z):218.95 [M+H] + .

[0154] Step 3: Synthesis of Compound 022-4 Add 2-(4-bromo-1H-pyrazole-1-yl)-2-methylpropan-1-ol (compound 022-3, 900 mg, 4.108 mmol, 1 eq) to the reaction flask, dissolve with N,N-dimethylformamide (15 mL), add sodium hydride (821.54 mg, 20.540 mmol, 5 eq, 60%) at 0°C, stir for 30 minutes, and then add methyl iodide (1166.19 mg, 8.216 mmol, 2 eq). In addition, the reaction was continued for 2 hours after raising the temperature to room temperature, then saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 022-4 (900 mg, 89.28%). LCMS:(ESI,m / z):232.90 [M+H] + .

[0155] Step 4: Synthesis of Compound 022-5 Under nitrogen gas protection, 4-bromo-1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole (compound 022-4,700 mg, 3.003 mmol, 1 eq) was added to the reaction flask and dissolved in tetrahydrofuran (25 mL). At -78°C, n-butyllithium (2.4 mL, 2 eq, 2.5 M) was added dropwise, and the mixture was stirred for 30 minutes. Then, propyl chloroformate (331.2 mg, 2.703 mmol, 0.9 eq) was added. The mixture was stirred for 1 hour, and after the reaction was complete, the reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate (3 × 150 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (1 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 022-5 (220 mg, 27.44%). LCMS:(ESI,m / z):241.30 [M+H] + .

[0156] Step 5: Synthesis of Compound 022-6 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxylate propyl (compound 022-5, 200 mg, 0.832 mmol, 1 eq) was added to a reaction flask and dissolved in methanol (2 mL). Sodium hydroxide (10 M) (1.6 mL, 8.32 mmol, 10 eq) was then added, and the mixture was reacted at 50°C for 1 hour. After the reaction was complete, the solvent was directly rotated dry, water was added, and the pH was adjusted to 4 with 1 M hydrochloric acid. Extraction was performed with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to directly obtain compound 022-6 (180 mg, 98.20%). LCMS:(ESI,m / z):199.10 [M+H] + .

[0157] Step 6: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidinyl-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxamide (compound 022) The reaction flask contains 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxylic acid (compound 022-6, 30 mg, 0.151 mmol, 1 eq), 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 58.03 mg, 0.151 mmol, 1 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate (86.32 mg, 0.226 mmol, 1.5 eq) and N,N-diisopropylethylamine (97.8 mg, 0.755 mmol, 5 eq) were added, dissolved with N,N-dimethylformamide (3 mL), and reacted at room temperature for 1 hour. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, backwashed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 36% B to 58% B in 8 minutes; wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.12); obtained N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidinyl-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxamide (12.28 mg, 14.14%) of compound 022.

[0158] LCMS:(ESI,m / z):564.25 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.62(t,J=5.5Hz,1H),8.27(s,1H),7.90(s,1H),7.28(t,J=8.2Hz,1H),7.02(d,J=8.7Hz,1H),6. 31(d,J=7.5Hz,1H),6.22(d,J=9.1Hz,,1H),4.87(d,J=49.3Hz,1H),4.34(d,J=5.5Hz,2H),3.84( m,1H),3.75(q,J=11.2Hz,2H),3.55(s,2H),3.17(s,3H),3.05(t,J=10.4Hz,1H),2.78(d,J=11.1 Hz,1H),2.36-2.25(m,1H),2.21(s,3H),2.13(t,J=11.2Hz,1H),1.99-1.80(m,2H),1.50(s,6H).

[0159] Example 14 [ka]

[0160] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide (compound 024) At room temperature, 1-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (16.91 mg, 0.094 mmol, 1.2 eq), N,N-diisopropylethylamine (20.23 mg, 0.156 mmol, 2 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluoro A solution of phosphate (35.7 mg, 0.094 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes, and then 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.078 mmol, 1 eq) was added. After stirring for 2 hours, the reaction mixture was quenched with water, extracted with ethyl acetate (3 × 10 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions: (Column specifications: Sunfire C18 5 μm, 30 mm × 150 mm; Mobile phase A: Water (0.1% ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 42% to 66% in 10 minutes; Detection wavelength: UV) At 254 nm / 220 nm (retention time: 9.08 minutes), compound 024 was converted to N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide (14.57 mg, 33.97%).

[0161] LCMS:(ESI,m / z):546.05 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.04(t,J=5.5Hz,1H),8.97(s,1H),8.33(3,1H),7.28(dd,J=8.7,7.6Hz,1H),7.02(d,J=8.6 Hz,1H),6.32(d,J=7.4Hz,1H),6.20(d,J=9.1Hz,1H),4.87(d,J=49.4Hz,1H),4.38(d,J=5.5H z,2H),3.92-3.82(m,1H),3.75(q,J=11.1Hz,2H),3.05(t,J=11.4Hz,1H),2.78(d,J=11.5Hz ,1H),2.29(dd,J=38.7,12.9Hz,1H),2.20(s,3H),2.14(t,J=10.3Hz,1H),1.98-1.80(m,2H).

[0162] Example 15 [ka]

[0163] Step 1: Synthesis of Compound 029-1 Under nitrogen gas protection, at room temperature, ethyl 1H-pyrazole-4-carboxylate (compound 006-1,100 mg, 0.714 mmol, 1 eq), 2,2,2-trifluoro-1-methylethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid (565.36 mg, 1.428 mmol, 2 eq), and cesium carbonate (697.48 mg, 2.142 mmol, 3 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred, and allowed to react overnight. After the reaction was complete, the reaction mixture was poured into water (10 mL), extracted with ethyl acetate (2 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 029-1 (120 mg, 71.20%). LCMS:(ESI,m / z):237.00 [M+H] + .

[0164] Step 2: Synthesis of Compound 029-2 At room temperature, 1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxylate ethyl (compound 029-1, 1,100 mg, 0.423 mmol, 1 eq) and lithium hydroxide (15.21 mg, 0.634 mmol, 1.5 eq) were added to a reaction flask, dissolved with tetrahydrofuran (2 mL) and water (1 mL), stirred, and reacted overnight. The resulting residue was concentrated under reduced pressure to obtain compound 029-2 (80 mg, 90.78%). LCMS:(ESI,m / z):209.35 [M+H] + .

[0165] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxamide (compound 029) At room temperature, add 1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxylic acid (compound 029-2, 18.25 mg, 0.088 mmol, 2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) and N,N-diisopropylethylamine (22.66 mg, 0.176 mmol, 4 eq) to a reaction flask, dissolve with N,N-dimethylformamide (1 mL), stir and react for 20 minutes, and then further react with 2-(3-aminopropa-1-in-1-yl)-N -((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was added gradually, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into water (10 mL), extracted with ethyl acetate (2 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 37% B to 67% B in 10 minutes; wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.22); compound 029 N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxamide (5.01 mg, 19.89%) was obtained.

[0166] LCMS:(ESI,m / z):573.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.81(t,J=5.6Hz,1H),8.42(s,1H),8.03(s,1H),7.28(t,J=8.0Hz,1H),7.03(d,J=8.7Hz,1H),6.32 (d,J=7.6Hz,1H),6.23(d,J=9.0Hz,1H),5.48(h,J=7.2Hz,1H),4.87(d,J=48.0Hz,1H),4.35(d,J=5 .5Hz,2H),3.92-3.81(m,1H),3.75(q,J=11.1Hz,2H),3.06(t,J=11.7Hz,1H),2.78(d,J=11.5Hz,1H ),2.37-2.22(m,1H),2.20(s,3H),2.14(t,J=10.2Hz,1H),1.88-1.81(m,2H),1.68(d,J=7.0Hz,3H).

[0167] Example 16 [ka]

[0168] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrido[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (compound 030) At room temperature, add 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (15.31 mg, 0.079 mmol, 1.2 eq), N,N-diisopropylethylamine (0.1 mL, 0.660 mmol, 10 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) to a reaction flask, dissolve with N,N-dimethylformamide (2 mL), stir at room temperature for 10 minutes, and then add 2-(3-aminopropane-1-yl) Add (-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq), stir at room temperature for 1 hour, dilute with ethyl acetate (5 mL) after reaction, wash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH Shield RP18 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 32% B to 57% B in 8 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.83), yielded compound 030, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrido[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (5.06 mg, 13.56%).

[0169] LCMS:(ESI,m / z):559.85 [M+H] + . 11H NMR (400MHz, Methanol-d4)δ 8.17(s,1H),7.91(s,1H),7.16(dd,J=8.8,7.6Hz,1H),6.85(d,J=8.7Hz,1H) ,6.10(d,J=7.3Hz,1H),4.92(q,J=8.7Hz,2H),4.33(s,2H),3.74(dt,J=27.9 ,7.5Hz,1H),3.55(q,J=10.8Hz,2H),3.13(t,J=11.9Hz,1H),2.83(d,J=11.6 Hz,1H),2.33(dd,J=37.4,13.3Hz,1H),2.20-2.16(m,4H),1.96-1.88(m,2H).

[0170] Example 17 [ka]

[0171] Step 1: Synthesis of 1-(difluoromethyl)-N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 035) Under nitrogen gas protection, add 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (15.22 mg, 0.094 mmol, 1.2 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.5 mg, 0.117 mmol, 1.5 eq), 1-hydroxy-benzotriazole (15.86 mg, 0.117 mmol, 1.5 eq), and N,N-diisopropylethylamine (50.57 mg, 0.390 mmol, 5 eq) to a reaction flask, dissolve with N,N-dimethylformamide (2 mL), and stir at room temperature for 10 minutes. Then, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.078 mmol, 1 eq) was added, and the mixture was stirred and allowed to react for 1 hour. After the reaction was complete, water was added to the reaction solution, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, backwashed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: XBridge BEH Shield RP18 5μm, 30mm * 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 30% B to 57% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.79), yielding compound 035, 1-(difluoromethyl)-N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (19.49 mg, 47.08%).

[0172] LCMS:(ESI,m / z):527.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.97(t,J=5.5Hz,1H),8.72(s,1H),8.20(s,1H),7.87(t,J=58.8Hz,1H),7.29(dd,J=8.8,7.6H z,1H),7.03(d,J=8.6Hz,1H),6.32(d,J=7.4Hz,1H),6.22(d,J=9.0Hz,1H),4.88(d,J=49.4Hz, 1H),4.37(d,J=5.5Hz,2H),3.94-3.80(m,1H),3.76(q,J=11.1Hz,2H),3.07(t,J=11.4Hz,1H), 2.79(d,J=11.4Hz,1H),2.39-2.24(m,1H),2.21(s,3H),2.19-2.12(m,1H),1.99-1.81(m,2H).

[0173] Example 18 [ka]

[0174] Step 1: Synthesis of compound 082-2 Under nitrogen gas protection, 2-isocyanoethyl acetate (compound 082-1, 5 g, 44.202 mmol, 1 eq) was added to the reaction flask and dissolved with anhydrous ethanol (50.0 mL). (Dimethoxymethyl)dimethylamine (10.53 g, 88.404 mmol, 2 eq) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was directly rotated dry, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 082-2 (5.6 g, 71.56%).

[0175] LCMS:(ESI,m / z):169.10 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.31(s,1H),4.11(q,J=7.1Hz,2H),3.19(s,6H),1.20(t,J=7.1Hz,3H). Step 2: Synthesis of Compound 082-3 Ethyl (2E)-3-(dimethylamino)-2-isocyanopropyl-2-enoate (compound 082-2, 1 g, 5.945 mmol, 1 eq) and tert-butylamine (2.5 mL, 0.034 mmol, 4 eq) were added to the reaction flask and stirred overnight at 140°C. After the reaction was complete, the reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 082-3 (600 mg, 48.85%). LCMS:(ESI,m / z):196.90 [M+H] + .

[0176] Step 3: Synthesis of Compound 082-4 1-tert-butyl-1H-imidazole-4-carboxylate ethyl (compound 082-3, 200 mg, 1.019 mmol, 1 eq), aqueous sodium hydroxide solution (5 M, 2 mL, 10 eq), and anhydrous ethanol (2 mL) were added to a reaction flask. The mixture was reacted at 50°C for 2 hours. After the reaction was complete, 3 M dilute hydrochloric acid was added to adjust the pH to neutral, and the solvent was rotated dry to obtain compound 082-4 (50 mg, 27.71%).

[0177] LCMS:(ESI,m / z):169.05 [M+H] + . Step 4: Synthesis of 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-imidazole-4-carboxamide (compound 082) In the reaction flask, 1-tert-butyl-1H-imidazole-4-carboxylic acid (compound 082-4, 35 mg, 0.208 mmol, 1 eq), 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 79.78 mg, 0.208 mmol, 1 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N Add ',N'-tetramethyluronium hexafluorophosphate (118.68 mg, 0.312 mmol, 1.5 eq) and N,N-diisopropylethylamine (134.48 mg, 1.040 mmol, 5 eq), dissolve with N,N-dimethylformamide (4 mL), react at room temperature for 2 hours, quench with water after reaction, extract with ethyl acetate (3 × 10 mL), combine organic phases, backwash with saturated sodium chloride solution (3 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 27% B to 58% B in 8 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.02), yielding compound 082, 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-imidazole-4-carboxamide (19.97 mg, 17.95%).

[0178] LCMS:(ESI,m / z):533.95 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.45(t,J=5.9Hz,1H),7.90-7.85(m,2H),7.27(t,J=8.2Hz,1H),7.01(d,J=8.7Hz,1H),6 .30(d,J=7.5Hz,1H),6.25(d,J=9.1Hz,1H),4.86(d,J=50.1Hz,1H),4.30(d,J=6.0Hz,2H ),3.83(m,1H),3.75(dd,J=22.0,11.0Hz,2H),3.03(t,J=9.9Hz,1H),2.77(d,J=11.2Hz, 1H),2.36-2.23(m,1H),2.20(s,3H),2.17-2.09(m,1H),2.00-1.80(m,2H),1.53(s,9H).

[0179] Example 19 [ka]

[0180] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]cyclopropylcarboxamide (compound 135) At room temperature, add cyclopropylformic acid (4.53 mg, 0.053 mmol, 1.2 eq), N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20.0 mg, 0.053 mmol, 1.2 eq) to a reaction flask, dissolve with N,N-dimethylformamide (1 mL), stir, and react for 30 minutes. Then, add 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1- Methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was added, and the mixture was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; elution gradient: 27% to 57% in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.93), yielding compound 135, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]cyclopropylcarboxamide (4.46mg, 22.43%).

[0181] LCMS:(ESI,m / z):452.05 [M+H] + . 1 1H NMR (400MHz, DMSO- d6)δ 8.64(t,J=5.5Hz,1H),7.29(dd,J=8.7,7.6Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7. 6Hz,1H),6.22(d,J=9.0Hz,1H),4.88(d,J=49.5Hz,1H),4.20(d,J=5.5Hz,2H),3.93-3. 66(m,3H),3.18-2.99(m,1H),2.78(d,J=11.2Hz,1H),2.36(s,1H),2.21(s,3H),2.17-2 .10(m,1H),1.99-1.81(m,2H),1.60(tt,J=7.6,4.9Hz,1H),0.70(tt,J=7.9,2.9Hz,4H).

[0182] Example 20 [ka]

[0183] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-4-(2-hydroxypropa-2-yl)benzamide (compound 230) Under nitrogen gas protection, 4-(2-hydroxypropane-2-yl)benzoic acid (11.85 mg, 0.066 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 mg, 0.066 mmol, 1.5 eq), 1-hydroxy-benzotriazole (8.88 mg, 0.066 mmol, 1.5 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl)-N-(( Add 3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), stir at room temperature and react for 1 hour. After the reaction is complete, add water to the reaction mixture and quench, extract with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 10% B to 35% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.78), formate (15.33 mg, 63.40%) of compound 230, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-4-(2-hydroxypropa-2-yl)benzamide, was obtained.

[0184] LCMS:(ESI,m / z):546.20 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.99(t,J=5.5Hz,1H),7.83(d,J=8.1Hz,2H),7.56(d,J=8.1Hz,2H),7.28(t,J=8.2Hz,1H),7.02( d,J=8.7Hz,1H),6.31(d,J=7.6Hz,1H),6.24(d,J=9.0Hz,1H),5.10(s,1H),4.88(d,J=49.5Hz,1H) ),4.38(d,J=5.5Hz,2H),3.94-3.82(m,1H),3.76(q,J=11.3Hz,2H),3.08(t,J=11.6Hz,1H),2.80 (d,J=11.5Hz,1H),2.41-2.25(m,1H),2.22(s,3H),2.16(m,1H),1.99-1.83(m,2H),1.44(s,6H).

[0185] Example 21 [ka]

[0186] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (compound 231) Under nitrogen gas protection, at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 40 mg, 0.088 mmol, 1 eq) and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (23.66 mg, 0.156 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (0.8 mL) and N,N-diisopropylethylamine (56 0.65 mg, 0.440 mmol, 5 eq) and O-(7-azobenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (50.00 mg, 0.132 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to the reaction mixture to quench it, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 30% B to 53% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.67), yielding compound 231, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (4.78 mg, 8.49%).

[0187] LCMS:(ESI,m / z):517.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.45(t,J=5.6Hz,1H),7.91(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.6Hz,1H),6.32(d,J=7.5H z,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.31(d,J=5.6Hz,2H),4.07(t,J=7.3Hz,2H),3.92 -3.81(m,1H),3.75(q,J=11.2Hz,2H),3.07(t,J=12.0Hz,1H),2.99(t,J=7.4Hz,2H),2.78(d,J=11.4Hz ,1H),2.57(t,J=7.3Hz,2H),2.37-2.23(m,1H),2.20(s,3H),2.14(t,J=11.2Hz,1H),1.99-1.80(m,2H).

[0188] Example 22

change

[0189] No. 1 Structural Research: Synthesis of Compound 232-1 In a reaction flask, add 2-(4-bromo-1H-pyrazole-1-yl)-2-methylpropan-1-ol (compound 022-3, 1.1g, 5.021 mmol, 1eq), palladium acetate (112.7mg, 0.502 mmol, 0.1eq), 1,3-bis(diphenylphosphine)propane (207.1mg, 0.502 mmol, 0.1eq), and triethylamine (5.5mL). Then add N,N-dimethylformamide (13.2mL) and anhydrous methanol (13.2mL), and add 0.4 mL of carbon monoxide. The mixture was introduced to MPa, reacted overnight at 140°C, filtered, water was added, extracted with ethyl acetate (3 × 50 mL), the organic phase was combined, backwashed with saturated sodium chloride solution (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by reversed-phase column chromatography under the following conditions (80 g C18 reversed-phase column, mobile phase: water (0.1% ammonium bicarbonate) and acetonitrile, gradient from 5% to 30% over 30 minutes, flow rate: 60 mL / min, detection wavelength: UV 254 nm), yielding compound 232-1 (300 mg, 28.64%). LCMS:(ESI,m / z):199.05 [M+H] + .

[0190] Step 2: Synthesis of Compound 232-2 Under nitrogen gas protection, at room temperature, a solution of 1-(1-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylate methyl (compound 232-1, 1,100 mg, 0.504 mmol, 1 eq) was prepared in methanol (1.0 mL) and water (1.0 mL). Sodium hydroxide (40.36 mg, 1.008 mmol, 2 eqs) was added, and the mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was acidified to pH=6 with dilute hydrochloric acid solution, extracted with ethyl acetate and dichloromethane (3:1) (5 × 20 mL), combined with the organic phase, backwashed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 232-2 (50 mg, 53.81%). LCMS:(ESI,m / z):184.95 [M+H] + .

[0191] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-1-(1-hydroxy-2-methylpropyl-2-yl)-1H-pyrazole-4-carboxamide (compound 232) Under nitrogen gas protection, at room temperature, 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was dissolved in N,N-dimethylformamide (1.0 mL) and 1-(1-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (compound 232-2, 12.11 mg, 0.066 mmol, 1.5 eq) and Add N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) and stir for 30 minutes. Then, at room temperature, add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) and continue stirring for 1 hour. After the reaction is complete, quench the mixture with methanol (1.0 mL) at room temperature, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Elution gradient: 5-5% B to 65% B in 10 minutes; Detection wavelength: UV 254nm / 220nm; Retention time (minutes): 6.8), yielding formate (6.43mg, 26.37%) of compound 232, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-hydroxy-2-methylpropyl-2-yl)-1H-pyrazole-4-carboxamide.

[0192] LCMS:(ESI,m / z):550.25 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.62(t,J=5.6Hz,1H),8.28(s,1H),8.14(s,1H),7.89(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.03(d,J=8.6Hz ,1H),6.32(d,J=7.6Hz,1H),6.24(d,J=9.0Hz,1H),5.00(t,J=5.6Hz,1H),4.88(d,J=49.4Hz,1H),4.33(d,J =5.6Hz,2H),3.95-3.81(m,1H),3.75(q,J=11.0Hz,1H),3.56(d,J=5.5Hz,2H),3.07(t,J=11.6Hz,1H),2.79 (d,J=11.4Hz,1H),2.39-2.24(m,1H),2.21(s,3H),2.14(t,J=11.4Hz,1H),1.98-1.82(m,2H),1.47(s,6H).

[0193] Example 23 [ka]

[0194] Step 1: Synthesis of Compound 236-2 At room temperature, methyl 6-(2-hydroxypropyl-2-yl)pyridine-3-carboxylate (compound 236-1, 20 mg, 0.102 mmol, 1 eq) and lithium hydroxide (4.91 mg, 0.204 mmol, 2 eq) were added to a reaction flask, dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), stirred overnight at room temperature, and after the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product compound 236-2. The resulting mixture was used directly in the next step without further purification. LCMS:(ESI,m / z):182.00 [M+H] + .

[0195] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6-(2-hydroxypropa-2-yl)pyridine-3-carboxamide (compound 236) At room temperature, 6-(2-hydroxypropyl-2-yl)pyridine-3-carboxylic acid (compound 236-2, 18 mg, 0.099 mmol, 1.2 eq), N,N-diisopropylethylamine (0.14 mL, 0.825 mmol, 10 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37.78 mg, 0.083 mmol, 1 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl) was added. Add ((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 37.78 mg, 0.083 mmol, 1 eq), stir at room temperature for 1 hour, and after the reaction is complete, dilute the reaction mixture with ethyl acetate (5 mL), wash with saturated sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30×150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 5% B to 32% B in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.05), the formate salt (4.77 mg, 10.32%) of compound 236, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6-(2-hydroxypropa-2-yl)pyridine-3-carboxamide, was obtained.

[0196] LCMS:(ESI,m / z):546.90 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.24(t,J=5.5Hz,1H),8.94(dd,J=2.3,0.9Hz,1H),8.21(dd,J=8.3,2.3Hz,1H),7.76(dd,J=8.3,0.9Hz ,1H),7.29(dd,J=8.8,7.6Hz,1H),7.03(d,J=8.7Hz,1H),6.41-6.29(m,1H),6.23(d,J=9.1Hz,1H),5.3 4(s,1H),4.88(d,J=49.3Hz,1H),4.42(d,J=5.5Hz,2H),3.77(q,J=11.0Hz,3H),3.06(t,J=11.6Hz,1H) ,2.79(d,J=11.5Hz,1H),2.36(s,1H),2.21(s,4H),2.01-1.89(m,1H),1.89-1.77(m,1H),1.45(s,6H).

[0197] Example 24 [ka]

[0198] Step 1: Synthesis of Compound 261-2 (E)-2-cyano-3-ethoxyacrylate ethyl (compound 261-1, 25.44 g, 150.353 mmol, 1.00 eq), ethyl hydrazine dihydrochloride (20 g, 150.353 mmol, 1 eq), and sodium acetate (12.33 g, 150.304 mmol, 1.00 eq) were mixed in anhydrous ethanol (200 mL) and stirred overnight at 80°C. After the reaction was complete, the reaction mixture was rotated dry, ethyl acetate and water were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 261-2 (8 g, 29.04%). LCMS:(ESI,m / z):183.95 [M+H] + .

[0199] Step 2: Synthesis of Compound 261-3 At 60°C, ethyl 5-amino-1-ethyl-1H-pyrazole-4-carboxylate (compound 261-2, 8g, 43.666 mmol, 1eq) and lithium hydroxide (5.23g, 218.330 mmol, 5eq) were added to a reaction flask. Methanol (24mL), tetrahydrofuran (24mL), and water (24mL) were then added to dissolve the compounds, and the mixture was stirred and allowed to react overnight. After the reaction was complete, the organic phase was removed by rotation, the solution was acidified to pH=5 with hydrochloric acid solution (2M), filtered, and the filter cake was collected. The mixture was washed with water (20mL x 2) to obtain compound 261-3 (3.2g, 47.23%). LCMS:(ESI,m / z):155.85 [M+H] + .

[0200] Step 3: Synthesis of 5-amino-1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 261) At room temperature, stir and react for 20 minutes a solution of 5-amino-1-ethyl-1H-pyrazole-4-carboxylic acid (compound 261-3, 2g, 12.890 mmol, 1eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.90g, 12.890 mmol, 1.00eq), and N,N-diisopropylethylamine (6.66g, 51.560 mmol, 4eq) in N,N-dimethylformamide (80.00mL). Furthermore, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 5.88g, 12.890 mmol, 1eq) was added, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: uLtimate). 5μm AQ-C18 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: methanol; flow rate: 100 mL / min; elution gradient: from 15% B to 30% B in 20 minutes; detection wavelength: 254 nm / 220 nm; retention time (minutes): 18.5); formate (748 mg, 10.13%) of compound 261, 5-amino-1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide, was obtained.

[0201] LCMS:(ESI,m / z):521.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.26(t,J=5.7Hz,1H),7.68(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.7Hz,1H),6.32(d,J=7 .4Hz,1H),6.28(d,J=8.8Hz,1H),6.22(s,2H),4.87(d,J=49.5Hz,1H),4.29(d,J=5.6Hz,2H),3.89(q ,J=7.1Hz,2H),3.84-3.68(m,3H),3.05(t,J=11.3Hz,1H),2.78(d,J=11.4Hz,1H),2.39-2.23(m,1H ),2.20(s,3H),2.14(t,J=11.4Hz,1H),1.99-1.90(m,1H),1.89-1.81(m,1H),1.21(t,J=7.1Hz,3H).

[0202] Example 25 [ka]

[0203] Step 1: Synthesis of Compound 268-1 Under nitrogen gas protection, ethyl 1H-pyrazole-4-carboxylate (compound 006-1,500 mg, 3.568 mmol, 1 eq), (bromomethyl)cyclopropane (963.34 mg, 7.136 mmol, 2 eq), and cesium carbonate (3487.38 mg, 10.704 mmol, 3 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (5 mL, 64.608 mmol), and the mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, backwashed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 268-1 (400 mg, 53.97%). LCMS:(ESI,m / z):195.00 [M+H] + .

[0204] Step 2: Synthesis of Compound 268-2 Under nitrogen gas protection, 1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylate ethyl (compound 268-1, 200 mg, 1.030 mmol, 1 eq) and lithium hydroxide (49.32 mg, 2.060 mmol, 2 eq) were added to a reaction flask, dissolved in anhydrous ethanol (1 mL) and water (1 mL), and the mixture was heated to 50°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, 10 mL of tetrahydrofuran was added to the crude product, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 268-2 (50 mg, 27.76%). LCMS:(ESI,m / z):167.05 [M+H] + .

[0205] Step 3: Synthesis of 1-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 268) Under nitrogen gas protection, add 1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid (compound 268-2, 10.93 mg, 0.066 mmol, 1.5 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) to a reaction flask, dissolve with N,N-dimethylformamide (1.33 mL, 17.296 mmol), stir at room temperature for 10 minutes, and 2-(3-aminopropane-1-in-1- Add (-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1.00 eq), stir at room temperature and react for 1 hour. After the reaction is complete, extract with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm * 150mm; mobile phase A: water (ammonium bicarbonate at 10 mmol / L), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 31% B to 51% B in 8 min; detection wavelength: UV 254 nm / 226 nm; retention time (minutes): 7.03), yielding compound 268, 1-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide.

[0206] LCMS:(ESI,m / z):532.20 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.69(t,J=5.6Hz,1H),8.27(s,1H),7.89(s,1H),7.29(dd,J=8.8,7.6Hz,1H),7.03(d,J=8.6Hz,1H),6.32(d,J= 7.4Hz,1H),6.28(d,J=9.0Hz,1H),4.87(d,J=49.3Hz,1H),4.34(d,J=5.6Hz,2H),3.99(d,J=7.1Hz,2H),3.94-3 .81(m,1H),3.76(q,J=11.1Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.1Hz,1H),2.39(dd,J=38.7,13.5Hz,1 H),2.20(s,3H),2.16-2.10(m,1H),1.97-1.82(m,2H),1.28-1.19(m,1H),0.57-0.52(m,2H),0.40-0.33(m,2H).

[0207] Example 26 [ka]

[0208] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (compound 270) Under nitrogen gas protection, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 1-methylpyrrole-3-carboxylic acid (8.23 mg, 0.066 mmol, 1.5 eq) were added to a reaction flask, and N,N-dimethylformamide (0.8 mL) was added to the solution, and then N,N-diisopropyl Pyrethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise, and the mixture was stirred and reacted for 2 hours. Then, at room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added and the mixture was stirred for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to quench the mixture, and the solvent was rotated dry. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 30% B to 48% B in 8 min; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.12), yielded compound 270, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (8.18 mg, 38.05%).

[0209] LCMS:(ESI,m / z):491.20 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.31(t,J=5.7Hz,1H),7.32-7.25(m,2H),7.02(d,J=8.4Hz,1H),6.71(t,J=2.5Hz,1H),6.47(dd, J=2.9,1.8Hz,1H),6.31(d,J=7.6Hz,1H),6.24(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.29(d, J=5.7Hz,2H),3.92-3.81(m,1H),3.75(q,J=11.2Hz,2H),3.63(s,3H),3.05(t,J=11.4Hz,1H),2. 78(d,J=11.1Hz,1H),2.39-2.25(m,1H),2.20(s,3H),2.13(t,J=11.1Hz,1H),1.99-1.80(m,2H).

[0210] Example 27 [ka]

[0211] Step 1: Synthesis of compound 271-2 Under nitrogen gas protection, 5-bromo-1-methyl-1H-pyrrole-3-carboxylic acid (compound 271-1,100 mg, 0.490 mmol, 1 eq), zinc cyanide (57.55 mg, 0.490 mmol, 1 eq), tris(dibenzylideneacetone)dipalladium (44.88 mg, 0.049 mmol, 0.1 eq), 1,1'-bis(diphenylphosphine)ferrocene (27.07 mg, 0.049 mmol, 0.1 eq), and zinc powder (6.41 mg, 0.098 mmol, 0.2 eq) were added to the reaction flask. The compound was dissolved in N,N-dimethylacetamide (2 mL, 21.510 mmol), the temperature was raised to 120°C, and the mixture was stirred and reacted for 1 hour. After the reaction was complete, the mixture was filtered, the filtered cake was washed with ethyl acetate (10 mL), the obtained filtrate was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 12:1) to obtain compound 271-2 (40 mg, 27.34%). LCMS:(ESI,m / z):149.25 [M+H] + .

[0212] Step 2: Synthesis of 5-cyano-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (compound 271) Under nitrogen gas protection, 5-cyano-1-methyl-1H-pyrrole-3-carboxylic acid (compound 271-2, 9.87 mg, 0.066 mmol, 1.5 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) were added to the reaction flask, dissolved with N,N-dimethylformamide (1 mL, 12.922 mmol), stirred at room temperature for 10 minutes, and 2-(3-aminopropane-1-in-1-yl)- N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1.00 eq) was added, and the mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, backwashed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm * 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 31% B to 51% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.02), yielding compound 271, 5-cyano-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide.

[0213] LCMS:(ESI,m / z):516.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.69(t,J=5.6Hz,1H),7.73(d,J=1.8Hz,1H),7.36(d,J=1.8Hz,1H),7.29(dd,J=8.8,7.6 Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7.4Hz,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=4 9.4Hz,1H),4.33(d,J=5.6Hz,2H),3.82-3.70(m,6H),3.06(t,J=11.5Hz,1H),2.78(d,J= 11.3Hz,1H),2.36-2.24(m,1H),2.20(s,3H),2.12(t,J=10.9Hz,1H),1.97-1.82(m,2H).

[0214] Example 28 [ka]

[0215] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methyl-1H-pyrrole-3-carboxamide (compound 272) At room temperature, 5-methylpyrrole-3-carboxylic acid (9.87 mg, 0.079 mmol, 1.2 eq), N,N-diisopropylethylamine (33.99 mg, 0.264 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropa-1-in-1-yl)-N-(( Add 3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq), stir at room temperature for 1 hour, dilute with ethyl acetate (5 mL) after reaction, wash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 6% B to 32% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.03), yielding formate (5.4 mg, 16.68%) of compound 272, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methyl-1H-pyrrole-3-carboxamide.

[0216] LCMS:(ESI,m / z):491.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 10.93(s,1H),8.19(t,J=5.7Hz,1H),7.28(dd,J=8.7,7.6Hz,1H),7.18(dd,J=2.9,1.7Hz,1H), 7.02(d,J=8.7Hz,1H),6.31(d,J=7.5Hz,1H),6.27(d,J=8.9Hz,1H),6.17(s,1H),4.88(d,J=49 .3Hz,1H),4.28(d,J=5.7Hz,2H),3.96-3.81(m,1H),3.75(q,J=11.4Hz,2H),3.08(t,J=11.3Hz ,1H),2.80(d,J=11.3Hz,1H),2.43-2.27(m,1H),2.22(s,3H),2.16(s,4H),2.01-2.79(m,2H).

[0217] Example 29 [ka]

[0218] Step 1: Synthesis of Compound 273-2 At room temperature, 5-methyl-1H-pyrrole-3-carboxylic acid (compound 273-1, 200 mg, 1.598 mmol, 1 eq) was added to a reaction flask and dissolved with dimethyl sulfoxide (3 mL). Potassium hydroxide (717.42 mg, 12.784 mmol, 8 eq) was then added, and the mixture was stirred and reacted for 50 minutes. Methyl iodide (181.5 mg, 1.278 mmol, 0.8 eq) was added dropwise, and the mixture was stirred for 4 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 20 mL), and the aqueous phase was left. The aqueous phase was acidified to pH=1 with 4 mol / L hydrochloric acid, backwashed with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 273-2 (170 mg, 61.15%). The crude product was used directly in the next step. LCMS:(ESI,m / z):140.45 [M+H] + .

[0219] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1,5-dimethyl-1H-pyrrole-3-carboxamide (compound 273) At room temperature, 1,5-dimethyl-1H-pyrrole-3-carboxylic acid (compound 273-2, 9.15 mg, 0.066 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq), and diisopropylethylamine (34 mg, 0.264 mmol, 4 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (1 mL), stirred, and reacted for 30 minutes. Then, 2-(3-aminopropane-1-in-1-yl)-N-((3S, Add 4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq) and react for 1 hour. Dilute the reaction mixture with water (20 mL), extract with ethyl acetate (3 × 20 mL), combine the organic phases, backwash with saturated saline (3 × 20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH C18 OBD Prep Column 130,5μm,30mm * 150mm; Mobile phase A: Water (17 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 36% B to 54% B in 7 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 5.98), yielding compound 273, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1,5-dimethyl-1H-pyrrole-3-carboxamide (8.81 mg, 26.21%). LCMS:(ESI,m / z):505.10 [M+H] + .

[0220] Example 30 [ka]

[0221] Step 1: Synthesis of Compound 274-2 At room temperature, autoclave 50 mL with 3-bromo-6,7-dihydro-4H-pyrazolo[3,2-c][1,4]oxazine (compound 274-1,200 mg, 0.985 mmol, 1 eq), 1,3-bis(diphenylphosphine)propane (40.63 mg, 0.099 mmol, 0.1 eq), palladium acetate (22.11 mg, 0.099 mmol, 0.1 eq), anhydrous methanol (2.0 mL), and N,N-dimethylformamide. 2.0 mL of iodine and 1.0 mL of triethylamine were added, and after the addition was complete, carbon monoxide (3-4 MPa) was packed into the system and stirred overnight at 140°C. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography under the following conditions: (40 g C18 reversed-phase column, mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, gradient from 5% to 30% over 30 minutes, detection wavelength: UV 254 nm). Compound 274-2 (110 mg, 61.30%) was obtained. LCMS:(ESI,m / z):183.05 [M+H] + .

[0222] Step 2: Synthesis of Compound 274-3 Under nitrogen gas protection, sodium hydroxide (21.95 mg, 0.548 mmol, 2 eq) was added to a solution of 6,7-dihydro-4H-pyrazolo[3,2-c][1,4]oxazine-3-carboxylate methyl (compound 274-2, 50 mg, 0.274 mmol, 1 eq) in water (0.5 mL) and methanol (1.0 mL), and the mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was acidified to pH=6 with hydrochloric acid solution, the resulting residue was concentrated under reduced pressure, the reaction mixture was dissolved in tetrahydrofuran (2 mL), filtered, the filter cake was washed with tetrahydrofuran (3 × 1 mL), and the filtrate was concentrated under reduced pressure to obtain compound 274-3 (40 mg, 86.67%). LCMS:(ESI,m / z):169.05 [M+H] + .

[0223] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide (compound 274) Under nitrogen gas protection, a solution of 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 6,7-dihydro-4H-pyrazolo[3,2-c][1,4]oxazine-3-carboxylic acid (compound 274-3, 11.06 mg, 0.066 mmol, 1.5 eq) in N,N-dimethylformamide (0.8 mL) was measured. N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise, and the mixture was stirred and reacted for 1 hour. Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added, and the mixture was stirred for another hour. After the reaction was complete, methanol (1.0 mL) was added to quench the mixture, and the solvent was rotated dry. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH C18 OBD Prep Column 130,5μm,30mm×150mm; Mobile phase A: Water (17 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 30% B to 48% B in 8 min; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 6.98), yielding compound 274, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide.

[0224] LCMS:(ESI,m / z):534.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.71(t,J=5.6Hz,1H),8.00(s,1H),7.29(t,J=8.2Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7.7Hz, 1H),6.22(d,J=9.1Hz,1H),4.98(s,2H),4.87(d,J=49.4Hz,1H),4.32(d,J=5.6Hz,2H),4.13(t,J=5. 0Hz,2H),4.04(t,J=5.0Hz,2H),3.92-3.82(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=11.5Hz,1H), 2.78(d,J=11.4Hz,1H),2.36-2.21(m,1H),,2.20(s,3H),2.13(t,J=10.5Hz,1H),1.99-1.79(m,1H).

[0225] Example 31 [ka]

[0226] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-(6-morpholine-4-yl)pyridine-3-carboxamide (compound 275) Under nitrogen gas protection, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 6-(morpholine-4-yl)pyridine-3-carboxylic acid (13.69 mg, 0.066 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (0.8 mL) and N,N-diisopropylethyl Add amine (28.32 mg, 0.220 mmol, 5 eq) dropwise, stir, and react for 1 hour. Then, at room temperature, add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), continue stirring for 1 hour, and after the reaction is complete, add methanol (1.0 mL) to the reaction mixture to quench, rotate dry the solvent, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH Shield RP18 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 34% B to 54% B in 8 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.65), yielded compound 275, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-(6-morpholin-4-yl)pyridine-3-carboxamide (14.07 mg, 55.63%).

[0227] LCMS:(ESI,m / z):574.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.88(t,J=5.5Hz,1H),8.66(d,J=2.4Hz,1H),8.01(dd,J=9.0,2.5Hz,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J =8.5Hz,1H),6.88(d,J=9.0Hz,1H),6.32(d,J=7.5Hz,1H),6.23(d,J=9.1Hz,1H),4.87(d,J=49.5Hz,1H),4.37(d ,J=5.5Hz,2H),3.92-3.82(m,1H),3.75(q,J=11.1Hz,2H),3.69(t,J=4.9Hz,4H),3.57(t,J=4.9,4H),3.05(t,J= 11.3Hz,1H),2.78(d,J=11.5Hz,1H),2.36-2.23(m,1H),2.20(s,3H),2.13(t,J=11.0Hz,1H),1.99-1.80(m,2H).

[0228] Example 32 [ka]

[0229] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-4,5,6,7-tetrahydropyrazo[1,5-a]pyridine-3-carboxamide (compound 276) At room temperature, add 4,5,6,7-tetrahydropyrazo[1,5-a]pyridine-3-carboxylic acid (8.74 mg, 0.053 mmol, 1.2 eq), N,N-diisopropylethylamine (0.04 mL, 0.220 mmol, 5 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) to a reaction flask, stir with N,N-dimethylformamide (2 mL) solution at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl) Add (L)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), stir for 1 hour, dilute with ethyl acetate (5 mL) after the reaction is complete, wash the reaction mixture with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH C18 OBD Prep Column 130,5μm,30mm×150mm; Mobile phase A: Water (17 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 33% B to 53% B in 7 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 6.07), yielding compound 276, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-4,5,6,7-tetrahydropyrazo[1,5-a]pyridine-3-carboxamide (5.43 mg, 22.33%).

[0230] LCMS:(ESI,m / z):531.85 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.50(t,J=5.6Hz,1H),7.91(s,1H),7.29(t,J=8.2Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7. 6Hz,1H),6.23(d,J=8.9Hz,1H),4.88(d,J=49.4Hz,1H),4.31(d,J=5.6Hz,2H),4.06(t,J=6.0Hz ,2H),3.94-3.83(m,1H),3.85(q,J=11.2Hz,2H),3.06(t,J=11.2Hz,1H),2.99(t,J=6.4Hz,2H) ,2.78(d,J=10.8Hz,1H),2.38-2.23(m,1H),2.20(s,3H),2.09-2.08(m,1H),2.00-1.71(m,6H).

[0231] Example 33 [ka]

[0232] Step 1: Synthesis of Compound 039-1 Under nitrogen gas protection, cesium carbonate (2.09 g, 6.423 mmol, 3 eq) and potassium iodide (177.68 mg, 1.071 mmol, 0.5 eq) were gradually added to a solution of ethyl 1H-pyrazole-4-carboxylate (compound 006-1,300 mg, 2.141 mmol, 1 eq) and 1-chloro-2-methyl-2-propanol (348.62 mg, 3.212 mmol, 1.5 eq) in acetonitrile (4.5 mL) and stirred overnight at 80°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, filtered, and the filter cake was washed with acetonitrile (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 10:1) to obtain compound 039-1 (450 mg, 84.89%). LCMS:(ESI,m / z):213.00 [M+H] + .

[0233] Step 2: Synthesis of Compound 039-2 Under nitrogen gas protection, at 0°C, add sodium hydride (45.23 mg, 1.884 mmol, 2 eqs) to a solution of ethyl 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylate (compound 039-1,200 mg, 0.942 mmol, 1 eq) in N,N-dimethylformamide (4.0 mL), stir, and react for 30 minutes. Then, add methyl iodide (267.5 mg, 1.884 mmol, 2 eqs) dropwise, and at room temperature. The mixture was stirred for 2 hours, and after the reaction was complete, 20 mL of ice water at room temperature was added to the reaction mixture to quench it. Extraction was performed with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 20:1) to obtain compound 039-2 (130 mg, 60.97%). LCMS:(ESI,m / z):227.00 [M+H] + .

[0234] Step 3: Synthesis of Compound 039-3 Under nitrogen gas protection at room temperature, a solution of 1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxylate ethyl (compound 039-2, 130 mg, 0.575 mmol, 1 eq) was added dropwise to a solution of sodium hydroxide (45.96 mg, 1.150 mmol, 2 eq) in water (0.5 mL). The mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was acidified to pH=5 with hydrochloric acid. The resulting residue was concentrated under reduced pressure, further dissolved in tetrahydrofuran (3.0 mL), filtered, and the filter cake was washed with tetrahydrofuran (3 × 3 mL). The filtrate was concentrated under reduced pressure to obtain compound 039-3 (100 mg, 87.81%). LCMS:(ESI,m / z):199.00 [M+H] + .

[0235] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxamide (compound 039) Under nitrogen gas protection at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (compound 039-3, 13.03 mg, 0.066 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (0.8 mL), N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise, and the mixture was stirred and reacted for 1 hour. Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added at room temperature, and the mixture was stirred for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to the reaction mixture at room temperature to quench it, and the mixture was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 33% B to 63% B in 8 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 7.1), yielding compound 039, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxamide (20.93 mg, 83.80%).

[0236] LCMS:(ESI,m / z):564.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.70(t,J=5.5Hz,1H),8.11(s,1H),7.86(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.7Hz,1H ),6.32(d,J=7.4Hz,1H),6.24(d,J=9.0Hz,1H),4.87(d,J=49.6Hz,1H),4.33(d,J=5.6Hz,2H),4.15 (s,2H),3.94-3.82(m,1H),3.75(q,J=11.1Hz,2H),3.18(s,3H),3.04(t,J=10.1,1H),2.78(d,J=11 .4Hz,1H),2.36-2.23(m,1H),2.20(s,3H),2.13(t,J=11.1Hz,1H),1.99-1.80(m,2H),1.07(s,6H).

[0237] Example 34

change

[0238] No. 1 Structural Research: Synthesis of Compound 277-1 Under nitrogen gas protection, at 0°C, sodium hydride (76.72 mg, 3.196 mmol, 2 eqs) was added to a solution of pyrazole-4-carboxylate methyl (compound 014-1, 200 mg, 1.598 mmol, 1 eq) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature and reacted for 30 minutes. Then, bromoethane (348.34 mg, 3.196 mmol, 2 eqs) dissolved in tetrahydrofuran (2 mL) was added dropwise at 0°C, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched at room temperature with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain compound 277-1 (240 mg, 98.02%). LCMS:(ESI,m / z):154.10 [M+H] + .

[0239] Step 2: Synthesis of Compound 277-2 At 50°C, methyl 1-ethyl-1H-pyrrole-3-carboxylate (compound 277-1, 20 mg, 0.131 mmol, 1 eq) and sodium hydroxide (5.22 mg, 0.131 mmol, 1 eq) were added to a reaction flask in methanol (1 mL) and water (1 mL). The mixture was stirred and allowed to react for 1 hour. After the reaction was complete, the reaction mixture was adjusted to pH=5 with a 1 mol / L hydrochloric acid solution, and then concentrated under vacuum to obtain compound 277-2 (15 mg, 82.56%). LCMS:(ESI,m / z):140.15 [M+H] + .

[0240] Step 3: Synthesis of 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrrole-3-carboxylic acid amide (compound 277) At room temperature, add 1-ethyl-1H-pyrrole-3-carboxylic acid (compound 277-2, 6.1 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) in a solution of N,N-dimethylformamide (1 mL) to a reaction flask, stir, and react for 30 minutes. Then, add 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluorinated methyl phosphate. (L-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (3 × 30 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL / min; elution gradient: 36% to 51% in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.22), yielding compound 277, 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrrole-3-carboxylic acid amide (13.84mg, 62.27%).

[0241] LCMS:(ESI,m / z):505.15 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.31(t,J=5.7Hz,1H),7.38(t,J=2.0Hz,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.6Hz,1H),6.79(t,J=2.5Hz,1H ),6.48(dd,J=2.9,1.8Hz,1H),6.31(d,J=7.3Hz,1H),6.25(d,J=9.0Hz,1H),4.87(d,J=49.1Hz,1H),4.29(d,J=5.6Hz, 2H),3.93(q,J=7.2Hz,2H),3.88-3.80(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=11.8Hz,1H),2.78(d,J=11.4Hz,1H) ,2.37-2.23(m,1H),2.20(s,3H),2.12(t,J=11.1Hz,1H),2.00-1.87(m,1H),1.86-1.79(m,1H),1.32(t,J=7.3Hz,3H).

[0242] Example 35 [ka]

[0243] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methylfuran-3-carboxamide (compound 278) At room temperature, add 5-methylfuran-3-carboxylic acid (8.29 mg, 0.066 mmol, 1.5 eq), N,N-diisopropylethylamine (0.03 mL, 0.176 mmol, 4 eq), and a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) in N,N-dimethylformamide (1 mL) to a reaction flask, stir at room temperature for 10 minutes, and then add 2-(3-aminopropa-1-in-1-yl)-N-((3S Add (4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1.00 eq), stir for 1 hour, and after the reaction is complete, dilute the reaction mixture with ethyl acetate (5 mL), wash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm * 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 31% B to 51% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.98); compound 278, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methylfuran-3-carboxamide (5.2 mg, 23.87%) was obtained.

[0244] LCMS:(ESI,m / z):492.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.70(t,J=5.6Hz,1H),8.05(s,1H),7.29(t,J=8.2Hz),7.03(d,J=8.7Hz,1H),6.48(s,1H),6. 32(d,J=7.7Hz,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.32(d,J=5.6Hz,2H),3.9 8-3.82(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=10.8Hz,1H),2.78(d,J=11.4Hz,1H),2.33( d,J=12.9Hz,1H),2.29-2.25(m,3H),2.20(s,3H),2.14(t,J=10.5Hz,1H),1.99-1.80(m,2H).

[0245] Example 36 [ka]

[0246] Step 1: Synthesis of Compound 021-1 Under nitrogen gas protection at room temperature, ethyl 1H-pyrazole-4-carboxylate (compound 006-1,500 mg, 3.568 mmol, 1 eq), concentrated sulfuric acid (220 μL, 4.086 mmol, 1.15 eq, 99%), and 2-methyl-2-butanol (3.06 mL, 27.652 mmol, 7.75 eq) solution were added to a reaction flask, and the mixture was stirred overnight at 90°C. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the resulting residue was purified by reverse-phase column chromatography under the following conditions (C18 column, mobile phase: petroleum ether and ethyl acetate, gradient from 0% to 30% over 15 minutes, detection wavelength: UV 254 nm) to obtain compound 021-1 (270 mg, 41.53%). LCMS:(ESI,m / z):211.00 [M+H] + .

[0247] Step 2: Synthesis of Compound 021-2 At room temperature, ethyl 1-(2-methylbutan-2-yl)pyrazole-4-carboxylate (compound 021-1, 270 mg, 1.284 mmol, 1 eq) and lithium hydroxide (61.5 mg, 2.568 mmol, 2 eq) were added to a reaction flask in tetrahydrofuran (2 mL) and water (1 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under vacuum, the residue was dissolved in tetrahydrofuran (10 mL), filtered by suction, and the filtrate was concentrated under vacuum to obtain compound 021-2 (240 mg, 93.44%). LCMS:(ESI,m / z):183.00 [M+H] + .

[0248] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methylbutan-2-yl)-1H-pyrazole-4-carboxamide (compound 021) At room temperature, add 1-(2-methylbutan-2-yl)pyrazole-4-carboxylic acid (compound 021-2, 23.96 mg, 0.132 mmol, 2 eq), N,N-diisopropylethylamine (33.99 mg, 0.264 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) in a solution of N,N-dimethylformamide (1.2 mL) to a reaction flask, stir for 10 minutes, and then add 2-(3-aminopropane-1-in-1-yl) -N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1.00 eq) was added, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Kinetex). 5μm EVO C18, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 35% B to 54% B in 7 minutes; Detection wavelength: UV 254 nm / 226 nm; Retention time (minutes): 6.55), yielded N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methylbutan-2-yl)-1H-pyrazole-4-carboxamide (14.31 mg, 39.55%) of compound 021.

[0249] LCMS:(ESI,m / z):548.25 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.63(t,J=5.5Hz,1H),8.29(s,1H),7.91(s,1H),7.29(dd,J=8.8,7.6Hz,1H),7.03(d,J=8.7Hz,1H),6. 32(d,J=7.5Hz,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.34(d,J=5.6Hz,2H),3.93-3.81(m, 1H),3.76(q,J=11.1Hz,2H),3.05(t,J=11.0Hz,1H),2.78(d,J=11.3Hz,1H),2.38-2.22(m,1H),2.20(s ,3H),2.13(t,J=10.6Hz,1H),2.01-1.88(m,1H),1.86-1.77(m,3H),1.50(s,6H),0.59(t,J=7.4Hz,3H).

[0250] Example 37 [ka]

[0251] Step 1: Synthesis of Compound 248-2 At room temperature, 1H-pyrazole-4-carboxylate tert-butyl (compound 248-1,200 mg, 1.189 mmol, 1 eq) was dissolved in acetonitrile (2 mL), to which bromoacetonitrile (171.16 mg, 1.427 mmol, 1.2 eq) and potassium carbonate (493.01 mg, 3.567 mmol, 3 eq) were added. The mixture was stirred at 85°C for 2 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with acetonitrile (3 × 50 mL), and the filtrate was concentrated under reduced pressure. The crude product was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 248-2 (265 mg), which was used directly in the next step without further purification. LCMS:(ESI,m / z):208.00 [M+H] + .

[0252] Step 2: Synthesis of Compound 248-3 At 0°C, add methyl iodide (890.4 mg, 6.275 mmol, 5 eq) to a solution of 1-(cyanomethyl)-1H-pyrazole-4-carboxylate tert-butyl (compound 248-2,260 mg, 1.255 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) and then slowly add lithium bistrimethylsilylamide (629.81 mg, 3.765 mmol, 3 eq) dropwise. Raise the temperature to room temperature and allow to react for 1 hour. After the reaction is complete, the reaction mixture is saturated at 0°C. The solution was quenched with ammonium chloride, diluted with water (20 mL), extracted with ethyl acetate (3 × 20 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by reversed-phase column chromatography under the following conditions (column specifications: 40 g, mobile phase: 0.001% trifluoroacetic acid and acetonitrile, gradient from 10% to 80% over 15 minutes, detection wavelength: UV 254 nm), yielding compound 248-3 (190 mg, 61.79%). LCMS:(ESI,m / z):236.00[M+H] + .

[0253] Step 3: Synthesis of Compound 248-4 At room temperature, trifluoroacetic acid (0.5 mL) was added to a solution of 1-(1-cyano-1-methylethyl)-1H-pyrazole-4-carboxylate tert-butyl (compound 248-3, 30 mg, 0.128 mmol, 1 eq) in dichloromethane (1.5 mL), and the mixture was stirred and reacted for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product compound 248-4 (30 mg, 59.70%), which was used directly in the next step without further purification. LCMS:(ESI,m / z):180.00 [M+H] + .

[0254] Step 3: Synthesis of 1-(1-cyano-1-methylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 248) At room temperature, to a solution of 1-(1-cyano-1-methylethyl)-1H-pyrazole-4-carboxylic acid (compound 248-4, 11.78 mg, 0.066 mmol, 1 eq) in N,N-dimethylformamide (1 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) and diisopropylethylamine (33.99 mg, 0.264 mmol, 4 eq) were added, and the mixture was stirred and reacted for 30 minutes. After that, 2-(3-aminopropane-1-in-1-yl)-N-((3S,4 Add (R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq) and continue reacting for 1 hour. After the reaction is complete, dilute the reaction mixture with water (20 mL), extract with ethyl acetate (3 × 20 mL), combine the organic phases, backwash with saturated saline (3 × 20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). Using a BEH Shield RP18 5μm, 30mm * 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 36% B to 54% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.17), compound 248, 1-(1-cyano-1-methylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (15.7 mg, 43.41%), was obtained.

[0255] LCMS:(ESI,m / z):545.25 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.81(t,J=5.5,5.5Hz,1H),8.53(s,1H),8.07(s,1H),7.29(t,J=8.8,7.6Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d, J=7.4Hz,1H),6.21(d,J=9.1Hz,1H),4.87(d,J=49.5Hz,1H),4.36(d,J=5.5Hz,2H),3.93-3.82(m,1H),3.76(q,J= 11.2Hz,2H),3.05(t,J=10.8Hz,1H),2.78(d,J=11.0Hz,1H),2.25-2.37(m,1H),2.20(s,3 H),2.13(t,J=10.3Hz,1H),1.99(s,6H),1.92(kdd,J=11.9,3.5Hz,1H),1.82-1.88(m,1H).

[0256] Example 38

change

[0257] No. 1 Structural: Synthesis of Compound 146-2 At room temperature, 3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (compound 146-1,250 mg, 1.162 mmol, 1 eq), palladium acetate (13.05 mg, 0.058 mmol, 0.05 eq), 1,3-bis(diphenylphosphine)propane (23.97 mg, 0.058 mmol, 0.05 eq), triethylamine (823.3 mg, 8.134 mmol, 7 eq), and methanol (2 mL) were added to the reaction flask, and then N,N-dimethylformamide (2 mL) was added. In addition, carbon monoxide was packed into the mixture, and the reaction was carried out overnight at 140°C under a pressure of 4 MPa. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (3 × 10 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by reversed-phase column chromatography under the following conditions (40 g C18 reversed-phase column, mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, gradient from 5% to 30% over 10 minutes, detection wavelength: UV 254 nm), yielding compound 146-2 (100 mg, 44.30%). LCMS:(ESI,m / z):195.05 [M+H] + .

[0258] Step 2: Synthesis of Compound 146-3 At room temperature, a solution of methyl 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (compound 146-2, 50 mg, 0.257 mmol, 1 eq) and sodium hydroxide (20.59 mg, 0.514 mmol, 2 eq) in methanol (1 mL) and water (1 mL) was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH=5 with a 1 mol / L hydrochloric acid solution, extracted with ethyl acetate (3 × 10 mL), combined with the organic phase, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 146-3 (40 mg, 86.23%). LCMS:(ESI,m / z):181.10 [M+H] + .

[0259] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]-1Hpyrazole-3-carboxamide (compound 146) At room temperature, first, a solution of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (compound 146-3, 7.9 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) in N,N-dimethylformamide (1 mL) is stirred and reacted for 30 minutes. Then, 2-(3-aminopropa-1-in-1-yl)-N-((3S Add (4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), stir continuously, and react for 2 hours. After the reaction is complete, quench the reaction mixture with water at room temperature, extract with ethyl acetate (3 × 10 mL), combine the organic phases, backwash with saturated sodium chloride solution (3 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; Mobile phase A: Water (0.1% ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Elution gradient: 32% to 58% in 8 minutes; Detection wavelength: UV 254nm / 220nm; Retention time (minutes): 7.63), yielding compound 146, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (14.94mg, 61.91%).

[0260] LCMS:(ESI,m / z):546.15 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.47(t,J=5.6Hz,1H),7.91(s,1H),7.28(dd,J=8.7,7.6Hz,1H),7.03(d,J=8.6Hz,1H),6.3 2(d,J=7.6Hz,1H),6.24(d,J=9.0Hz,1H),4.87(d,J=49.4Hz,1H),4.30(d,J=5.6Hz,2H),3.8 5(s,3H),3.76(q,J=11.1Hz,2H),3.05(t,J=11.4Hz,1H),2.84(s,2H),2.78(d,J=11.4Hz,1 H),2.36-2.21(m,1H),2.20(s,3H),2.13(t,J=10.6Hz,1H),1.99-1.78(m,2H),1.22(s,6H).

[0261] Example 39 [ka]

[0262] Step 1: Synthesis of Compound 279-2 Under air protection, a solution of pyrazole-4-carboxylate methyl (compound 014-1,500 mg, 3.996 mmol, 1 eq) and 2-bromoethyl methyl ether (1.11 g, 7.992 mmol, 2 eq) in dimethyl sulfoxide (5 mL) was stirred at room temperature and allowed to react overnight. After the reaction was complete, the reaction mixture was extracted with dichloromethane (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 279-1 (600 mg, 81.96%). LCMS:(ESI,m / z):170.00 [M+H] + .

[0263] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(methoxyethyl)-1H-pyrrole-3-carboxamide (compound 279) At room temperature, 1-(2-methoxyethyl)pyrrole-3-carboxylic acid (compound 279-1, 6.62 mg, 0.039 mmol, 1.5 eq) is dissolved in N,N-dimethylformamide (1 mL), to which 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.84 mg, 0.052 mmol, 2 eq) is added, and the mixture is stirred and reacted for 10 minutes. Further reaction is carried out using (3S,4R)-N-[2-(3-aminopropane-1-in-1-yl)- Add 3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-7-yl]-3-fluoro-1-methylpiperidine-4-amine (10 mg, 0.026 mmol, 1.00 eq), stir, and react for 90 minutes. Extract the reaction mixture with ethyl acetate (3 × 10 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 17% B to 35% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.42), yielding compound 279, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(methoxyethyl)-1H-pyrrole-3-carboxamide (6.14 mg, 18.00%).

[0264] LCMS:(ESI,m / z):535.00 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.33(t,J=5.6Hz,1H),7.36(t,J=1.9Hz,1H),7.28(t,J=8.2Hz,1H),7.02(d,J=8.6Hz,1H),6.77(t,J=2.6Hz,1H),6.47 (dd,J=2.7,1.8Hz,1H),6.31(dd,J=7.9Hz,1H),6.27(d,J=8.9Hz,1H),4.88(d,J=49.6Hz,1H),4.29(d,J=5.5Hz,2H),4 .06(t,J=5.2Hz,2H),3.91-3.83(m,1H),3.75(q,J=11.3Hz,2H),3.58(t,J=5.2Hz,2H),3.23(s,3H),3.13-3.02(m,1H) ,2.80(d,J=10.2Hz,1H),2.41-2.26(m,1H),2.22(s,3H),2.15(t,J=10.5Hz,1H),2.02-1.90(m,1H),1.88-1.79(m,1H).

[0265] Example 40 [ka]

[0266] Step 1: Synthesis of Compound 280-1 Under oxygen gas protection, at 70°C, a solution of pyrazole-4-carboxylate methyl (compound 014-1,500 mg, 3.996 mmol, 1 eq), sodium carbonate (423.52 mg, 3.996 mmol, 1 eq), cyclopropylboronic acid (686.5 mg, 7.992 mmol, 2 eq), anhydrous copper acetate (725.8 mg, 3.996 mmol, 1 eq), and 2,2'-bipyridine (624.1 mg, 3.996 mmol, 1 eq) in 1,2-dichloroethane (5 mL) was stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (3 × 20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 280-1 (250 mg, 37.87%). LCMS:(ESI,m / z):166.00 [M+H]+ .

[0267] Step 2: Synthesis of Compound 280-2 To a methanol (0.5 mL) / water (0.5 mL) solution of methyl 1-cyclopropylpyrrole-3-carboxylate (compound 280-1, 50 mg, 0.303 mmol, 1 eq), lithium hydroxide (21.75 mg, 0.909 mmol, 3 eq) was added and the mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was acidified to pH=3 with hydrochloric acid solution, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 280-2 (43 mg, 93.98%). LCMS:(ESI,m / z):151.00 [M+H] + .

[0268] Step 3: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroacetate)pyrazolo[1,5-a]pyridine-2-yl)-propa-2-in-1-yl]-1H-pyrrole-3-carboxamide (compound 280) 1-Cyclopropylpyrrole-3-carboxylic acid (compound 280-2, 10 mg, 0.066 mmol, 1.5 eq), 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), N,N-diisopropyl A solution of ethylamine (28.5 mg, 0.220 mmol, 5 eq) in N,N-dimethylformamide (1 mg, 0.014 mmol, 0.21 eq) was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm * 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 40% B to 59% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.98), yielding compound 280, 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroacetate)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrrole-3-carboxamide (19.36 mg, 47.66%).

[0269] LCMS:(ESI,m / z):517.00 [M+H] + . 1H(400MHz,DMSO-d6,ppm)δ 8.32(t,J=5.6Hz,1H),7.39(t,J=2.0Hz,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.7Hz,1H),6.81(t,J=2.5 Hz,1H),6.45(dd,J=2.9,1.8Hz,1H),6.31(d,J=7.4Hz,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=49.9Hz,1H),4.29 (d,J=5.6Hz,2H),3.91-3.81(m,1H),3.75(q,J=11.2Hz,2H),3.50-3.43(m,1H),3.05(t,J=11.5Hz,1H),2.78(d ,J=11.3Hz,1H),2.36-2.24(m,1H),2.20(s,3H),2.13(t,J=10.5Hz,1H),2.00-1.84(m,2H),0.94-0.85(m,4H).

[0270] Example 41 [ka]

[0271] Step 1: Synthesis of Compound 260-2 At room temperature, 2-pyrrolecarboxaldehyde (compound 260-1, 2g, 21.030 mmol, 1eq), methyl 3-bromopropionate (7.02g, 42.060 mmol, 2eq), and cesium carbonate (20.56g, 63.090 mmol, 3eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (20.0mL, 258.459 mmol, 12.29eq), reacted at 80°C for 1 hour, quenched with water, extracted with ethyl acetate (3 × 20mL), combined the organic phases, backwashed with saturated sodium chloride solution (1 × 10mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the resulting residue by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain compound 260-2 (2.4g, 59.83%). LCMS:(ESI,m / z):182.05 [M+H] + .

[0272] Step 2: Synthesis of Compound 260-3 At room temperature, methyl 3-(2-formylpyrrole-1-yl)propanoate (compound 260-2, 1 g, 5.519 mmol, 1 eq) and sodium ethoxide (0.33 g, 6.071 mmol, 1.1 eq) were added to a reaction flask, dissolved in ethanol (10.0 mL), and the mixture was reacted overnight at 50°C. After the reaction was complete, water was added to quench the reaction mixture, and the reaction mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 260-3 (210 mg, 22.15%). LCMS:(ESI,m / z):164.10 [M+H] + .

[0273] Step 3: Synthesis of Compound 260-4 At room temperature, methyl 3H-pyrrolidine-6-carboxylate (compound 260-3, 1,100 mg, 0.613 mmol, 1 eq) and rhodium carbon (25.23 mg, 0.245 mmol, 0.4 eq) were added to a reaction flask, dissolved in ethanol (5 mL), and stirred under a hydrogen atmosphere at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound 260-4 (98.7 mg, 97.50%). LCMS:(ESI,m / z):166.05 [M+H] + .

[0274] Step 4: Synthesis of Compound 260-5 At room temperature, methyl 2,3-dihydro-1H-pyrrolidine-6-carboxylate (compound 260-4, 50 mg, 0.303 mmol, 1 eq) was added to a reaction flask and dissolved in methanol (1 mL, 24.699 mmol, 81.60 eq). Further, a solution of sodium hydroxide (48.42 mg, 1.212 mmol, 4 eq) in water (2 mL) was added, and the mixture was reacted overnight at 50°C. After the reaction was complete, the solution was neutralized with 3 M hydrochloric acid. The resulting residue was concentrated under reduced pressure, dissolved in tetrahydrofuran solution (5 mL), filtered, dried over anhydrous sodium sulfate, filtered again, and the filtrate was concentrated under reduced pressure to obtain compound 260-5 (35 mg, 72.59%). LCMS:(ESI,m / z):152.00 [M+H] + .

[0275] Step 5: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-2,3-dihydro-1H-pyrrolidine-6-carboxamide (compound 260) At room temperature, 2,3-dihydro-1H-pyrrolidine-6-carboxylic acid (compound 260-5, 13.25 mg, 0.088 mmol, 2 eq), N,N-diisopropylethylamine (22.66 mg, 0.176 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (1 mL), stirred for 10 minutes, and then 2-(3-aminopropa-1-in-1-yl)-N -((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1.00 eq) was added, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 12% B to 34% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.48), compound 260, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-2,3-dihydro-1H-pyrrolidine-6-carboxamide (9.86 mg, 39.71%), was obtained. LCMS:(ESI,m / z):517.15 [M+H] + .

[0276] Example 42 [ka]

[0277] Step 1: Synthesis of compound 281-2 Under nitrogen gas protection, 4-bromo-1H-pyrrole-2-formaldehyde (compound 281-1, 5g, 28.736 mmol, 1eq), 2-bromoethanol (5.39g, 43.104 mmol, 1.5eq), and cesium carbonate (18.73g, 57.472 mmol, 2eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (10mL), and reacted with stirring at 80°C for 1 hour. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (50mL x 2), the organic phase was combined, backwashed with saturated sodium chloride solution (50mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 281-2 (4g, 63.65%). LCMS:(ESI,m / z):219.95 [M+H] + .

[0278] Step 2: Synthesis of Compound 281-3 Under nitrogen gas protection, 4-bromo-1-(2-hydroxyethyl)-1H-pyrrole-2-formaldehyde (compound 281-2, 3.3 g, 15.134 mmol, 1 eq) and triethylamine (6.31 mL, 45.402 mmol, 3 eq) were added to a reaction flask and dissolved with dichloromethane (20 mL). At 0°C, p-toluenesulfonyl chloride (3.46 g, 18.161 mmol, 1.2 eq) was added and the mixture was stirred at room temperature and allowed to react overnight. After the reaction was complete, the reaction mixture was quenched at 0°C with ice water (15 mL), extracted with dichloromethane (20 mL x 3), the organic phases were combined, backwashed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 281-3 (3 g, 42.44%).

[0279] Step 3: Synthesis of Compound 281-4 Under nitrogen gas protection, 2-(4-bromo-2-formyl-1H-pyrrole-1-yl)ethyl-4-methylbenzenesulfonate (compound 281-3, 2g, 5.373 mmol, 1eq) was added to a reaction flask and dissolved in anhydrous ethanol (10 mL). Sodium borohydride (101.63 mg, 2.687 mmol, 0.5 eq) was added at 0°C and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, ice water (10 mL) was added to the reaction mixture at 0°C to quench it, and the mixture was concentrated under reduced pressure. 20 mL of dichloromethane was added, the mixture was stirred for 5 minutes, and the mixture was filtered to obtain compound 281-4 (1.5 g, 62.21%).

[0280] Step 4: Synthesis of Compound 281-5 Under nitrogen gas protection, 2-(4-bromo-2-(hydroxymethyl)-1H-pyrrole-1-yl)ethyl-4-methylbenzenesulfonate (compound 281-4, 1 g, 2.672 mmol, 1 eq) was added to the reaction flask and dissolved with tetrahydrofuran (10 mL, 123.428 mmol). Sodium hydride (76.95 mg, 3.206 mmol, 1.2 eq) was added at 0°C and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with ice water at 0°C, and the mixture was purified by reverse-phase column chromatography under the following conditions (column specifications: mobile phase: water and acetonitrile, gradient from 10% to 45% over 20 minutes, detection wavelength: UV 254 nm) to obtain compound 281-5 (160 mg, 22.05%). LCMS:(ESI,m / z):201.95 [M+H] + .

[0281] Step 5: Synthesis of Compound 281-6 Add 7-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (compound 281-5, 160 mg, 0.792 mmol, 1 eq), palladium acetate (17.78 mg, 0.079 mmol, 0.1 eq), 1,3-bis(diphenylphosphine)propane (65.32 mg, 0.158 mmol, 0.2 eq), and triethylamine (560.93 mg, 5.544 mmol, 7 eq) to a 20 mL autoclave. The compound was dissolved in water-methanol (3 mL, 74.096 mmol, 93.57 eq) and N,N-dimethylformamide (3 mL, 38.765 mmol). The autoclave was packed with carbon monoxide at 4 MPa, the temperature was raised to 140°C, and the mixture was stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography under the following conditions (column specifications: mobile phase: water and acetonitrile, gradient from 5% to 20% over 15 minutes, detection wavelength: UV 254 nm), yielding compound 281-6 (90 mg, 62.66%). LCMS:(ESI,m / z):182.00 [M+H] + .

[0282] Step 6: Synthesis of Compounds 281-7 Under nitrogen gas protection, 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylate methyl (compound 281-6, 80 mg, 0.442 mmol, 1 eq) and sodium hydroxide (35.32 mg, 0.884 mmol, 2 eq) were added to a reaction flask, dissolved in water (1 mL, 55.509 mmol) and anhydrous methanol (3 mL, 74.096 mmol), and the mixture was stirred at 50°C and allowed to react overnight. After the reaction was complete, the reaction mixture was acidified to pH=3 with a 1 mol / L hydrochloric acid solution, the mixture was concentrated under reduced pressure, 10 mL of dichloromethane was added, the mixture was stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 281-7 (70 mg, 90.38%). LCMS:(ESI,m / z):167.95 [M+H] + .

[0283] Step 7: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxamide (compound 281) Under nitrogen gas protection, 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid (compound 281-7, 13.19 mg, 0.079 mmol, 1.2 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.5 mg, 0.073 mmol, 1.1 eq), and N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction flask, dissolved with N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in- Add 1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1.00 eq), stir continuously, and react for 1 hour. After the reaction is complete, extract the reaction mixture with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (30 mL x 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 10% B to 32% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.05), compound 281, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxamide (13.62 mg, 38.08%), was obtained.

[0284] LCMS:(ESI,m / z):533.15 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.34(t,J=5.7Hz,1H),7.31-7.25(m,2H),7.02(d,J=8.6Hz,1H),6.31(d,J=7.6Hz,1H),6. 26-6.21(m,2H),4.87(d,J=49.5Hz,1H),4.70(s,2H),4.29(d,J=5.6Hz,2H),3.96(p,J=2. 0Hz,4H),3.91-3.81(m,1H),3.87-3.71(q,J=11.2Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d ,J=11.2Hz,1H),2.35-2.24(m,1H),2.20(s,3H),2.13(t,J=10.8Hz,1H,1.97-1.79(m,2H).

[0285] Example 43 [ka]

[0286] Step 1: Synthesis of Compound 282-2 Ethyl 2-acetyl-3-(dimethylamino)acrylate (compound 282-1, 1 g, 5.399 mmol, 1 eq) and cyclopropylhydrazine hydrochloride (586.16 mg, 5.399 mmol, 1 eq) were added to a reaction flask, dissolved in ethanol (8 mL), and reacted at 80°C for 2 hours. After the reaction was complete, the mixture was diluted with 10 mL of dichloromethane, washed with saturated sodium chloride solution (1 × 20 mL), dried over anhydrous sodium sulfate, and the solvent was rotated dry. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 282-2 (454 mg, 41.13%). LCMS:(ESI,m / z):195.10 [M+H] + .

[0287] Step 2: Synthesis of Compound 282-3 1-Cyclopropyl-5-methyl-1Hpyrazole-4-carboxylate ethyl (compound 282-2, 100 mg, 0.515 mmol, 1 eq) was added to a reaction flask and dissolved with methanol (3 mL). Sodium hydroxide (1 M) (1 mL, 1.0 mmol, 2 eq) was then added, and the mixture was reacted at 50°C for 10 hours. After the reaction was complete, the solvent was rotated dry, hydrochloric acid (1 M) was added to adjust the pH to acidic, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to directly obtain compound 282-3 (compound 282-3, 90 mg, 94.67%). LCMS:(ESI,m / z):167.05 [M+H] + .

[0288] Step 3: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)-pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methyl-1H-pyrazole-4-carboxamide (compound 282) The reaction flask contains 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylic acid (compound 282-3, 30 mg, 0.181 mmol, 1 eq), 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 69.21 mg, 0.181 mmol, 1 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. 102.96 mg, 0.271 mmol, 1.5 eq of phosphate and 116.66 mg, 0.905 mmol, 5 eq of N,N-diisopropylethylamine were added sequentially, dissolved with 2 mL of N,N-dimethylformamide, and reacted at room temperature for 1 hour. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 10% B to 33% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.8), yielding compound 282, 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)-pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-methyl-1H-pyrazole-4-carboxamide (34.25 mg, 35.58%).

[0289] LCMS:(ESI,m / z):532.55 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.53(t,J=5.6Hz,1H),7.83(s,1H),7.28(t,J=8.2Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7.6 Hz,1H),6.25(d,J=9.0Hz,1H),4.89(d,J=49.4Hz,1H),4.30(d,J=5.6Hz,2H),3.95-3.81(m,1H), 3.75(q,J=11.1Hz,2H),3.53(td,J=7.0,3.7Hz,1H),3.16-3.02(m,1H),2.81(d,J=11.3Hz,1H), 2.58(s,3H),2.42-2.28(m,1H),2.23(s,3H),2.18(s,1H),2.01-1.76(m,2H),1.07-0.96(m,4H).

[0290] Example 44 [ka]

[0291] Step 1: Synthesis of Compound 047-2 At room temperature, water (100 mL) was added to the reaction flask, and sodium hydroxide (11.36 g, 0.284 mol, 3.0 eq) was added while stirring. Then ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (compound 047-1, 20 g, 94.67 mmol, 1 equiv) was added, the temperature was raised to 60°C, and the mixture was stirred and allowed to react overnight. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to 2-2.5 with 4 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate (3 × 150 mL). The organic phases were combined, backwashed with saturated sodium chloride (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 047-2 (15.6 mg, 90.1%). LCMS:(ESI,m / z):183.95 [M+H] + .

[0292] Step 2: Synthesis of 5-amino-1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 047) At room temperature, 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid (compound 047-2, 20 mg, 0.109 mmol, 1 eq) and 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 41.85 mg, 0.109 mmol, 1.0 eq), O-(7-azabenzo A solution of riazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (45.66 mg, 0.120 mmol, 1.1 eq) and N,N-diisopropylethylamine (70.25 mg, 0.545 mmol, 5 eq) in N,N-dimethylformamide (2 mL) was stirred and reacted for 1 hour. After the reaction was complete, the resulting residue was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography under the following conditions (Column:Xselect Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 15% B to 31% B in 7 minutes; detection wavelength: 254 nm / 220 nm; retention time (minutes): 6.43), compound 047, 5-amino-1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (9.3 mg, 15.42%), was obtained.

[0293] LCMS:(ESI,m / z):549.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.31(t,J=5.6Hz,1H),7.65(s,1H),7.28(t,J=8.3Hz,1H),7.02(d,J=8.7Hz,1H),6.31(d,J=7.6 Hz,1H),6.25(d,J=9.0Hz,1H),6.18(s,2H),4.87(d,J=49.5Hz,1H),4.28(d,J=5.6Hz,2H),3.94- 3.81(m,1H),3.75(q,J=11.2Hz,2H),3.06(t,J=10.6Hz,1H),2.79(d,J=10.6Hz,1H),2.38-2.22 (m,1H),2.21(s,3H),2.14(t,J=10.7Hz,1H),1.98-2.85(m,1H),1.87-1.79(m,1H),1.52(s,9H).

[0294] Example 45 [ka]

[0295] Step 1: Synthesis of Compound 304-1 Under nitrogen gas protection at room temperature, a solution of ethyl 1H-pyrazole-4-carboxylate (compound 006-1, 1,180 mg, 1,284 mmol, 1 eq), 1(phenylsulfone)cyclopropan-1-ol (280.08 mg, 1,412 mmol, 1.1 eq), and triethylamine (129.97 mg, 1,284 mmol, 1 eq) in acetonitrile (18.00 mL) was stirred and reacted for 1 hour. After the reaction was complete, the resulting residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 304-1 (150 mg, 59.52%). LCMS:(ESI,m / z):197.05 [M+H] + .

[0296] Step 2: Synthesis of Compound 304-2 Under nitrogen gas protection, at -78°C, a solution of 1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxylate ethyl (compound 304-1, 130 mg, 0.663 mmol, 1 eq) and N,N-diethylaminosulfur trifluoride (160.20 mg, 0.995 mmol, 1.5 eq) in dichloromethane (2 mL) was stirred and reacted for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture at room temperature and quenched. Extraction was performed with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 304-2 (110 mg, 83.77%). LCMS:(ESI,m / z):199.35 [M+H] + .

[0297] Step 3: Synthesis of Compound 304-3 At 50°C, a solution of 1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxylate ethyl (compound 304-2, 130 mg, 0.656 mmol, 1 eq) and lithium hydroxide (78.55 mg, 3.280 mmol, 5 eq) in tetrahydrofuran (2 mL) and water (2 mL) was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH=5 with hydrochloric acid solution, extracted with ethyl acetate (3 × 30 mL), combined with the organic phase, backwashed with saturated sodium chloride (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 304-3 (100 mg, 89.61%). LCMS:(ESI,m / z):171.35 [M+H] + .

[0298] Step 4: Synthesis of N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxamide (compound 304) At room temperature, 1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxylic acid (compound 304-3, 20 mg, 0.118 mmol, 1 eq) and 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 45 mg, 0.118 mmol, 1 eq), 2-(7-a A solution of 44.7 mg, 0.118 mmol, 1 eq of zabenzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and 75.96 mg, 0.590 mmol, 5 eq of diisopropylethylamine in N,N-dimethylformamide (1.66 mL) was stirred and reacted for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography. The conditions were as follows (Column:XBridge Using a BEH Shield RP18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 15% B to 31% B in 7 minutes; detection wavelength: 254 nm / 220 nm; retention time (minutes): 6.43), compound 304, N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxamide (10.06 mg, 15.28%), was obtained.

[0299] LCMS:(ESI,m / z):535.85 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.86(t,J=5.4Hz,1H),8.63(s,1H),8.08(s,1H),7.29(t,J=8.2Hz,1H),7.03(d,J=8.7Hz,1 H),6.32(d,J=7.6Hz,1H),6.22(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.36(d,J=5.4Hz,2 H),3.93-3.70(m,3H),3.05(t,J=11.9Hz,1H),2.78(d,J=11.2Hz,1H),2.33(d,J=12.9Hz,1 H),2.20(s,3H),2.13(t,J=11.8Hz,1H),2.01-1.88(m,2H),1.76-1.62(m,2H),1.50(s,2H).

[0300] Example 46 [ka]

[0301] Step 1: Synthesis of Compound 286-2 Under nitrogen gas protection at room temperature, a solution of (2-methylpropyl)hydrazine hydrochloride (compound 286-1,300 mg, 2.408 mmol, 1 eq) and (2E)-2-cyano-3-ethoxyacrylate ethyl (448.03 mg, 2.649 mmol, 1.1 eq) in anhydrous ethanol (6.0 mL) was mixed with sodium acetate (197.5 mg, 2.408 mmol, 1 eq), and the mixture was stirred at 80°C for 2 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with anhydrous ethanol (3 × 4 mL), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 286-2 (250 mg, 49.15%). LCMS:(ESI,m / z):211.90 [M+H] + .

[0302] Step 2: Synthesis of Compound 286-3 Under nitrogen gas protection at room temperature, a solution of ethyl 5-amino-1-(2-methylpropyl)-1H-pyrazole-4-carboxylate (compound 286-2, 100 mg, 0.473 mmol, 1 eq) in anhydrous ethanol (1.0 mL) was added dropwise to a solution of sodium hydroxide (37.86 mg, 0.946 mmol, 2 eq) in water (0.5 mL), and the mixture was stirred overnight at 50°C. After the reaction was complete, the reaction mixture was acidified to pH=5 with hydrochloric acid solution (3 M), the resulting residue was concentrated under reduced pressure, the reaction mixture was dissolved in tetrahydrofuran (3 mL) and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 286-3 (100 mg). The obtained crude product was used directly in the next step without further purification. LCMS:(ESI,m / z):184.05 [M+H] + .

[0303] Step 3: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-1-isobutyl-1H-pyrazole-4-carboxamide (compound 286) Under nitrogen gas protection at room temperature, a small amount of N-hydroxybenzotriazole (35.54 mg, 0.262 mmol, 1.5 eq) and N,N-diisopropylethylamine (113.3 mg, 0.875 mmol, 5 eq) were added to a solution of 5-amino-1-(2-methylpropyl)-1H-pyrazole-4-carboxylic acid (compound 286-3, 51.39 mg, 0.280 mmol, 1.6 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.41 mg, 0.262 mmol, 1.5 eq) in N,N-dimethylformamide (1.5 mL). The compounds were added one by one and reacted for 1 hour. Then, at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 80 mg, 0.175 mmol, 1 eq) was added and the reaction was continued for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to the reaction mixture, the reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 17% B to 30% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 5.67), formate (26.9 mg, 25.75%) of compound 286, 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-1-isobutyl-1H-pyrazole-4-carboxamide, was obtained.

[0304] LCMS:(ESI,m / z):549.15 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.27(t,J=5.7Hz,1H),7.68(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.6Hz,1H),6.31(dd ,J=7.9,1.1Hz,1H),6.25(m,3H),4.87(d,J=49.6Hz,1H),4.29(d,J=5.6Hz,2H),3.93-3.81(m,1 H),3.75(q,J=11.2Hz,2H),3.68(d,J=7.4Hz,2H),3.06(t,J=11.5Hz,1H),2.78(d,J=11.4Hz,1H ),2.36-2.21(m,1H),2.20(s,3H),2.18-2.03(m,2H),2.00-1.80(m,2H),0.83(d,J=6.7Hz,6H).

[0305] Example 47 [ka]

[0306] Step 1: Synthesis of Compound 263-2 Under nitrogen gas protection, 1-methylcyclopropane-1-carboxylic acid (compound 263-1, 3g, 29.965 mmol, 1eq) was added to a reaction flask and dissolved with tert-butanol (10mL). Diphenyl phosphoryl azide (6.5mL, 30.067 mmol, 1.00eq) and triethylamine (4mL) were then added, and the mixture was heated to 80°C and stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain compound 263-2 (2g, 35.12%).

[0307] 1 H NMR(400MHz,DMSO-d6,ppm)δ 7.04(s,1H),1.36(s,9H),1.22(s,3H),0.57(q,J=4.4Hz,2H),0.46-0.42(m,2H).

[0308] Step 2: Synthesis of Compound 263-3 Under nitrogen gas protection, tert-butyl (1-methylcyclopropyl)carbamate (compound 263-2, 1.9 g, 11.096 mmol, 1 eq) was added to the reaction flask and dissolved with dichloromethane (20 mL). The reaction flask was purged three times with nitrogen gas, and tert-butyl nitrite (2.29 g, 22.192 mmol, 2 eq) was added. The mixture was stirred at room temperature and reacted for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12:1) to obtain compound 263-3 (1.2 g, 53.96%).

[0309] 1 H NMR(400MHz,DMSO-d6,ppm)δ 1.59(s,9H),1.09(s,3H),0.87-0.83(m,2H),0.64(s,2H).

[0310] Step 3: Synthesis of Compound 263-4 Under nitrogen gas protection, tert-butyl (1-methylcyclopropyl)(nitroso)carbamate (compound 263-3, 1.1 g, 5.493 mmol, 1 eq) and zinc powder (0.72 g, 10.986 mmol, 2 eq) were added to the reaction flask, the mixture was purged with nitrogen gas three times, cooled to 0°C, 8 mL of 4 mol / L hydrochloric acid aqueous solution was added, the mixture was allowed to return to room temperature and stirred, and the reaction was allowed to proceed overnight. After the reaction was complete, the mixture was filtered, the filter cake was washed with water (5 mL x 2), and the filtrate was concentrated under reduced pressure to obtain compound 263-4 (1.2 g, 89.09%).

[0311] Step 4: Synthesis of Compound 263-5 Under nitrogen gas protection, (1-methylcyclopropyl)hydrazine hydrochloride (compound 263-4, 1 g, 8.157 mmol, 1 eq), (E)-2-cyano-3-ethoxyacrylate ethyl (1.38 g, 8.157 mmol, 1 eq), and sodium acetate (669.12 mg, 8.157 mmol, 1 eq) were added to a reaction flask, dissolved in anhydrous ethanol (10 mL), and stirred at 80°C to react overnight. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography under the following conditions (column specifications: C18; mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, gradient from 10% to 50% over 10 minutes, detection wavelength: UV 254 nm), yielding compound 263-5 (70 mg, 4.10%). LCMS:(ESI,m / z):210.05 [M+H] + .

[0312] Step 5: Synthesis of Compound 263-6 Under nitrogen gas protection, 5-amino-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylate ethyl (compound 263-5, 60 mg, 0.287 mmol, 1 eq) and sodium hydroxide (22.94 mg, 0.574 mmol, 2 eq) were added to a reaction flask, dissolved in anhydrous ethanol (5 mL) and water (2 mL), and stirred at 80°C and reacted overnight. After the reaction was complete, the reaction mixture was acidified to pH ~3 with a 1 mol / L hydrochloric acid solution, and the mixture was concentrated under reduced pressure to obtain the crude product. 10 mL of tetrahydrofuran was added to the crude product, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 263-6 (30 mg, 56.18%).

[0313] LCMS:(ESI,m / z):181.95 [M+H] + . Step 6: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide (compound 263) Under nitrogen gas protection, 5-amino-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylic acid (compound 263-6, 14.3 mg, 0.079 mmol, 1.2 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq), and N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction flask, dissolved with N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1- Add (-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1.00 eq), stir at room temperature and react for 1 hour. After the reaction is complete, add water, extract with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (30 mL x 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 10% B to 34% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 5.88), the formate salt (13.4 mg, 36.47%) of compound 263, 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide, was obtained.

[0314] LCMS:(ESI,m / z):547.05 [M+H] + . 1H NMR(400MHz,DMSO)δ 8.25(t,J=5.6Hz,1H),7.63(s,1H),7.29(dd,J=14.0,5.5Hz,1H),7.02(d,J=8.6Hz,1H),6.31(d,J=7 .4Hz,1H),6.23(d,J=9.1Hz,1H),6.18(s,2H),4.87(d,J=49.8Hz,1H),4.28(d,J=5.6Hz,2H),3.92-3. 82(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=10.7Hz,1H),2.78(d,J=11.2Hz,1H),2.37-2.23(m,1H), 2.20(s,3H),2.13(t,J=10.4Hz,1H),2.00-1.80(m,2H),1.36(s,3H),1.07-1.01(m,2H),0.89(m,2H).

[0315] Example 48 [ka]

[0316] Step 1: Synthesis of compound 305-2 Under nitrogen gas protection, cyclopropylhydrazine hydrochloride (compound 305-1, 1 g, 9.211 mmol, 1 eq), ethyl (E)-2-cyano-3-ethoxyacrylate (1.56 g, 9.211 mmol, 1 eq), and sodium acetate (0.76 g, 9.211 mmol, 1 eq) were added to a reaction flask, dissolved in anhydrous ethanol (10 mL), and the mixture was heated to 80°C and stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain compound 305-2 (900 mg, 49.50%). LCMS:(ESI,m / z):196.05 [M+H] + .

[0317] Step 2: Synthesis of Compound 305-3 Under nitrogen gas protection, ethyl 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylate (compound 305-2, 300 mg, 1.537 mmol, 1 eq) and sodium hydroxide (122.93 mg, 3.074 mmol, 2 eq) were added to a reaction flask, dissolved in anhydrous ethanol (5 mL) and water (2 mL), and the mixture was heated to 80°C and stirred and reacted overnight. After the reaction was complete, the reaction mixture was acidified to pH ~3 with a 1 mol / L hydrochloric acid solution, the mixture was concentrated under reduced pressure, 10 mL of anhydrous ethanol was added to the crude product, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 305-3 (150 mg, 57.22%). LCMS:(ESI,m / z):167.95 [M+H] + .

[0318] Step 3: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-1-(cyclopropyl)-1H-pyrazole-4-carboxamide (compound 305) Under nitrogen gas protection, 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (compound 305-3, 73.27 mg, 0.438 mmol, 2 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (83.33 mg, 0.219 mmol, 1 eq), and N,N-diisopropylethylamine (141.62 mg, 1.095 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (5 mL, 64.608 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl) was added. Add )-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 100 mg, 0.219 mmol, 1.00 eq), stir at room temperature and react for 1 hour. After the reaction is complete, extract the reaction mixture with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (30 mL x 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: YMC). Using a Triart C18 ExRs 5μm, 30mm * 150mm column; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 35% B to 55% B in 9 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.05, the crude product of compound 305 was obtained. The crude product was prepared twice and purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: 12% B to 30% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 5.75) The formate salt (52.16 mg, 44.47%) of compound 305, 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-1-(cyclopropyl)-1H-pyrazole-4-carboxamide, was obtained.

[0319] LCMS:(ESI,m / z):533.55 [M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.24(t,J=5.7Hz,1H),7.62(s,1H),7.28(dd,J=8.7,7.6Hz,1H),7.02(d,J=8.6Hz,1H),6.31( d,J=7.6Hz,1H),6.22(m,3H),4.87(d,J=49.4Hz,1H),4.28(d,J=5.6Hz,2H),3.93-3.80(m,1H) ),3.74(q,J=11.2Hz,2H),3.28-3.19(m,1H),3.06(t,J=11.2Hz,1H),2.78(d,J=11.1Hz,1H), 2.37-2.24(m,1H),2.21(s,3H),2.14(t,J=10.8Hz,1H),1.99-1.80(m,2H),0.95-0.91(m,4H).

[0320] Example 49 [ka]

[0321] Step 1: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-isopropyl-1H-pyrazole-4-carboxamide (compound 306) At room temperature, 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (444.92 mg, 2.629 mmol, 1.2 eq), N,N-diisopropylethylamine (1132.98 mg, 8.764 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (833.28 mg, 2.191 mmol, 1 eq) were added to a reaction flask, and the mixture was stirred at room temperature for 10 minutes with N,N-dimethylformamide (20 mL) solution. Further stirring was carried out, and 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methyl Lupiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 1g, 2.191 mmol, 1eq) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain the crude product compound 306. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 14% B to 26% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.3), formate (31.21 mg, 2.64%) of compound 306, 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1-isopropyl-1H-pyrazole-4-carboxamide, was obtained.

[0322] LCMS:(ESI,m / z):534.90 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.27(t,J=5.6Hz,1H),7.70(s,1H),7.28(dd,J=8.7,7.6Hz,1H),7.02(d,J=8.7Hz,1H),6.31(d,J=7. 6Hz,1H),6.25(d,J=9.2Hz,1H),6.22(s,2H),4.87(d,J=49.4Hz,1H),4.40(p,J=6.5Hz,1H),4.28(d,J =5.6Hz,2H),3.95-3.82(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=11.4Hz,1H),2.78(d,J=11.6Hz,1 H),2.36-2.24(m,1H),2.20(s,3H),2.13(t,J=11.3Hz,1H),2.00-1.79(m,2H),1.28(d,J=6.5Hz,6H).

[0323] Example 50 [ka]

[0324] Step 1: Synthesis of Compound 283-2 2-Cyanoethyl acetate (compound 283-1, 5g, 44.202 mmol, 1eq) was added to a reaction flask and dissolved in aqueous acetic acid solution (45 w / w%, 20 mL). The mixture was reacted at 0°C for 15 minutes. Sodium nitrite (9.15g, 132.606 mmol, 3eq) was then added, the temperature was raised to room temperature, and the mixture was stirred and allowed to react overnight. After the reaction was complete, diethyl ether and water were added to the reaction mixture until it became clear. The mixture was extracted with diethyl ether (3 × 30 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 283-2 (5.5g, 83.18%).

[0325] 1 H NMR(400MHz,DMSO-d6,ppm)δ 15.07(s,1H),4.31(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0326] Step 2: Synthesis of Compound 283-3 2-Cyano-2-(hydroxyimino)ethyl acetate (compound 283-2, 3g, 21.110 mmol, 1eq) and platinum oxide (239.68 mg, 1.056 mmol, 0.05eq) were added to a reaction flask, dissolved in ethanol (15.0 mL), and then the mixture was placed under a hydrogen atmosphere of 0.4 MPa and stirred at room temperature to react overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, and the filtrate was rotary-dried to directly obtain compound 283-3 (2.2 g, 77.27%).

[0327] 1 H NMR(400MHz,DMSO-d6,ppm)δ 4.80(s,1H),4.20(q,J=7.1,2H),1.24(t,J=7.1Hz,3H).

[0328] Step 3: Synthesis of Compound 283-4 2-amino-2-cyanoethyl acetate (compound 283-3, 1 g, 7.805 mmol, 1 eq) and triethyl orthoformate (2.08 g, 14.049 mmol, 1.8 eq) were added to a reaction flask and dissolved with acetonitrile (20.0 mL). The reaction was carried out at 90°C for 35 minutes, and the solvent was further rotated to obtain an oily substance. Tert-butylamine (970.38 mg, 13.268 mmol, 1.7 eq) was added and dissolved with acetonitrile (20.0 mL). The reflux reaction was continued for 30 minutes. After the reaction was complete, the solvent was rotated to obtain compound 283-4 (300 mg, 17.29%). LCMS:(ESI,m / z):212.05 [M+H] + .

[0329] Step 4: Synthesis of Compound 283-5 5-amino-1-tert-butyl-1H-imidazole-4-carboxylate ethyl (compound 283-4, 100 mg, 0.473 mmol, 1 eq) and 1 mol / L aqueous sodium hydroxide solution (0.94 mL, 0.946 mmol, 2 eq) were added to a reaction flask, dissolved in ethanol (2 mL), and reacted overnight at 80°C. After the reaction was complete, the reaction mixture was acidified to pH=3 with a 1 mol / L hydrochloric acid solution, and the solvent was further rotated to directly obtain compound 283-5 (90 mg, 98.59%).

[0330] LCMS:(ESI,m / z):184.05 [M+H] + . Step 5: Synthesis of 5-amino-1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 283) The reaction flask contains 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 84 mg, 0.219 mmol, 1 eq), 5-amino-1-tert-butyl-1H-imidazole-4-carboxylic acid (compound 283-5, 40.14 mg, 0.219 mmol, 1.00 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflu. Olophosphate (99.97 mg, 0.263 mmol, 1.2 eq) and N,N-diisopropylethylamine (141.59 mg, 1.095 mmol, 5 eq) were added, dissolved with N,N-dimethylformamide (3 mL), and reacted at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 13% B to 29% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.4), compound 283, 5-amino-1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (35.0 mg, 28.94%), was obtained.

[0331] LCMS:(ESI,m / z):549.20 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.97(t,J=6.0Hz,1H),7.30-7.25(m,1H),7.23(s,1H),7.01(d,J=8.7Hz,1H),6.30(d,J=7.4Hz ,1H),6.26(d,J=9.0Hz,1H),5.82(s,2H),4.87(d,J=49.6Hz,1H),4.26(d,J=6.0Hz,2H),3.91-3 .82(m,1H),3.75(q,J=11.2Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.4Hz,1H),2.36-2.23( m,1H),2.20(s,3H),2.13(t,J=11.3Hz,1H),2.01-1.88(m,1H),1.87-1.79(m,1H),1.56(s,9H).

[0332] Example 51 [ka]

[0333] Step 1: Synthesis of Compound 292-2 Under nitrogen gas protection, (cyclopropylmethyl)hydrazine dihydrochloride (compound 292-1,500 mg, 3.144 mmol, 1 eq), ethyl (2E)-2-cyano-3-ethoxyacrylate (531.85 mg, 3.144 mmol, 1 eq), and sodium acetate (257.89 mg, 3.144 mmol, 1 eq) were added to a reaction flask, dissolved in anhydrous ethanol (5 mL), and the mixture was heated to 80°C and stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain compound 292-2 (250 mg, 37.97%). LCMS:(ESI,m / z):210.10 [M+H] + .

[0334] Step 2: Synthesis of Compound 292-3 Under nitrogen gas protection, ethyl 5-amino-1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylate (compound 292-2, 200 mg, 0.956 mmol, 1 eq) and sodium hydroxide (76.46 mg, 1.912 mmol, 2 eq) were added to a reaction flask. The mixture was dissolved in anhydrous ethanol (5 mL, 86.067 mmol) and water (2 mL, 111.019 mmol). The mixture was heated to 50°C and stirred for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. 20 mL of water was added to the crude product, the pH was adjusted to 3 with 1 mol / L hydrochloric acid solution, and the mixture was further extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 292-3 (100 mg, 45.33%). LCMS:(ESI,m / z):182.05 [M+H] + .

[0335] Step 3: Synthesis of 5-amino-4-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 292) Under nitrogen gas protection, add 5-amino-1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid (compound 292-3, 15.49 mg, 0.086 mmol, 1.3 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq), and N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) to a reaction flask, dissolve with N,N-dimethylformamide (2 mL, 25.843 mmol), stir at room temperature for 10 minutes, and 2-(3-aminopropane-1-in-1-yl) -N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1.00 eq) was added and stirred at room temperature for 1 hour. After the reaction was complete, 20 mL was added and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 7% B to 33% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.1), yielding formate (15.92 mg, 44.17%) of compound 292, 5-amino-4-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide.

[0336] LCMS:(ESI,m / z):547.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.26(t,J=5.6Hz,1H),7.68(s,1H),7.28(t,J=8.2Hz,1H),7.02(d,J=8.7Hz,1H),6.31(d,J=7.7Hz, 1H),6.26-6.21(m,3H),4.87(d,J=49.4Hz,1H),4.29(d,J=5.6Hz,2H),3.92-3.82(m,1H),3.81-3.68 (m,4H),3.05(t,J=10.9Hz,1H),2.78(d,J=11.3Hz,1H),2.30(dd,J=38.3,13.0Hz,1H),2.20(s,3H), 2.15(t,J=10.6Hz,1H),1.99-1.79(m,2H),1.22-1.10(m,1H),0.47-0.40(m,2H),0.35-0.28(m,2H).

[0337] Example 52 [ka]

[0338] Step 1: Synthesis of Compound 307-1 Under nitrogen gas protection, ethyl 5-amino-1-(tert-butyl)-1H-pyrazole-4-carboxylate (compound 047-1, 300 mg, 1.420 mmol, 1 eq) was added to a reaction flask and dissolved with tetrahydrofuran (3 mL, 37.028 mmol). Sodium hydride (51.12 mg, 2.130 mmol, 1.5 eq) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.11 mL, 1.704 mmol, 1.2 eq) was then added, and the temperature was raised to 70°C and the mixture was stirred and reacted for 2 hours. After the reaction was complete, 2 mL of water was added, and the mixture was further extracted with ethyl acetate (3 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 307-1, which was used directly in the next step without further purification. LCMS:(ESI,m / z):226.00 [M+H] + .

[0339] Step 2: Synthesis of Compound 307-2 Under nitrogen gas protection, a mixture of crude products of 1-(tert-butyl)-5-(methylamino)-1H-pyrazole-4-carboxylate ethyl (compound 307-1,300 mg, 1.332 mmol, 1 eq) and sodium hydroxide (106.52 mg, 2.664 mmol, 2 eq) were added to a reaction flask. The mixture was dissolved in anhydrous ethanol (2 mL, 34.427 mmol) and water (0.5 mL, 27.755 mmol), and the temperature was raised to 50°C and the mixture was stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a mixture of crude products of compound 307-2 (220 mg, 53.02%). LCMS:(ESI,m / z):198.05 [M+H] + .

[0340] Step 3: Synthesis of 1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide (compound 307) Under nitrogen gas protection, 1-(tert-butyl)-5-(methylamino)-1H-pyrazole-4-carboxylic acid (compound 307-2, 64.84 mg, 0.329 mmol, 1.50 eq) and tetramethyluronium chlorohexafluorophosphate (245.96 mg, 0.876 mmol, 4 eq) were added to the reaction flask and dissolved with acetonitrile (5 mL). Then, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 100 mL) were added. (g, 0.219 mmol, 1.00 eq) and N-methylimidazole (179.93 mg, 2.190 mmol, 10 eq) were added, and the mixture was stirred at room temperature and reacted for 4 hours. After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, backwashed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the crude product of compound 307. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 17% B to 33% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.52), yielding formate (11.34 mg, 9.16%) of compound 307, 1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]5-(methylamino)-1H-pyrazole-4-carboxamide.

[0341] LCMS:(ESI,m / z):563.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.38(t,J=5.7Hz,1H),7.68(s,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8.6Hz,1H),6.32(d,J=7. 3Hz,1H),6.24(d,J=9.0Hz,1H),4.98(q,J=5.5Hz,1H),4.88(d,J=49.5Hz,1H),4.31(d,J=5.6Hz,2H), 3.94-3.80(m,1H),3.75(q,J=11.1Hz,2H),3.07(t,J=11.5Hz,1H),2.79(d,J=11.4Hz,1H),2.74(d,J =5.6Hz,3H),2.40-2.24(m,1H),2.22(s,3H),2.16(t,J=11.0Hz,1H),1.99-1.81(m,2H),1.57(s,9H).

[0342] Example 53 [ka]

[0343] Step 1: Synthesis of 6-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]nicotinamide (compound 296) At room temperature, a solution of 6-aminonicotinic acid (1.66 mg, 0.012 mmol, 1.1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.58 mg, 0.012 mmol, 1.1 eq), and N,N-diisopropylethylamine (7.08 mg, 0.055 mmol, 5 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes. Further reaction was carried out using 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperyl Add din-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 5 mg, 0.011 mmol, 1 eq), stir continuously, and react for 2 hours. After the reaction is complete, add water to quench, extract with ethyl acetate (3 × 10 mL), combine the organic phases, backwash with saturated sodium chloride solution (1 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60mL / min; elution gradient: from 15% B to 35% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.22), yielding formate (19.37mg, 63.82%) of compound 296, 6-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]nicotinamide.

[0344] LCMS:(ESI,m / z):504.00 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.75(t,J=5.6Hz,1H),8.48(d,J=2.4Hz,1H),7.84(dd,J=8.7,2.5Hz,1H),7.28(t,J=8.2Hz,1H),7.03(d,J= 8.7Hz,1H),6.53(s,2H),6.43(d,J=8.7Hz,1H),6.32(d,J=7.6Hz,1H),6.26(d,J=9.0Hz,1H),4.89(d,J=49.4 Hz,1H),4.34(d,J=5.5Hz,2H),3.94-3.82(m,1H),3.76(q,J=11.1Hz,2H),3.09(t,J=11.6Hz,1H),2.81(d,J =11.5Hz,1H),2.42-2.26(m,1H),2.23(s,3H),2.16(t,J=11.7Hz,1H),2.01-1.90(m,1H),1.88-1.80(m,1H).

[0345] Example 54 [ka]

[0346] Step 1: Synthesis of 2-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6-methylnicotinamide (compound 295) At room temperature, add 2-amino-6-methylnicotinic acid (6.67 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) to a reaction flask, add N,N-dimethylformamide (1 mL) solution, stir, and react for 30 minutes, then add 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1- Methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was added, and the mixture was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm * 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 15% B to 35% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.22), yielding formate (18.89 mg, 83.03%) of compound 295, 2-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6-methylnicotinamide.

[0347] LCMS:(ESI,m / z):518.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.91(t,J=5.5Hz,1H),7.85(d,J=7.9Hz,1H),7.29(dd,J=8.7,7.6Hz,1H),7.13(s,2H),7.03(d,J=8.6Hz ,1H),6.47(d,J=7.9Hz,1H),6.32(d,J=7.6Hz,1H),6.26(d,J=9.0Hz,1H),4.89(d,J=49.4Hz,1H),4.33(d ,J=5.4Hz,2H),3.94-3.81(m,1H),3.76(q,J=11.4Hz,2H),3.09(t,J=11.6Hz,1H),2.81(d,J=11.1Hz,1H ),2.42-2.34(m,1H),2.28(s,3H),2.23(s,3H),2.20-2.12(m,1H),2.01-1.88(m,1H),1.87-1.80(m,1H).

[0348] Example 55 [ka]

[0349] Step 1: Synthesis of 4-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propyl-2-in-1-yl]-6-methylnicotinamide (compound 294) Under nitrogen gas protection, 4-amino-6-methylnicotinic acid (12.0 mg, 0.079 mmol, 1.2 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq), and N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R Add )-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq), stir, and react for 1 hour. After the reaction is complete, extract the reaction mixture with ethyl acetate (20 mL x 2), combine the organic phases, backwash with saturated sodium chloride solution (30 mL x 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 100 mL / min; elution gradient: to 26% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.27), formate (20.3 mg, 59.36%) of compound 294, 4-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-6-methylnicotinamide, was obtained.

[0350] LCMS:(ESI,m / z):518.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.95(t,J=5.5Hz,1H),8.46(s,1H),7.29(t,J=8.2Hz,1H),7.18(s,2H),7.03(d,J=8.7Hz,1H),6 .48(s,1H),6.32(d,J=7.6Hz,1H),6.24(d,J=9.0Hz,1H),4.88(d,J=49.2Hz,1H),4.33(d,J=5.4 Hz,2H),3.94-3.83(m,1H),3.78(q,J=11.4Hz,2H),3.07(t,J=11.0Hz,1H),2.79(d,J=11.3Hz,1 H),2.35(d,J=13.2Hz,1H),2.26(s,3H),2.21(s,3H),2.15(t,J=10.6Hz,1H),1.97-1.81(m,2H).

[0351] Example 56 [ka]

[0352] Step 1: Synthesis of Compound 269-2 Under nitrogen gas protection at 0°C, 1-cyclopropylethanol (compound 269-1, 614.62 mg, 7.136 mmol, 2.00 eq), ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.568 mmol, 1.00 eq), and triphenylphosphine (1.87 g, 7.136 mmol, 2.00 eq) were dissolved in tetrahydrofuran (40 mL), to which diisopropyl azodicarboxylate (1.44 g, 7.136 mmol, 2.00 eq) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature, the resulting residue was concentrated under reduced pressure, then diethyl ether was added, the mixture was cooled to 0°C, filtered, and the filtrate was rotated dry. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 269-2 (700 mg, 94.21%). LCMS:(ESI,m / z):208.90 [M+H] + .

[0353] Step 2: Synthesis of Compound 269-3 At room temperature, a solution of (1-cyclopropylethyl)-1H-pyrazole-4-carboxylate ethyl (compound 269-2, 160 mg, 0.768 mmol, 1 eq) and sodium hydroxide (5 M) (0.312 mL, 1.536 mmol, 2 eq) in ethanol (3.2 mL) was stirred and reacted overnight. The resulting residue was concentrated under reduced pressure, acidified to pH ~5 with hydrochloric acid solution (2 M), concentrated under reduced pressure, washed with tetrahydrofuran / methanol (3 / 1 mL), filtered, washed the filter cake with tetrahydrofuran (1 × 4 mL), and concentrated the filtrate under reduced pressure to obtain compound 269-3 (100 mg, 72.23%). LCMS:(ESI,m / z):181.05 [M+H] + .

[0354] Step 3: Synthesis of 1-(1-cyclopropylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide (compound 269) At room temperature, a solution of 1-(1-cyclopropylethyl)-1H-pyrazole-4-carboxylic acid (compound 269-3, 37.91 mg, 0.210 mmol, 1.2 eq), N,N-diisopropylethylamine (90.64 mg, 0.700 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.0 mg, 0.210 mmol, 1.2 eq) in N,N-dimethylformamide (4.0 mL) was stirred and reacted for 20 minutes, followed by 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R) Add -3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 80 mg, 0.175 mmol, 1 eq), stir at room temperature for 1 hour, and after the reaction is complete, quench the reaction mixture with water (20 mL), extract with ethyl acetate (2 × 20 mL), combine the organic phases, backwash with saturated sodium chloride (2 × 20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 16% B to 32% B in 7 minutes; detection wavelength: UV 254 nm / 225 nm; retention time (minutes): 6.42), formate (2.07 mg, 1.98%) of compound 269, 1-(1-cyclopropylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1H-pyrazole-4-carboxamide, was obtained.

[0355] LCMS:(ESI,m / z):545.95 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.67(t,J=5.6Hz,1H),8.30(s,1H),7.90(s,1H),7.29(dd,J=8.7,7.7Hz,1H),7.03(d,J=8.7Hz,1H),6.32(d,J=7 .6Hz,1H),6.24(d,J=9.1Hz,1H),4.87(d,J=48.0Hz,1H),4.34(d,J=5.6Hz,2H),3.92-3.82(m,1H),3.81-3.63(m, 3H),3.05(t,J=10.6Hz,1H),2.78(d,J=11.7Hz,1H),2.37-2.23(m,1H),2.20(s,3H),2.13(d,J=9.5Hz,1H),2.00 -1.78(m,2H),1.50(d,J=6.8Hz,3H),1.28-1.15(m,1H),0.65-0.55(m,1H),0.50-0.40(m,1H),0.40-0.26(m,2H).

[0356] Example 57 [ka] Step 1: Synthesis of Compound 300-1 Under nitrogen gas protection at room temperature, cesium carbonate (3.91 g, 11.988 mmol, 3 eq) and potassium iodide (331.67 mg, 1.998 mmol, 0.5 eq) were gradually added to a 10.0 mL solution of methyl 1H-pyrrole-3-carboxylate (compound 014-1,500 mg, 3.996 mmol, 1 eq) and 1-chloro-2-methyl-2-propanol (650.76 mg, 5.994 mmol, 1.5 eq) in acetonitrile (10.0 mL). The mixture was stirred overnight at 80°C. After the reaction was complete, the solution was filtered, the filter cake was washed with acetonitrile (3 × 10 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound 300-1 (320 mg, 40.60%). LCMS:(ESI,m / z):197.95 [M+H] + .

[0357] Step 2: Synthesis of Compound 300-2 Under nitrogen gas protection, at 0°C, add sodium hydride (65.7 mg, 2.738 mmol, 2 eq) to a solution of methyl 1-(2-hydroxy-2-methylpropyl)-1H-pyrrole-3-carboxylate (compound 300-1,270 mg, 1.369 mmol, 1 eq) in N,N-dimethylformamide (4.0 mL), stir, and react for 30 minutes. At 0°C, add methyl iodide (388.61 mg, 2.738 mmol, 2 eq) dropwise and allow to stand naturally. The mixture was allowed to return to room temperature and stirred for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, backwashed with saturated brine (3 × 15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound 300-2 (250 mg, 86.44%). LCMS:(ESI,m / z):212.00 [M+H] + .

[0358] Step 3: Synthesis of Compound 300-3 Under nitrogen gas protection at room temperature, a methanol (1.0 mL) solution of 1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxylate methyl (compound 300-2, 100 mg, 0.473 mmol, 1 eq) was added dropwise to an aqueous (0.5 mL) solution of sodium hydroxide (37.87 mg, 0.946 mmol, 2 eq) and stirred overnight at 50°C. After the reaction was complete, the reaction mixture was acidified to pH=5 with hydrochloric acid solution. The resulting residue was concentrated under reduced pressure and then dissolved in tetrahydrofuran (3 mL). The resulting residue was filtered and concentrated again under reduced pressure to obtain compound 300-3 (60 mg, 64.27%). The crude product was used directly in the next step without further purification. LCMS:(ESI,m / z):198.00 [M+H] + .

[0359] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxamide (compound 300) Under nitrogen gas protection at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq) and 1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxylic acid (compound 300-3, 16 To a solution of 0.86 mg, 0.086 mmol, 1.3 eq of N,N-dimethylformamide (0.8 mL), N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) was added dropwise, and the mixture was stirred and allowed to react for 1 hour. Then, at room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.5 mg, 0.073 mmol, 1.1 eq) was added. After the addition was complete, the system was stirred at room temperature for 1 hour, and after the reaction was complete, methanol (1.0 mL) was added to the reaction mixture at room temperature to quench it. The crude product was purified by high-performance liquid chromatography under the following conditions: (Column specifications: XBridge BEH C18 OBD Prep Column 130, 5μm, 30mm × 150mm; Mobile phase A: Water (17 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 38% B to 56% B over 8 minutes; Detection wavelength: UV) At a wavelength of 254 nm / 220 nm (retention time: 6.6 minutes), compound 300 was converted to N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxamide (5.81 mg, 15.64%).

[0360] LCMS:(ESI,m / z):563.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.35(t,J=5.7Hz,1H),7.32-7.24(m,2H),7.02(d,J=8.7Hz,1H),6.69(t,J=2.5Hz,1H),6.46(dd,J=2. 9,1.7Hz,1H),6.31(d,J=7.6Hz,1H),6.26(d,J=9.0Hz,1H),4.87(d,J=49.3Hz,1H),4.29(d,J=5.7Hz,2 H),3.89(s,2H),3.87-3.68(m,3H),3.16(s,3H),3.05(t,J=11.4Hz,1H),2.78(d,J=11.5Hz,1H),2.36 -2.24(m,1H),2.20(s,3H),2.13(d,J=10.3Hz,1H),2.00-1.88(m,1H),1.87-1.79(m,1H),1.03(s,6H).

[0361] Example 58 [ka]

[0362] Step 1: Synthesis of compound 302-2 Under nitrogen gas protection, proline (compound 302-1, 1 g, 8.686 mmol, 1 eq) was added to a reaction flask and dissolved with formic acid (8.5 mL). At 0°C, acetic anhydride (5.75 mL, 60.802 mmol, 7 eq) was added, and the mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was quenched with ice water at 0°C, and the resulting residue was concentrated under reduced pressure to obtain compound 302-2 (1.2 g, 88.60%). LCMS:(ESI,m / z):144.00 [M+H] + .

[0363] Step 2: Synthesis of Compound 302-3 Under nitrogen gas protection, formylproline (compound 302-2,500 mg, 3.493 mmol, 1 eq) and ethyl propioate (2.40 g, 24.451 mmol, 7 eq) were added to a reaction flask, dissolved with acetic anhydride (5 mL, 52.895 mmol), and the mixture was heated to 120°C and stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, backwashed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain compound 302-3 (200 mg, 23.96%). LCMS:(ESI,m / z):180.05 [M+H] + .

[0364] Step 3: Synthesis of Compound 302-4 Under nitrogen gas protection, ethyl 2,3-dihydro-1H-pyrrolidine-7-carboxylate (compound 302-3, 200 mg, 1.116 mmol, 1 eq) and sodium hydroxide (89.27 mg, 2.232 mmol, 2 eq) were added to a reaction flask. The mixture was dissolved in anhydrous ethanol (5 mL, 86.067 mmol) and water (2 mL, 111.019 mmol). The mixture was heated to 50°C and stirred, and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. 20 mL of ethyl acetate and 20 mL of water were added to the crude product. The product was in the aqueous phase. The aqueous phase was adjusted to pH 3 with 1 mol / L hydrochloric acid solution, and further extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 302-4. LCMS:(ESI,m / z):152.05 [M+H] + .

[0365] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-2,3-dihydro-1H-pyrrolidine-7-carboxamide (compound 302) Under nitrogen gas protection, 2,3-dihydro-1H-pyrrolidine-7-carboxylic acid (compound 302-4, 12.92 mg, 0.086 mmol, 1.3 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq), and N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to a reaction flask, dissolved with N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1-in-1-yl)-N-( (3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1.00 eq) was added, and the mixture was stirred at room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, backwashed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). A CSHTM Prep C18 5μm 30*150mm OBD column was used to obtain the crude product compound 302. Chiral resolution of the mixture was performed under the following conditions (column specifications: CHIRALPAK-IA 2*25cm, 5μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol:DCM=1:1; flow rate: 20mL / min; elution gradient: equal 45; detection wavelength: UV 254 / 220nm; retention time (min): UV 254 / 220nm; retention time (min): 6.097; post-peak retention time (min): 8.463; sample dissolution solvent: methanol; single injection volume: 2.0 mL (1 injection) was used to obtain N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-2,3-dihydro-1H-pyrrolidine-7-carboxamide (4.7 mg, 13.76%) of compound 302.

[0366] LCMS:(ESI,m / z):517.15 [M+H] + . 1 H NMR(400MHz,DMSO-d6,ppm)δ 8.10(s,1H),7.28(t,J=8.2Hz,1H),7.02(d,J=8.7Hz,1H),6.66(d,J=2.9Hz,1H),6.56(s,1H),6.3 1(d,J=7.4Hz,1H),6.26(d,J=9.1Hz,1H),4.87(d,J=49.5Hz,1H),4.28(d,J=5.6Hz,2H),3.91(t,J =7.2Hz,3H),3.86-3.69(m,3H),3.05(t,J=11.6Hz,1H),2.94(t,J=7.3Hz,2H),2.78(d,J=11.1Hz, 1H),2.46-2.40(m,1H),2.36-2.25(m,1H),2.20(s,3H),2.12(t,J=11.2Hz,1H),1.97-1.80(m,2H).

[0367] Example 59 [ka]

[0368] Step 1: Synthesis of Compound 148-2 Benzohydrazide (5 g, 36.723 mmol, 1 eq) and acetic acid (44.11 mg, 0.734 mmol, 0.02 eq) were added to a reaction flask, dissolved in acetone (22 mL), and reacted overnight at room temperature. After the reaction was complete, the mixture was diluted with water, the reaction mixture was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to directly obtain compound 148-2 (5.1 g, 74.87%). LCMS:(ESI,m / z):176.70 [M+H] + .

[0369] Step 2: Synthesis of Compound 148-3 Add N-(propa-2-ylidene)benzohydrazide (compound 148-2, 1 g, 5.675 mmol, 1 eq) to a reaction flask, dissolve with 1,2-dichloroethane (10 mL), add allyltrimethylsilane (972.6 mg, 8.512 mmol, 1.5 eq) and boron trifluoride diethyl ether (1.21 g, 8.512 mmol, 1.5 eq), react at 85°C for 5 minutes, rotate dry the solvent, dissolve the remaining solution in N,N-dimethylformamide (10 mL), and add (trifluoromethyl)trimethylsilane (1.61 g, 11.350 mmol, 2 eq), Sodium acetate (1.86 g, 22.700 mmol, 4 eq) was added and the mixture was reacted at 55°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, saturated sodium carbonate was added to quench the reaction, and the mixture was stirred for 5 minutes. The mixture was diluted with water, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 148-3 (1.1 g, 74.79%). LCMS:(ESI,m / z):246.85 [M+H] + .

[0370] Step 3: Synthesis of Compound 148-4 N-(1,1,1-trifluoro-2-methylpropa-2-yl)benzohydrazide (compound 148-3, 1.1 g, 4.467 mmol, 1 eq) was added to a reaction flask, dissolved with methanol (6.6 mL), and then hydrochloric acid (6 mL) was added. The reaction was carried out overnight at 80°C. After the reaction was complete, the reaction mixture was cooled to room temperature, the solvent was rotated dry, and the product after the addition of diethyl ether was precipitated. The product was filtered, and the filtered cake was washed with diethyl ether to obtain the hydrochloride salt of compound 148-4 (570 mg, 85.29%).

[0371] 1 H NMR(400MHz,DMSO-d6,ppm)δ 9.44(s,2H),6.02(s,1H),1.33(s,6H). Step 4: Synthesis of Compound 148-5 Add (1,1,1-trifluoro-2-methylpropa-2-yl)hydrazine hydrochloride (compound 148-4, 2.2g, 15.479 mmol, 1eq) and 2-bromomalondialdehyde (2.80g, 18.575 mmol, 1.2eq) to a reaction flask, dissolve with acetic acid (33mL), stir overnight at room temperature, and after the reaction is complete, adjust the pH to 7 by adding 1 mol / L sodium hydroxide aqueous solution, and dissolve the reaction mixture with ethyl acetate (3 Extraction was performed with 50 mL of solution, the organic phase was combined, backwashed with saturated sodium chloride solution (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography under the following conditions (120 g C18 column, mobile phase: water and acetonitrile, gradient from 10% to 80% over 10 minutes, UV 220 nm detection), yielding compound 148-5 (200 mg, 4.27%). LCMS:(ESI,m / z):256.85 [M+H] + .

[0372] Step 5: Synthesis of Compound 148-6 Under nitrogen gas protection, 4-bromo-1-(1,1,1-trifluoro-2-methylpropa-2-yl)-1H-pyrazole (compound 148-5, 120 mg, 0.467 mmol, 1 eq) was added to the reaction flask and dissolved in tetrahydrofuran (5 mL). At -78°C, 2.5 mol / L n-butyllithium solution in n-hexane (0.373 mL, 0.934 mmol, 2 eq) was added dropwise, and the mixture was reacted at this temperature for 30 minutes. Then, propyl chloroformate (62.93 mg, 0.514 mmol, 1.1 eq) was added, and the reaction was continued for another 30 minutes. The reaction was then continued at room temperature for 72 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography under the following conditions (column specifications: C18; mobile phase: water and acetonitrile, gradient from 10% to 90% over 10 minutes, UV 220 nm), yielding compound 148-6 (25 mg, 19.25%). LCMS:(ESI,m / z):265.00 [M+H] + .

[0373] Step 6: Synthesis of Compound 148-7 1-(1,1,1-trifluoro-2-methylpropa-2-yl)-1H-pyrazole-4-carboxylate propyl (compound 148-6, 25 mg, 0.094 mmol, 1 eq) and 1 mol / L aqueous sodium hydroxide solution (0.188 mL, 0.188 mmol, 2 eq) were added to a reaction flask, dissolved with methanol (1 mL), and reacted overnight at 50°C. After the reaction was complete, the reaction mixture was acidified to pH=3 with 1 mol / L hydrochloric acid solution, and the solvent was rotated dry to obtain compound 148-7 (20 mg, 95.15%). LCMS:(ESI,m / z):222.95 [M+H] + .

[0374] Step 7: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1,1,1-trifluoro-2-methylpropa-2-yl)-1H-pyrazole-4-carboxamide (compound 148) The reaction flask contains 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 35 mg, 0.091 mmol, 1 eq), 1-(1,1,1-trifluoro-2-methylpropa-2-yl)-1H-pyrazole-4-carboxylic acid (compound 148-7, 20.28 mg, 0.091 mmol, 1 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate (41.65 mg, 0.109 mmol, 1.2 eq) and N,N-diisopropylethylamine (58.99 mg, 0.455 mmol, 5 eq) were added, dissolved with N,N-dimethylformamide (1 mL), and reacted at room temperature for 2 hours. After the reaction was complete, water was added, and the reaction mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 18% B to 36% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.05), the formate salt (4.51 mg, 8.34%) of compound 148, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1,1,1-trifluoro-2-methylpropa-2-yl)-1H-pyrazole-4-carboxamide, was obtained.

[0375] LCMS:(ESI,m / z):588.10 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.77(t,J=5.6Hz,1H),8.60(s,1H),8.02(s,1H),7.29(dd,J=8.7,7.6Hz,1H),7.03(d,J=8. 7Hz,1H),6.32(d,J=7.6Hz,1H),6.23(d,J=9.0Hz,1H),4.87(d,J=49.5Hz,1H),4.36(d,J=5. 5Hz,2H),3.90-3.82(m,1H),3.76(q,J=11.4Hz,2H),3.05(t,J=11.6Hz,1H),2.78(d,J=11.5 Hz,1H),2.36-2.21(m,1H),2.20(s,3H),2.17-2.09(m,1H),1.99-1.86(m,2H),1.84(s,6H).

[0376] Example 60 [ka]

[0377] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methylindole-3-carboxamide (compound 308) At room temperature, add 1-methylindole-3-carboxylic acid (13.82 mg, 0.079 mmol, 1.2 eq), N,N-diisopropylethylamine (33.99 mg, 0.264 mmol, 4 eq), and O--(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) to a reaction flask, stir with N,N-dimethylformamide (2 mL) solution at room temperature for 10 minutes, and then add 2-(3-aminopropane-1-in-1-yl)-N-(( Add 3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq), stir for 1 hour, and after the reaction is complete, dilute the reaction mixture with ethyl acetate (5 mL), wash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). Using a C18 5μm, 30mm * 150mm sample; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 19% B to 33% B in 1 min; detection wavelength: UV 254 nm / 220 nm), compound 308 was obtained as N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methylindole-3-carboxamide (13.82 mg, 38.65%).

[0378] LCMS:(ESI,m / z):541.20 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.46(t,J=5.6Hz,1H),8.17(d,J=7.9Hz,1H),8.03(s,1H),7.50(d,J=8.1Hz,1H),7.32-7.20(m,2H) ,7.17(t,J=7.2Hz,1H),7.02(d,J=8.7Hz,1H),6.31(d,J=7.5Hz,1H),6.23(d,J=9.1Hz,1H),4.87(d ,J=49.5Hz,1H),4.39(d,J=5.6Hz,2H),3.84(s,4H),3.77(q,J=11.4Hz,2H),3.05(t,J=11.8Hz,1H) ,2.77(d,J=11.4Hz,1H),2.36-2.22(m,1H),2.20(s,3H),2.11(t,J=10.9Hz,1H),1.98-1.80(m,2H).

[0379] Example 61 [ka]

[0380] Step 1: Synthesis of compound 301-2 Under nitrogen gas protection, at 0°C, a solution of 3-morpholinecarboxylic acid (compound 301-1, 1 g, 7.626 mmol, 1 eq) and acetic anhydride (7 mL) in formic acid (2 mL) was stirred and reacted for 1 hour. After the reaction was complete, the reaction mixture was quenched with water at room temperature, and the resulting residue was concentrated under reduced pressure to obtain compound 301-2 (1.5 g). LCMS:(ESI,m / z):159.95 [M+H] + .

[0381] Step 2: Synthesis of Compound 301-3 Under nitrogen gas protection, a solution of 4-formylmorpholine-3-carboxylic acid (compound 301-2, 1.5 g, 9.426 mmol, 1 eq) and ethyl propioate (1.29 g, 13.196 mmol, 1.40 eq) in acetic anhydride (3 mL) was stirred and reacted overnight at 120 °C. After the reaction was complete, the resulting residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain compound 301-3 (600 mg, 32.61%). LCMS:(ESI,m / z):196.05 [M+H] + .

[0382] Step 3: Synthesis of Compound 301-4 Under air protection, at 60°C, a solution of 3,4-dihydro-1H-pyrrole[2,1-c][1,4]oxazine-8-carboxylate ethyl (compound 301-3, 230 mg, 1.178 mmol, 1 eq) and lithium hydroxide (141.09 mg, 5.890 mmol, 5 eq) in tetrahydrofuran (1 mL) and water (1 mL) was stirred and reacted overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain compound 301-4 (182 mg, 92.41%).

[0383] LCMS:(ESI,m / z):168.00 [M+H] + . Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-3,4-dihydro-1H-pyrrole[2,1-c][1,4]oxazine-8-carboxamide (compound 301) At room temperature, 3,4-dihydro-1H-pyrrole[2,1-c][1,4]oxazine-8-carboxylic acid compound (compound 301-4, 10 mg, 0.060 mmol, 1 eq), N,N-diisopropylethylamine (30.93 mg, 0.240 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.75 mg, 0.060 mmol, 1 eq) are dissolved in N,N-dimethylformamide (1 mL), stirred, and reacted for 20 minutes. Further reaction is carried out to 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3 -(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 27.3 mg, 0.060 mmol, 1 eq) was added and stirred overnight. After the reaction was complete, the reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (2 × 5 mL), the organic phases were combined, backwashed with saturated sodium chloride (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the crude product compound 301. The crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). CSHTM Prep C18 5μm 30x150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 15% B to 29% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.77), yielded formate (2.81 mg, 8.05%) of compound 301, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-3,4-dihydro-1H-pyrrole[2,1-c][1,4]oxazine-8-carboxamide. LCMS:(ESI,m / z):533.15 [M+H] + .

[0384] Example 62 [ka]

[0385] Step 1: Synthesis of compound 303-2 Under nitrogen gas protection at room temperature, triethylamine (132.36 mg, 1.308 mmol, 1.1 eq) was added dropwise to a solution of 1H-pyrazole-4-carboxylate tert-butyl (compound 303-1, 200 mg, 1.189 mmol, 1 eq) and 1-(benzenesulfonyl)cyclopropan-1-ol (259.3 mg, 1.308 mmol, 1.1 eq) in acetonitrile (3.0 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol (2.0 mL) was added to the reaction mixture at room temperature to quench it. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound 303-2 (200 mg, 75.00%). LCMS:(ESI,m / z):225.00 [M+H] + .

[0386] Step 2: Synthesis of Compound 303-3 Under nitrogen gas protection at room temperature, trifluoroacetic acid (0.5 mL) was added dropwise to a solution of 1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxylate tert-butyl (compound 303-2, 100 mg, 0.446 mmol, 1 eq) in dichloromethane (1.0 mL). After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound 303-3 (100 mg), and the resulting mixture was used directly in the next step without further purification. LCMS:(ESI,m / z):168.95 [M+H] + .

[0387] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxamide (compound 303) Under nitrogen gas protection at room temperature, 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxylic acid (compound 303-3, 9.58 mg, 0.057 mmol, 1.3 eq) To a solution of N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.08 mg, 0.053 mmol, 1.2 eq) and N,N-dimethylaminopyridine (0.54 mg, 0.004 mmol, 0.1 eq) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to the reaction mixture to quench it, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: YMC). Triart C18 ExRs 5μm, 30mm×150mm; Mobile phase A: Water (10 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: From 28% B to 52% B in 10 min; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 9.5), yielding compound 303, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxamide (2.14 mg, 8.51%).

[0388] LCMS:(ESI,m / z):534.05 [M+H] + . 1 H NMR-PH-CCJS-P-477-0:(400MHz,DMSO-d6,ppm)δ 8.73(t,J=5.6Hz,1H),8.39(d,J=0.8Hz,1H),7.89(d,J=0.8Hz,1H),7.62(s,1H),7.29(dd,J=8.8,7.6Hz,1H),7 .03(d,J=8.7Hz,1H),6.32(d,J=7.5Hz,1H),6.23(d,J=9.1Hz,1H),4.87(d,J=49.4Hz,1H),4.34(d,J=5.5Hz,2H) ,3.92-3.82(m,1H),3.76(q,J=11.1Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.4Hz,1H),2.37-2.22(m,1H),2 .20(s,3H),2.13(t,J=11.1Hz,1H),2.01-1.90(m,1H),1.89-1.80(m,1H),1.34-1.26(m,2H),1.22-1.15(m,2H).

[0389] Example 63 [ka]

[0390] Step 1: Synthesis of compound 309-2 Under argon protection at -50°C, trifluoromethyltrimethylsilane (2.03 g, 14.272 mmol, 2 eq) was slowly added dropwise to a solution of methyl 1-methyl-1H-imidazole-4-carboxylate (compound 309-1, 1 g, 7.136 mmol, 1 eq) and tetra-n-butylammonium difluorotriphenylsilicate (0.77 g, 1.427 mmol, 0.2 eq) in tetrahydrofuran (69.4 mL). After the addition was complete, the mixture was raised to room temperature and stirred overnight under argon protection. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:petroleum ether = 10:01) to obtain compound 309-2 (300 mg, 20.12%). LCMS:(ESI,m / z):191.05 [M+H] + .

[0391] Step 2: Synthesis of Compound 309-3 At room temperature, 2-(difluoromethyl)-1-methyl-1H-imidazole-4-carboxylate methyl (compound 309-2, 100 mg, 0.526 mmol, 1 eq) and lithium hydroxide (25.19 mg, 1.052 mmol, 2 eq) were added to a reaction flask, dissolved in tetrahydrofuran (5 mL) and water (1 mL), and stirred at room temperature for 2 hours. After the reaction was complete, the solution was neutralized with 3 mol / L hydrochloric acid solution, the resulting residue was concentrated under reduced pressure, further dissolved in tetrahydrofuran (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 309-3 (90 mg, 97.17%). LCMS:(ESI,m / z):176.95 [M+H] + .

[0392] Step 3: Synthesis of 2-difluoromethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-imidazole-4-carboxamide (compound 309) At room temperature, the reaction flask was filled with 2-difluoromethyl-1-methyl-1H-imidazole-4-carboxylic acid (compound 309-3, 23.16 mg, 0.132 mmol, 2 eq), 4-dimethylaminopyridine (0.8 mg, 0.007 mmol, 0.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (15.12 mg, 0.079 mmol, 1.2 eq), and 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2, 2-Trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 12% B to 33% B in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.2), compound 309, 2-difluoromethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propa-2-in-1-yl]-1-methyl-1H-imidazole-4-carboxamide (5.94 mg, 15.22%), was obtained.

[0393] LCMS:(ESI,m / z):542.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.61(t,J=5.9Hz,1H),7.93(s,1H),7.31-7.23(m,1H),7.17(s,1H),7.07-6.96(m,1H),6.31(d, J=7.4Hz,1H),6.25(d,J=8.9Hz,1H),4.87(d,J=49.7Hz,1H),4.30(d,J=5.9Hz,2H),3.91-3.85( m,1H),3.81(s,3H),3.75(q,J=11.2Hz,2H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.4Hz,1H),2.3 7-2.21(m,1H),2.20(s,3H),2.13(t,J=11.2Hz,1H),2.00-1.87(m,1H),1.83(d,J=12.4Hz,1H).

[0394] Example 64 [ka]

[0395] Step 1: Synthesis of Compound 310-2 At 0°C, a solution of 2-hydrazinoethanol (compound 310-1, 76.1 mg, 1,000 mmol, 1 eq) in ethanol (100 mL) was added dropwise to a solution of 2-formyl-3-oxopropionate ethyl (144.13 mg, 1,000 mmol, 1 eq) in ethanol (100 mL). The mixture was allowed to return to room temperature and stirred overnight. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound 310-2 (180 mg, 97.8%). LCMS:(ESI,m / z):184.95 [M+H] + .

[0396] Step 2: Synthesis of Compound 310-3 At room temperature, 1-(2-hydroxyethyl)-1H-pyrazole-4-carboxylate ethyl (compound 310-2, 100 mg, 0.543 mmol, 1 eq) and lithium hydroxide (26.01 mg, 1.086 mmol, 2 eq) were added to a reaction flask. Further, tetrahydrofuran (5 mL, 61.714 mmol, 113.67 eq) and water (1 mL, 55.509 mmol, 102.25 eq) were added to dissolve the compounds, and the mixture was stirred overnight at 50°C. After the reaction was complete, the reaction solution was neutralized with 3 mol / L hydrochloric acid solution. The resulting residue was concentrated under reduced pressure, dissolved in tetrahydrofuran (10 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 310-3 (80 mg, 94.37%). LCMS:(ESI,m / z):157.00 [M+H] + .

[0397] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (compound 310) At room temperature, add 1-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid (compound 310-3, 20.53 mg, 0.132 mmol, 2 eq), N,N-diisopropylethylamine (33.99 mg, 0.264 mmol, 4 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) to a reaction flask, dissolve with N,N-dimethylformamide (2 mL), stir at room temperature for 10 minutes, and then further add 2-(3-aminopropane-1-in-1) Add -yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 30 mg, 0.066 mmol, 1 eq), stir for 1 hour, and after the reaction is complete, dilute the reaction mixture with ethyl acetate (5 mL), wash with saturated sodium chloride solution (10 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: XBridge). BEH C18 OBD Prep Column 130, 5μm, 30mm * 150mm; Mobile phase A: Water (17 mmol / L ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Elution gradient: 25% B to 44% B in 8 minutes; Detection wavelength: UV 254 nm / 220 nm; Retention time (minutes): 6.95), yielded compound 310, N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (9.4 mg, 26.89%).

[0398] LCMS:(ESI,m / z):522.00 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.67(t,J=5.6Hz,1H),8.19(s,1H),7.89(d,J=0.8Hz,1H),7.28(dd,J=8.8,7.6Hz,1H),7.02(d,J=8 .7Hz,1H),6.32(d,J=7.4Hz,1H),6.23(d,J=9.0Hz,1H),4.96-4.79(m,2H),4.33(d,J=5.6Hz,2H),4. 16(t,J=5.4Hz,2H),3.92-3.82(m,1H),3.80-3.66(m,4H),3.05(t,J=11.5Hz,1H),2.78(d,J=11.5Hz ,1H),2.36-2.24(m,1H),2.20(s,3H),2.13(t,J=10.5Hz,1H),1.98-1.89(m,1H),1.88-1.80(m,1H).

[0399] Example 65 [ka]

[0400] Step 1: Synthesis of Compound 312-1 Under nitrogen gas protection, at 50°C, a solution of methyl 1H-pyrrole-3-carboxylate (compound 014-1, 1 g, 7.992 mmol, 1 eq) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanedi(tetrafluoroboric acid) salt (4.25 g, 11.988 mmol, 1.5 eq) in acetonitrile (20.0 mL) was stirred and reacted for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 312-1 (58 mg, 5.07%). LCMS:(ESI,m / z):144.00 [M+H] + .

[0401] Step 2: Synthesis of Compound 312-2 At 80°C, a solution of methyl 5-fluoro-1H-pyrrole-3-carboxylate (compound 312-1, 48 mg, 0.335 mmol, 1 eq), cesium carbonate (327.83 mg, 1.005 mmol, 3 eq), and methyl iodide (95.21 mg, 0.670 mmol, 2 eq) in N,N-dimethylformamide (3 mL) was stirred and reacted for 1 hour. After the reaction was complete, the reaction mixture was quenched with water at room temperature, extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, backwashed with saturated sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 312-2 (40 mg, 75.89%), which was not further purified. LCMS:(ESI,m / z):158.00 [M+H] + .

[0402] Step 3: Synthesis of Compound 312-3 At 50°C, methyl 5-fluoro-1-methyl-1H-pyrrole-3-carboxylate (compound 312-2, 80 mg, 0.509 mmol, 1 eq) and sodium hydroxide (40.72 mg, 1.018 mmol, 2 eq) were reacted in methanol (2 mL) and water (2 mL) solutions with stirring for 1 hour. After the reaction was complete, the reaction mixture was acidified to pH=5 with a 1 mol / L hydrochloric acid solution, and then concentrated under vacuum to obtain the crude product compound 312-3 (35 mg, 48.04%), which was not further purified. LCMS:(ESI,m / z):144.00 [M+H] + .

[0403] Step 4: Synthesis of 5-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (compound 312) At room temperature, a solution of 5-fluoro-1-methyl-1H-pyrrole-3-carboxylic acid (compound 312-3, 6.27 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), and N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) in N,N-dimethylformamide (1 mL) was stirred and reacted for 30 minutes. Further reaction was carried out with 2-(3-aminopropa-1-in-1-yl)-N-((3S,4R)-3-fluoro Add -1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), stir continuously, and react for 2 hours. After the reaction is complete, quench the reaction mixture with water at room temperature, extract with ethyl acetate (3 × 10 mL), combine the organic phases, backwash with saturated sodium chloride solution (3 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by high-performance liquid chromatography under the following conditions (column specifications: Sunfire). C18 5μm, 30mm×150mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Elution gradient: 15% to 30% in 10 minutes; Detection wavelength: UV 254nm / 220nm; Retention time (minutes): 9.08), yielding compound 312, 5-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-yl)propa-2-in-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (12.59mg, 56.15%).

[0404] LCMS:(ESI,m / z):509.05 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.48(s,1H),7.32(t,J=8.1Hz,1H),7.06(d,J=8.7Hz,1H),7.01(d,J=2.5Hz,1H),6 .33(d,J=7.7Hz,1H),6.00(s,1H),5.13(d,J=47.6Hz,1H),4.29(d,J=4.8Hz,2H),4 .06(dd,J=28.8,9.0Hz,1H),3.73-3.59(m,4H),3.53(s,3H),3.33(d,J=10.6Hz,1H ),3.21(d,J=39.8Hz,1H),3.14(d,J=13.7Hz,1H),2.69(s,3H),2.25-1.95(m,2H).

[0405] Example 66 [ka]

[0406] Step 1: Synthesis of Compound 313-2 Under argon protection, at 90°C, 2,5-dimethoxytetrahydrofuran (compound 313 - 1,500 mg, 3.783 mmol, 1 eq), 1-methylcyclopropylamine (269.08 mg, 3.783 mmol, 1 eq), and anhydrous sodium acetate (772.25 mg, 5.675 mmol, 1.50 eq) were reacted in a solution of acetic acid (2 mL) / dichloroethane (10 mL) / water (6 mL) with stirring for 4 hours. After the reaction was complete, the reaction mixture was quenched at room temperature with a 2 mol / L sodium hydroxide solution, extracted with dichloromethane (3 × 30 mL), combined with the organic phase, backwashed with saturated sodium chloride (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 313-2 (480 mg). The resulting mixture was used directly in the next step without further purification.

[0407] 1 H NMR(400MHz,DMSO-d6,ppm)δ 6.79(t,J=2.2Hz,2H),5.94(t,J=2.2Hz,2H),1.46(s,3H),1.03-0.99(m,2H),0.82-0.78(m,2H).

[0408] Step 2: Synthesis of Compound 313-3 At 70°C, a solution of 1-(1-methylcyclopropyl)-1H-pyrrole (compound 313-2, 480 mg, 3.961 mmol, 1 eq) and trichloroacetyl chloride (1.08 g, 5.940 mmol, 1.50 eq) in dichloromethane (5 mL) was stirred and allowed to react overnight. After the reaction was complete, the reaction mixture was quenched at 0°C with saturated sodium carbonate aqueous solution, extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, backwashed with saturated sodium chloride (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography under the following conditions (column size C18; mobile phase: water and acetonitrile (0.1% formic acid), gradient from 20% to 60% over 15 minutes, detection wavelength: UV 254 nm), yielding compound 313-3 (450 mg, 42.62%). LCMS:(ESI,m / z):267.85 [M+2+H] + .

[0409] Step 3: Synthesis of Compound 313-4 Under nitrogen gas protection at room temperature, a solution of 2,2,2-trichloro-1-(1-(1-methylcyclopropyl)-1H-pyrrole-3-yl)ethane-1-one (compound 313-3, 200 mg, 0.750 mmol, 1 eq) and tetrahydrofuran (10.0 mL) in 10 mol / L sodium hydroxide (0.1 mL, 5 eq) was stirred and reacted for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH ~5 with hydrochloric acid solution and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 313-4 (120 mg, 96.81%). The resulting mixture was used directly in the next step without further purification.

[0410] 1H NMR(400MHz,DMSO-d6,ppm)δ 11.70(s,1H),7.39(t,J=2.0Hz,1H),6.88(t,J=2.6Hz,1H),6.32(dd,J=2.9,1.7Hz,1H),1.49(s,3H),1.09-1.04(m,2H),0.87-0.83(m,2H).

[0411] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazole[1,5a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxamide (compound 313) At room temperature, 1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxylic acid (compound 313-4, 20 mg, 0.121 mmol, 1 eq) and 2-(3-aminopropane-1-in-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidine-4-yl)-3-(2,2,2-trifluoroethyl)pyrazole[1,5-a]pyridine-7-amine dihydrochloride (compound 001-12, 46.42 mg, 0.121 mmol, 1 eq), N,N-diisopropyl A solution of pyrethylamine (78.24 mg, 0.605 mmol, 5 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46.04 mg, 0.121 mmol, 1 eq) in N,N-dimethylformamide (2 mL) was stirred and reacted for 1 hour. After the reaction was complete, the resulting residue was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography under the following conditions (column specifications: Xselect). Using a CSHTM Prep C18 5μm 30*150mm OBD; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; elution gradient: from 18% B to 34% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.9), compound 313 was obtained as N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidine-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazole[1,5a]pyridine-2-yl)propa-2-in-1-yl]-1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxamide (6.12 mg, 9.44%).

[0412] LCMS:(ESI,m / z):531.20 [M+H] + . 1H NMR(400MHz,DMSO-d6,ppm)δ 8.32(t,J=5.8Hz,1H),7.44(t,J=2.0Hz,1H),7.28(t,J=8.2Hz,1H),7.02(d,J...

Claims

1. Compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 In the formula, R １ , R ２ They are the same or different, and are independent of each other: H, halogen, C １－１２ alkyl group, C １－１２ Selected from alkoxy groups, R ３ H, C １－１２ Selected from alkyl groups, R ４ is selected from H, halogen, cyano group, C １－１２ alkyl group, C １－１２ alkoxy group, C ２－１２ alkenyl group, C ２－１２ alkynyl group, C ３－１２ cycloalkyl group, halo C １－１２ alkyl group, halo C １－１２ alkoxy group, halo C ３－１２ cycloalkyl group, cyano C １－１２ alkyl group, cyano C １－１２ alkoxy group, and is selected from W is C ２－６ Alkenylene group, C ２－６ Alkynylene group, C ３－１４ Cycloalkylene group, C ６－１０ Selected from allirene groups and 5-10 membered heteroarylene groups, Ring A is C ３－１４ Cycloalkyl group, 3-14 membered heterocyclyl group, C ６－１０ Selected from aryl groups and 5-10 membered heteroaryl groups, R ａ This is H, CN, oxo (=O), halogen, OH, unsubstituted, or selectively one, two or more R ａ１ C is replaced by １－１２ alkyl group, C １－１２ Alkoxy group, C ３－１２ Cycloalkyl group, 3-14 membered heterocyclyl group, C ６－１０ Aryl group, 5-10 membered heteroaryl group, -C(O)N(R ａ１１ ) (Caution ａ１２ ), -N(R ａ１３ ) (Caution ａ１４ ), -S(O) ２ -R ａ１５ , -S(O)(=NR ａ１６ ) (Caution ａ１７ ), -P(O)(R ａ１８ ) (Caution ａ１９ ) are selected from each R ａ１ These are identical or different, independently of each other, H, OH, CN, halogen, unsubstituted, or selectively one, two or more R ａ２ C is replaced by １－１２ alkyl group, C １－１２ Alkoxy group, C ３－１２ Cycloalkyl group, 3-14 membered heterocyclyl group, C ６－１０ Aryl group, 5-10 membered heteroaryl group, -NH ２ , -S(O) ２ -C １－１２ Selected from alkyl groups, each R ａ２ H, OH, NH are identical or different, and are independent of each other. ２ CN, halogen, C １－６ alkyl group, C １－６ Selected from alkoxy groups, R ａ１１ , R ａ１２ , R ａ１３ , R ａ１４ , R ａ１５ , R ａ１６ , R ａ１７ , R ａ１８ , R ａ１９ H and C are the same or different, and are independent of each other. １－１２ alkyl group, C ３－７ Selected from cycloalkyl groups and 3-8 membered heterocyclyl groups, m is selected from 0, 1, 2, 3, 4, and 5. Z does not exist, or it is NH, S, O, C １－６ Alkylene group, C １－６ Selected from alkylene-NH, Ring E is a 3-14 member heterocyclyl group, C ３－１２ Selected from cycloalkyl groups, R ｅ is H, halogen, unsubstituted, or selectively one, two or more R ｅ１ C is replaced by １－１２ Alkyl, halo C １－１２ Alkyl alkyl groups, deuterated C １－１２ alkyl group, C １－１２ Alkoxy group, C ３－１２ Cycloalkyl group, 3-14 membered heterocyclyl group, C １－１２ Alkyl-NH-, (C １－１２ Alkyl) ２ Selected from -N-, each R ｅ１ H, OH, NH are identical or different, and are independent of each other. ２ CN, halogen, C １－６ alkyl group, C １－６ Selected from alkoxy groups, or two R groups bonded to the same carbon atom ｅ Each of them, along with the atom to which it is bonded, is C ３－１２ A cycloalkane ring, a 3-14 membered heterocycle, or two R atoms bonded to different carbon atoms ｅ Each atom forms a 3-14 member heteroring with the atom it is bonded to, and p is selected from 0, 1, 2, 3, 4, and 5. X １ , X ２ , X ３ They are identical or different, independently selected from CH or N, and X １ , X ２ , X ３ At least two of them are CH, R ｘ is selected from H, CN, halogen, C １－１２ alkyl group, C １－１２ alkoxy group, n is selected from 0, 1, 2 or 3, Y is C(O), C(O)NH, C(S), SO ２ Compounds and their racemic mixtures, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, selected from the above.

2. R １ 、 R ２ 、 R ３ are the same or different and are independently selected from H, C １－６ alkyl groups, Preferably, R １ , R ２ , R ３ All of them are H, Preferably, R ４ C １－６ alkyl group, C ２－６ Alkenyl group, Halo C １－６ Alkyl alkyl, cyano C １－６ Selected from alkyl groups, Preferably, R ４ C １－６ Alkyl, halo C １－６ Alkyl alkyl, cyano C １－６ Selected from alkyl groups, Preferably, R ４ The group is selected from methyl group, ethyl group, propyl group, isopropyl group, vinyl group, cyanomethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, and 2,2,2-trifluoroethyl group. Preferably, R ４ The compound according to claim 1, characterized in that the group is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyanomethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group, as well as a racemic mixture thereof, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof.

3. W is C ２－４ Alkenylene group, C ２－４ Alkynylene group, C ３－６ Cycloalkylene group, C ６－１０ Selected from allirene groups and 5-6 membered heteroarirene groups, Preferably, W is 【Chemistry 2】 A compound according to claim 1 or 2, characterized by being selected from, and its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

4. Ring A consists of a phenyl group, a 5-6 membered heteroaryl group, an 8-9 membered heteroaryl group, a 6-10 membered heterocyclyl group, and C ３－６ Selected from member cycloalkyl groups, Preferably, ring A consists of a phenyl group, a 5-6 membered heteroaryl group, an 8-9 membered heteroaryl group, an 8-9 membered heterocyclyl group, and C ３－６ Selected from member cycloalkyl groups, Preferably, ring A is 【Transformation 3】 Selected from, Preferably, R ａ is H, CN, oxo (=O), halogen, OH, unsubstituted, or selectively one, two or more R ａ１ C is replaced by １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 4-7 membered heterocyclyl group, phenyl group, 5-6 membered heteroaryl group, -C(O)(NHC １－６ Alkyl), -S(O) ２ -C １－６ Alkyl alkyl group, -S(O)(=NH)(C) １－６ Alkyl), -S(O)(NC １－６ (Alkyl) (C １－６ Alkyl), -P(O)(C １－６ (Alkyl) (C １－６ Alkyl), -NH ２ Selected from, each R ａ１ They are the same or different, and are independent of each other: H, OH, CN, halogen, C １－６ Alkyl, halo C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 5-6 membered heterocyclyl group, phenyl group, 5-6 membered heteroaryl group, cyanoC １－６ Alkyl alkyl, cyano C １－６ Alkoxy group, C １－６ Alkyl alkyl-NH-, (C １－６ Alkyl) ２ -N-, -S(O) ２ -C １－６ alkyl group, C １－６ Alkylalkyl-O-C １－６ Alkyl alkyl groups, hydroxy C １－６ Selected from alkyl groups, Preferably, R ａ is H, F, Cl, CN, oxo (=O), OH, unsubstituted, or selectively one, two or more R ａ１ Methyl group, ethyl group, propyl group, isopropyl group, tert-butyl, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methoxy group, isopropoxy group, propoxy group, phenyl group, pyridyl group, benzyl group, piperidinyl group, 【Chemistry 4】 -C(O)NHCH ３ , -S(O) ２ -CH ３ , -S(O)(=NH)(CH ３ ), -P(O)(CH ３ ) (CH ３ ), -NH ２ Selected from, each R ａ１ These are identical or different, and independently of each other, H, CN, OH, F, Cl, methyl group, ethyl group, methoxy group, trifluoromethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, -CH ２ OCH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ OH, -CH ２ CN, -N(CH ３ ) ２ , -S(O) ２ -CH ３ , 【Transformation 5】 Selected from, Preferably, R ａ H, F, Cl, CN, oxo (=O), OH, NH ２ methylamino group, dimethylamino group, methyl group, ethyl group, isopropyl group, tert-butyl, -C(CH ３ ) ２ CH ２ CH ３ ien-CH ２ C (CH ３ ) ３ Cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyridyl group, benzyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, trifluoromethoxy group, methoxy group, isopropyloxy group, 2-hydroxyethyl group, 【Transformation 6】 Selected from, Preferably, 【Transformation 7】 teeth, 【Transformation 8】 A compound according to any one of claims 1 to 3, characterized by being selected from, and a racemic mixture thereof, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

5. Z does not exist, or NH, S, O, CH ２ ,CH ２ Selected from NH, Preferably, ring E is a 5-9 membered heterocyclyl group or C ５－６ Selected from cycloalkyl groups, Preferably, ring E is a 6-9 membered heterocyclyl group or C ５－６ Selected from cycloalkyl groups, Preferably, ring E is 【Chemistry 9】 Selected from, Preferably, ring E is 【Chemistry 10】 Selected from, Preferably, R ｅ This is H, halogen, unsubstituted, or selectively one, two or more R ｅ１ C is replaced by １－６ Alkyl, halo C １－６ Alkyl alkyl groups, deuterated C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 4-9 membered heterocyclyl group, (C １－６ Alkyl) ２ Selected from -N-, each R ｅ１ They are the same or different, and are independent of each other as OH, halogen, and C. １－３ alkyl group, C １－３ Selected from alkoxy groups, or two R groups ｅ Each of them, along with the atom to which it is bonded, is C ３－６ Forming a cycloalkane ring, Preferably, R ｅ H, halogen, C １－６ Alkyl, halo C １－６ Alkyl alkyl groups, deuterated C １－６ alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, 5-6 membered heterocyclyl group, (C １－６ Alkyl) ２ -N- selected, or two R ｅ Each of them, along with the atom to which it is bonded, is C ３－６ Forming a cycloalkane ring, Preferably, R ｅ H, F, Cl, methyl group, deuterated methyl group (CD) ３ ), trifluoromethyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, dimethylamino group, 【Chemistry 11】 Selected from, or two R atoms bonded to the same carbon atom ｅ Each atom, along with the atom to which it is bonded, forms a cyclopropane ring. 【Chemistry 12】 or two R atoms bonded to different carbon atoms ｅ Each atom, along with the atoms to which it is bonded 【Chemistry 13】 Forming, Preferably, R ｅ H, F, Cl, methyl group, deuterated methyl group (CD) ３ ), trifluoromethyl group, ethyl group, isopropyl group, cyclopropyl group, methoxy group, dimethylamino group, 【Chemistry 14】 Selected from, or two R atoms bonded to the same carbon atom ｅ Each atom, along with the atom to which it is bonded, forms a cyclopropane ring. 【Chemistry 15】 or two R atoms bonded to different carbon atoms ｅ Each atom, along with the atoms to which it is bonded 【Chemistry 16】 Forming, Preferably, X １ , X ２ , X ３ Both are CH, or X １ , X ２ , X ３ One of them is N, Preferably, R ｘ H, CN, halogen, C １－６ alkyl group, C １－６ Selected from alkoxy groups, Preferably, R ｘ The compound according to any one of claims 1 to 4, characterized in that is H, F, Cl, CN, a methoxy group, or a methyl group, and its racemic mixture, stereoisomer, tautomer, isotope-labeled, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

6. The compound shown in formula (I) has the structure shown below, 【Chemistry 17】 In the formula, ring A, ring E, X １ , X ２ , X ３ , Y, R １ , R ２ , R ３ , R ４ , R ａ , R ｅ , R ｘ m, n, and p have the definitions described in any one of claims 1 to 5. Preferably, the compound represented by formula (I) has the structure shown below, [Chemistry 18] In the formula, ring A, ring E, X １ , X ２ , X ３ , Y, R １ , R ２ , R ３ , R ４ , R ａ , R ｅ , R ｘ m, n, and p have the definitions described in any one of claims 1 to 5. Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 19】 In the formula, R ａ , R ｘ m and n have the definitions described in any one of claims 1 to 5. Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 20】 In the formula, ring A, R ａ , R ｘ m and n have the definitions described in any one of claims 1 to 5. Preferably, the compound represented by formula (I) has the structure shown below, 【Chemistry 21】 In the formula, R ａ , R ｅ The compound according to any one of claims 1 to 5, racemates thereof, stereoisomers, tautomers, isotope-labeled compounds thereof, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, characterized by having the definitions described in any one of claims 1 to 5.

7. The compound shown in formula (I) is 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 A compound according to any one of claims 1 to 6, characterized by being a structure selected from, a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound thereof, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug, or a pharmaceutically acceptable salt thereof.

8. The process includes one step of reacting compound 1 and compound 2 to obtain the compound shown in formula (I), 【Transformation 60】 In the formula, ring A, ring E, X １ , X ２ , X ３ W, Y, Z, R １ , R ２ , R ３ , R ４ , R ａ , R ｅ , R ｘ A method for producing a compound according to any one of claims 1 to 7, a racemate thereof, a stereoisomer, a tautomer, an isotope-labeled compound thereof, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug, or a pharmaceutically acceptable salt thereof, wherein m, n, and p have the definitions set out in any one of claims 1 to 7.

9. A pharmaceutical composition comprising at least one of the compounds described in any one of claims 1 to 7, a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound thereof, a racemic mixture thereof, a stereoisomer, a tautomer, a isotope-labeled compound thereof, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount.

10. Use in the manufacture of a drug of at least one of the compounds described in any one of claims 1 to 7, racemates, stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, Preferably, the use may be in the manufacture of a drug to combat tumors containing the p53-Y220C mutant, for example, in the manufacture of a p53-Y220C reactivator drug. Preferably, tumors containing the p53-Y220C variant include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendiceal cancer, astrocytoma, basal cell tumor, cholangiocarcinoma, bladder cancer, bone cancer, brain tumors such as cerebellar astrocytoma, cerebral astrocytoma / glioblastoma, ependymal cell tumor, neuromedulloblastoma, supratentorial blastoma, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt lymphoma, cancer of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancer, and chronic cancer. Lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid diseases, colon cancer, cutaneous T-cell lymphoma, fibrinogenic round cell tumor, endometrial cancer, ependymal cell tumor, esophageal cancer, Ewing's sarcoma, germ cell tumor, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, glioma, hairy cell leukemia, head and neck cancer, cardiac tumor, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip cancer and oral cancer, liposarcoma, liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), phosphorus P-type, leukemia, macroglobulinemia, malignant fibrous histiocytoma / osteosarcoma, medulloblastoma, melanoma, mesothelioma, primary metastatic squamous cell carcinoma, oral cancer, multiple endocrine neoplasia, myelodysplastic syndrome, myeloid leukemia, nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, pancreatic cancer, carcinoid, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, penile cancer, pharyngeal cancer, chromosomal cell tumor, pineal astrocytoma, Uses include pineal germ cell tumor, pituitary adenoma, pleuroblastoma, plasmacytoma, primary central nervous system islet cell carcinoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, non-epithelial malignancies, skin cancer, cutaneous Merkel cell tumor, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, T-cell lymphoma, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, gestational trophoblastoma, cancer of unknown primary origin, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor.

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