P53-y220c selective small-molecular reactivator compound, pharmaceutical composition and use thereof

Abstract

Provided in the present invention are compounds shown as formula (I) and racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, which have good p53-Y220C mutant activation effect, can be used for treating tumor diseases containing p53-Y220C mutant proteins, and can be used for preparing drugs for such disorders or diseases.

Description

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

[0001] The present invention claims the rights of patent application number 202310767412.7 filed with the State Intellectual Property Office of China on June 27, 2023, entitled “p53-Y220C selective small molecule reactivator compounds, pharmaceutical compositions and uses thereof”; patent application number 202310972386.1 filed with the State Intellectual Property Office of China on August 3, 2023, entitled “p53-Y220C selective small molecule reactivator compounds, pharmaceutical compositions and uses thereof”; patent application number 202311158861.8 filed with the State Intellectual Property Office of China on September 8, 2023, entitled “p53-Y220C selective small molecule reactivator compounds, pharmaceutical compositions and uses thereof”; Priority is claimed to the prior application, patent application number 202311378644.X, filed with the State Intellectual Property Office of China on October 23, 2023, entitled “p53-Y220C Selective Small Molecule Reactivator Compounds, Pharmaceutical Compositions, and Uses Thereof”; patent application number 202311566589.7, filed with the State Intellectual Property Office of China on November 22, 2023, entitled “p53-Y220C Selective Small Molecule Reactivator Compounds, Pharmaceutical Compositions, and Uses Thereof”; and patent application number 202410171815.X, filed with the State Intellectual Property Office of China on February 6, 2024, entitled “p53-Y220C Selective Small Molecule Reactivator Compounds, Pharmaceutical Compositions, and Uses Thereof”. The entire contents of the aforementioned prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compounds, and in particular relates to p53-Y220C selective small molecule reactivator compounds, pharmaceutical compositions and uses thereof. Background Art

[0003] Cancer is a collection of related diseases characterized by the uncontrolled proliferation of tumor cells, which may metastasize throughout the body. Tumor cell proliferation relies on oncogenes and tumor suppressor genes. Genetic mutations can lead to abnormal activation or inhibition of these genes, further promoting uncontrolled cell division. TP53, a well-known tumor suppressor gene, is known as the "guardian of the genome." TP53 belongs to the p53-like transcription factor family and consists of three members: the TP53, TP63, and TP73 genes, which encode three proteins, p53, p63, and p73, respectively. They share structural similarities: their DNA-binding domains are nearly identical, binding to similar DNA-specific sequences and regulating the transcription of the same and some different genes. Their C-terminal domains differ in size, sequence, and function, regulating DNA binding and transcription and mediating protein-protein interactions. Their N-terminal sequences encode at least two distinct transcriptional activation domains. Similar to p53, p63 is also a key transcription factor that responds to DNA damage by inducing apoptosis. It acts in the skull, face, limbs, and central nervous system, participating in the generation and regeneration of squamous cell 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 hearing system, the trachea, the lungs, the central nervous system, etc.

[0004] The p53 tumor suppressor factor is mainly distributed in the nucleus and cytoplasm of cells. As a sensor of cell stress, it can respond to a variety of cell stresses, including ultraviolet radiation, hypoxia, oncogene activation and DNA damage. After activation, p53 binds to specific DNA sequences in the form of a tetramer, mediating downstream gene transcription and inhibiting cancer progression through various mechanisms, such as regulating the cell cycle, apoptosis, aging, stem cell differentiation, metabolism (reducing sugar synthesis), ROS and mitochondria, DNA damage repair, etc. p53 can activate proteins involved in the above pathways, including, for example, Fas / Apol, KILLER / DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9 and p21. In addition, p53 can also inhibit the transcription of multiple genes, including c-MYC, CyclinB, VEGF, RAD51, and hTERT.

[0005] Due to its critical role in tumor suppression, the TP53 gene is the most frequently mutated gene in human cancers, with mutations occurring in nearly 50% of malignant tumors. In contrast to mutations in other tumor suppressor genes such as RB1, APC, and PTEN, the majority of TP53 mutations are missense mutations, accounting for up to 75%. Missense mutations are primarily located within the DNA-binding domain of p53, leading to abnormal folding of the protein sequence required for DNA recognition and binding. Numerous amino acid positions within p53 are potentially susceptible to mutation, including Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg299, Phe270, Arg273, and Arg282. Accordingly, p53 mutations that can abrogate wild-type p53 activity include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 mutations can both distort the structure of the DNA binding site and disrupt its thermodynamic stability. TP53 mutations can result in the loss of wild-type p53's tumor suppressor transcriptional activity through homozygous deletions (LOHs); dominant negative effects through heterozygous deletions; and gain-of-function effects, such as increased binding to p63 and p73, which promote tumorigenesis and progression. Therefore, mutant p53 proteins can be considered a heterogeneous group of proteins, exhibiting varying degrees of loss of normal tumor suppressor function and gain of oncogenic properties (GOF).

[0006] Although different p53 mutants exhibit varying activities, missense TP53 mutants can be considered proto-oncogenes, promoting tumor migration and drug resistance, leading to poor prognosis, and thus becoming therapeutic targets for drug development. Among them, the oncogenic p53 Y220C mutant exhibits a particularly suitable structure for the development of small-molecule stabilizers. It is the ninth most common missense p53 mutation found in cancer, accounting for approximately 100,000 new cancer cases worldwide each year. The mutation of Tyr220 to Cys creates a narrow hydrophobic cleft on the p53 DBD surface, reducing its thermal stability by approximately 4 kcal / mol. While wild-type p53 is moderately stable, melting and denaturing at 44°C, the Y220C mutant protein rapidly unfolds from its folded state and denatures at physiological body temperature, effectively abolishing the tumor suppressor signaling of wild-type p53 and driving tumorigenesis. Importantly, the hydrophobic cleft created by the Y220C mutation is located away from p53 protein surfaces involved in DNA recognition or protein-protein interactions, allowing for the development of small-molecule drugs without interfering with its binding to its natural DNA substrate. The Y220C mutant is a temperature-sensitive mutant that binds to DNA at lower temperatures and denatures at body temperature. When a small molecule compound selectively binds to the p53-Y220C mutant, it stabilizes the Y220C mutant, reducing the likelihood of p53 protein denaturation at body temperature. This compound converts p53 from its unfolded state to a folded state, restoring its wild-type conformation and transcriptional activity.

[0007] Studies have shown that several small molecules, such as PK083, PK7088, PK5196, and PC14586, can bind to the hydrophobic cleft of the Y220C mutant. However, these molecules, such as PK083, PK7088, PK5196, and PC14586, are effective at relatively high concentrations, and therefore, off-target effects cannot be ruled out. Therefore, there is a need to develop better small molecules that can more specifically bind to the Y220C mutant, better restore the structure and transcriptional activity of wild-type p53, and more effectively suppress tumors.

[0008] Summary of the Invention

[0009] To solve the problems existing in the prior art, the present invention provides a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt:

[0010] Wherein, R1 and R2 are the same or different and are independently selected from H, halogen, C 1-12 Alkyl, C 1-12 alkoxy;

[0011] R3 is selected from H, C 1-12 alkyl;

[0012] R4 is selected from H, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 3-12 Cycloalkyl, cyano C 1-12 Alkyl, cyano C 1-12 alkoxy;

[0013] W is selected from C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, C 6-10 Arylene, 5-10 membered heteroarylene;

[0014] Ring A is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0015] R a selected from H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)N(R a11 )(R a12 )、-N(R a13 )(R a14 )、-S(O)2-R a15 、-S(O)(=NR a16 )(R a17 )、-P(O)(R a18 )(R a19 ); each R a1 The same or different, independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R a2 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NH2, -S(O)2-C 1-12 Alkyl; each R a2The same or different, independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 The same or different, independently selected from H, C 1-12 Alkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5;

[0016] Z is absent or selected from NH, S, O, C 1-6 Alkylene, C 1-6 Alkylene-NH;

[0017] Ring E is selected from 3-14 membered heterocyclic group, C 3-12 Cycloalkyl;

[0018] R e Selected from H, halogen, unsubstituted or optionally substituted by one, two or more R e1 Substituted with the following groups: C 1-12 Alkyl, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 1-12 Alkyl-NH-, (C 1-12 Alkyl) 2-N-; each R e1 The same or different, independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; or, two R attached to the same carbon atom e and their respective atoms to form C 3-12 Cycloalkane ring, 3-14 membered heterocycle; or, two R e The atoms to which they are attached form a 3-14 membered heterocyclic ring; p is selected from 0, 1, 2, 3, 4, 5;

[0019] X1, X2, X3 are the same or different and are independently selected from CH or N, and at least two of X1, X2, X3 are CH;

[0020] R x Selected from H, CN, halogen, C 1-12 Alkyl, C 1-12Alkoxy; n is selected from 0, 1, 2 or 3;

[0021] Y is selected from C(O), C(O)NH, C(S), SO2.

[0022] According to some embodiments, R1, R2, and R3 are the same or different and are independently selected from H, C 1-6 alkyl.

[0023] According to some embodiments, R1, R2, and R3 are all H.

[0024] According to some embodiments, R4 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, halogenated C 1-6 Alkyl, cyano C 1-6 alkyl;

[0025] According to some embodiments, R4 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 alkyl;

[0026] According to some embodiments, R4 is selected from methyl, ethyl, propyl, isopropyl, vinyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0027] According to some embodiments, R4 is selected from methyl, ethyl, propyl, isopropyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0028] According to some embodiments, W is selected from C 2-4 Alkenylene, C 2-4 Alkynylidene, C 3-6 Cycloalkylene, C 6-10 Arylene, 5-6 membered heteroarylene;

[0029] According to some embodiments, W is selected from:

[0030] According to some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 5-10 membered heterocyclyl, C 3-6 cycloalkyl;

[0031] According to some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 8-9 membered heterocyclyl, C 3-6 cycloalkyl;

[0032] According to some embodiments, Ring A is selected from:

[0033] According to some embodiments, R a selected from H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -C(O)(NHC 1-6 Alkyl), -S(O)2-C 1-6 Alkyl, -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 The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, cyano 1-6 Alkyl, cyano C 1-6 Alkoxy, C 1-6 Alkyl-NH-, (C 1-6 alkyl)2-N-, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, hydroxyl C 1-6 alkyl;

[0034] According to some embodiments, R a selected from H, F, Cl, CN, oxo (=O), OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted groups: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, isopropoxy, propoxy, phenyl, pyridyl, benzyl, piperidyl, -C(O)NHCH3, -S(O)2-CH3, -S(O)(=NH)(CH3), -P(O)(CH3)(CH3), -NH2; each R a1the same or different, independently selected from H, CN, OH, F, Cl, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2OCH3, -CH2CH2OCH3, -CH2OH, -CH2CN, -N(CH3)2, -S(O)2-CH3,

[0035] According to some embodiments, R a Selected from H, F, Cl, CN, oxo (=O), OH, NH2, methylamino, dimethylamino, methyl, ethyl, isopropyl, tert-butyl, -C(CH3)2CH2CH3, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, benzyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, isopropyloxy, 2-hydroxyethyl,

[0036] According to some embodiments, Selected from

[0037] According to some embodiments, Z is absent or is selected from NH, S, O, CH2, CH2NH.

[0038] According to some embodiments, ring E is selected from 5-9 membered heterocyclyl or C 5-6 Cycloalkyl;

[0039] According to some embodiments, ring E is selected from 6-9 membered heterocyclyl or C 5-6 Cycloalkyl;

[0040] According to some embodiments, ring E is selected from

[0041] According to some embodiments, ring E is selected from

[0042] According to some embodiments, R e Selected from H, halogen, unsubstituted or optionally substituted by one, two or more R e1 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, (C1-6 Alkyl) 2-N-; each R e1 the same or different, independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy; or, two R e and their respective atoms to form C 3-6 Cycloalkane ring:

[0043] According to some embodiments, R e Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, (C 1-6 Alkyl) 2-N-; or, two R e and their respective atoms to form C 3-6 Cycloalkane ring;

[0044] According to some embodiments, R e Selected from H, F, Cl, methyl, deuterated methyl (CD3), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, Alternatively, two R attached to the same carbon atom e and the atoms to which they are attached to form a cyclopropane ring, Alternatively, two R attached to different carbon atoms e With their respective attached atoms

[0045] According to some embodiments, R e Selected from H, F, Cl, methyl, deuterated methyl (CD3), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, Alternatively, two R attached to the same carbon atom e and the atoms to which they are attached to form a cyclopropane ring, Alternatively, two R attached to different carbon atoms e With their respective attached atoms

[0046] According to some embodiments, X1, X2, and X3 are all CH, or one of X1, X2, and X3 is N;

[0047] According to some embodiments, R x Selected from H, CN, halogen, C 1-6 Alkyl, C1-6 alkoxy;

[0048] According to some embodiments, R x Selected from H, F, Cl, CN, methoxy, methyl.

[0049] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0050] Among them, 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 described in the present invention.

[0051] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0052] Among them, 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 described in the present invention.

[0053] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0054] Among them, R a 、R x , m, and n have the definitions described in the present invention.

[0055] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0056] Among them, ring A, R a 、R x , m, and n have the definitions described in the present invention.

[0057] According to some embodiments, the compound represented by formula (I) has the structure shown below:

[0058] Among them, R a 、R e Has the definition described in the present invention.

[0059] According to some embodiments, among the compounds represented by formula (I) and their racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, illustrative, non-limiting specific examples of the compounds represented by formula (I) are as follows:

[0060] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps: reacting compound 1 with compound 2 to obtain the compound represented by formula (I);

[0061] Among them, 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 described in the present invention.

[0062] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

[0063] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0064] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more other therapeutic agents.

[0065] The present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

[0066] According to an embodiment of the present invention, the tumor is a tumor containing a p53-Y220C mutant.

[0067] The present invention also provides a method for treating tumor diseases, comprising administering to a patient a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition.

[0068] In some embodiments, the patient comprises a mammal, preferably a human.

[0069] The present invention also provides a compound represented by formula (I), at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts for treating tumor diseases, or a pharmaceutical composition thereof.

[0070] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof in the preparation of a drug.

[0071] According to an embodiment of the present invention, the use can be in the preparation of an anti-tumor drug containing a p53-Y220C mutant, such as in the preparation of a p53-Y220C reactivator drug.

[0072] According to an embodiment of the present invention, the tumor containing the p53-Y220C mutant includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumors such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive cell tumor, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt lymphoma, unknown primary cancer, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive cell tumor, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt lymphoma, unknown primary cancer, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma, gli ... cell tumors, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip and oral cancer, liposarcoma, liver cancer, lung cancer such as non-small cell lung cancer and small cell lung cancer Lung cancer, lymphoma, leukemia, macroglobulinemia, malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma, melanoma, mesothelioma, metastatic squamous cell carcinoma with occult primary, oral cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myeloid leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pine Astrocytoma, pineal germ cell tumor, pituitary adenoma, pleuropulmonary blastoma, plasmacytoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, Merkel cell carcinoma of the skin, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (pregnancy), cancer of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor. Beneficial effects

[0073] The compounds of the present invention have excellent activation effects on the p53-Y220C mutant and can effectively restore the activity of the p53-Y220C mutant protein. They are used to treat tumor diseases caused by the p53-Y220C mutant protein, as well as to prepare medicaments for such conditions or diseases. Furthermore, the novel compounds of the present invention, obtained through structural optimization, exhibit superior anti-tumor effects in various tumor models compared to prior art compounds, and have improved pharmacokinetic properties and safety.

[0074] Definitions and Explanations of Terms

[0075] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0076] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to reciting each integer value in the numerical range "1-14", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0077] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0078] "More" means three or more, for example, 3, 4, 5, 6, 7, 8, 9 or 10.

[0079] The term "C 1-12 "Alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, 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 the like or isomers thereof.

[0080] The term "C 2-12 "Alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical 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, a radical having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., C 2-8 alkenyl), for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-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-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0081] The term "C 2-12 “Alkynyl” is understood to mean a straight or branched monovalent hydrocarbon radical having 1 to 12 carbon atoms, containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, for example, having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., “C 2-8 alkynyl”), having 2, 3, 4, 5, or 6 carbon atoms (i.e., “C 2-6 Alkynyl”), having 2 or 3 carbon atoms (“C 2-3The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent- In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0082] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane 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 borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0083] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or polyaromatic rings fused together, preferably "C 6-10Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0084] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is 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, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzofused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 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-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4- 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6- , 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzoisoquinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[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-furo[3,4-c]cinnolinyl, 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-, or 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, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 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. When the 5- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0085] The term "carbocycle" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, a monocyclic ring such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as a bicyclo[11.1]pentane ring, a bicyclo[2.2.1]heptane ring, a bicyclo[3.2.1]octane ring or a bicyclo[5.2.0]nonane ring, a tertiary naphthalene ring, etc.), which may be optionally substituted with one or more (such as one, two or three) suitable substituents. The term "3-6 membered carbocycle" refers to a carbocycle containing 3, 4, 5 or 6 ring-forming carbon atoms.

[0086] Unless otherwise defined, the term "3-14 membered heterocyclyl" 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 (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetane; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-14-membered heterocyclic group or to a heteroatom on the 3-14-membered heterocyclic group ring. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0087] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0088] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0089] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0090] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0091] "Halo" means substituted with one or more halogens.

[0092] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0093] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom, or a sulfur atom is oxidized to form an oxy group (=O).

[0094] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0095] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above. Non-limiting examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, dihydroxypropyl, and the like.

[0096] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0097] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a linear or branched saturated divalent hydrocarbon radical. The definition of "alkyl" with respect to the number of carbon atoms in "alkylene" applies as defined above. It will be understood by those skilled in the art that an alkyleneoxy or oxyalkylene group can be attached to the remainder of the molecule in which it is contained in any orientation, i.e., the two terms are used interchangeably.

[0098] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure.

[0099] Unless otherwise specified, a heterocyclyl, heterocyclylene, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, etc. (if present) substituted at one, two, or more positions thereof or bonded to other groups include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0100] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., exists in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc.

[0101] Wavy lines intersecting chemical bonds Used to indicate the connection position between a group and other atoms in the molecular structure. Indicates connection with the 3-position of pyridyl. When the group connection position is not fixed, taking pyridyl as an example, It is shown in the following manner, which means that it can be connected to any connectable position on the pyridyl group. It means that it can be connected to any connectable position on the heteroaryl ring, for example, it can be connected to any of the four carbon atoms on the pyridine ring on the right side of the heteroaryl group, or it can be connected to a carbon atom on the pyrazole ring on the left side. Unless otherwise specified, similar expressions in this application are interpreted the same as above.

[0102] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are stereoisomers in the chemical structure, the bond Can be or include both Two configurations.

[0103] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 H or D) substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The presence of hydrogen in a substituent of the present invention without the separate listing of the term deuterium or tritium does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0104] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0105] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0106] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0107] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0108] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0109] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Figure 1: Tumor growth curve of experimental animals in the NUGC-3 human gastric cancer subcutaneous transplant tumor model.

[0111] Figure 2: Tumor growth curves of experimental animals in the female NOD / SCID model of subcutaneous xenografts of human lung cancer LU5269. DETAILED DESCRIPTION

[0112] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0113] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0114] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), or deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0115] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0116] Thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao Ocean Chemical GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0117] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0118] Example 1

[0119] Step 1: Synthesis of Compound 001-2

[0120] A solution of acetonitrile (4.72 g, 114.872 mmol, 3.4 eq) in tetrahydrofuran (150 mL) was added to the reaction flask. n-Butyl lithium (44 mL) was added dropwise at -78°C and stirring continued for 1 hour. A solution of 2,6-dichloropyridine (compound 001-1, 5 g, 33.786 mmol, 1 eq) in tetrahydrofuran (50 mL) was then added dropwise. The reaction was continued at -78°C for 2 hours before warming to room temperature for 30 minutes. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (3 x 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 crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to afford compound 001-2 (4.66 g, 89.49%).

[0121] 1 H NMR (400MHz, DMSO-d6) δ7.92 (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).

[0122] Step 2: Synthesis of Compound 001-3

[0123] 2-(6-chloropyridin-2-yl)acetonitrile (compound 001-2, 5 g, 32.770 mmol, 1 eq) was added to a reaction flask and dissolved in dichloromethane (100 mL). A solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (14.11 g, 65.546 mmol, 2.00 eq) in dichloromethane (70 mL) was added at 0°C and stirred at 0°C for 2 hours. After the reaction was complete, diethyl ether was added and the solvent was evaporated to give the crude product 001-3 (7 g, 40.65%), which was used directly in the next step.

[0124] Step 3: Synthesis of Compound 001-4

[0125] 1-Amino-2-chloro-6-(cyanomethyl)pyridin-1-ium-2,4,6-trimethylbenzenesulfonate (Compound 001-3, 8 g, 21.748 mmol, 1 eq) was added to a reaction flask and dissolved in methanol (80.0 mL). Potassium carbonate (6.01 g, 43.496 mmol, 2.00 eq) was added under an ice bath and the mixture was allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated, water was added, and the mixture was extracted with dichloromethane (3 x 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 crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to afford Compound 001-4 (1.7 g, 39.64%).

[0126] 1 H NMR (400MHz, DMSO-d6) δ7.28 (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).

[0127] Step 4: Synthesis of Compound 001-5

[0128] To a reaction flask, 7-chloropyrazolo[1,5-a]pyridin-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-butyl dicarbonate (2.01 g, 9.188 mmol, 1.1 eq) were added sequentially and dissolved in 1,4-dioxane (20 mL). The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with water and 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 crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford compound 001-5 (634 mg, 22.68%).

[0129] LCMS: (ESI, m / z): 267.85[M+H] + .

[0130] Step 5: Synthesis of Compound 001-6

[0131] N, N-dimethylformamide (344.03 mg, 4.706 mmol, 2 eq) and tetrahydrofuran (13 mL) were added to the reaction flask, and phosphorus oxychloride (1.08 g, 7.059 mmol, 3 eq) was added at 0°C and reacted for 30 minutes. Then, tert-butyl (7-chloropyrido[1,5-a]pyridin-2-yl)carbamate (compound 001-5, 630 mg, 2.353 mmol, 1 eq) was added and the temperature was raised to 40°C for 30 minutes. After the reaction was completed, 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%).

[0132] LCMS: (ESI, m / z): 296.00[M+H] + .

[0133] Step 6: Synthesis of Compound 001-7

[0134] To a reaction flask, tert-butyl (7-chloro-3-formylpyrido[1,5-a]pyridin-2-yl)carbamate (compound 001-6, 740 mg, 2.502 mmol, 1 eq) was added and dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The mixture was allowed to react at room temperature for 30 minutes. After the reaction, the solvent was directly evaporated to afford the crude product 001-7 (800 mg, 138.92%), which was used directly in the next step.

[0135] LCMS: (ESI, m / z): 196.00[M+H] + .

[0136] Step 7: Synthesis of Compound 001-8

[0137] 2-Amino-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (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 in acetonitrile (8 mL). Sodium nitrite (345.66 mg, 5.010 mmol, 2 eq) and potassium iodide (1.04 g, 6.262 mmol, 2.5 eq) were added to another reaction flask and dissolved in water (2 mL). This mixed aqueous solution was then added dropwise to the acetonitrile solution and allowed to react at room temperature overnight. After completion of the reaction, saturated aqueous sodium thiosulfate was added to quench the reaction, followed by extraction 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 obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 001-8 (180 mg, 23.21%).

[0138] 1 H NMR (400MHz, DMSO-d6) δ9.76 (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).

[0139] Step 8: Synthesis of Compound 001-9

[0140] To a reaction flask, 7-chloro-2-iodopyrazolo[1,5-a]pyridine-3-carbaldehyde (compound 001-8, 160 mg, 0.522 mmol, 1 eq) and (triphenylphosphonium)difluoroacetic acid inner salt (372.01 mg, 1.044 mmol, 2 eq) were added and dissolved in N,N-dimethylformamide (8.0 mL). The mixture was reacted at 60°C for 2 hours. Tetrabutylammonium fluoride solution (1 M in tetrahydrofuran, 1.566 mL, 1.566 mmol, 3.00 eq) was then added and the reaction continued for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate, followed by water and extraction 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 obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 001-9 (57 mg, 29.98%).

[0141] 1 H NMR (400MHz, DMSO-d6) δ7.85-7.82 (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).

[0142] Step 9: Synthesis of Compound 001-10

[0143] Under nitrogen protection, at 50 ° C, 7-chloro-2-iodo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (compound 001-9, 400 mg, 1.110 mmol, 1 eq), N-Boc-aminopropyne (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 were added. Propylamine (1.12 g, 11.100 mmol, 10 eq) was dissolved in tetrahydrofuran (6 mL) and stirred for 1 hour. After the reaction, 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 (2×20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:9) to give compound 001-10 (400 mg, 92.96%).

[0144] LCMS: (ESI, m / z): 387.95[M+H] + .

[0145] Step 10: Synthesis of Compound 001-11

[0146] Under nitrogen protection, the compound {3-[7-chloro-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]prop-2-yn-1-yl}carbamic acid tert-butyl ester (compound 001-10, 380 mg, 0.980 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-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-imidazol-2-ylidene]dichloro(2-methylpyridine)-1,3-dihydro-2H-imidazol-2-ylidene)carbamate was added. ) Palladium (82.43 mg, 0.098 mmol, 0.1 eq) and cesium carbonate (1.277 g, 3.920 mmol, 4 eq) were dissolved in 1,4-dioxane (4 ml) and stirred at 120°C for 4 hours. After the reaction was completed, the temperature was cooled to room temperature and diluted with water. The reaction mixture was extracted with ethyl acetate (3×50 mL), and 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 crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 001-11 (380 mg, 80.20%).

[0147] LCMS: (ESI, m / z): 483.90[M+H] + .

[0148] Step 11: Synthesis of Compound 001-12

[0149] At room temperature, tert-butyl N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (Compound 001-11, 100 mg, 0.207 mmol, 1 eq) was added to the reaction flask and dissolved in methanol (2 mL). 4M HCl / 1,4-dioxane (2 mL) was added dropwise at 0°C and reacted at room temperature for 1 hour. After completion of the reaction, the residue was concentrated in vacuo to afford Compound 001-12. LCMS: (ESI, m / z): 383.85 [M+H] + .

[0150] Step 12: Synthesis of 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 001)

[0151] At room temperature, N-hydroxybenzotriazole (22.21 mg, 0.0.164 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) were added to the reaction flask and stirred for 5 minutes. 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2 -trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (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) were stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was 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 crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: Sunfire C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 32% to 55% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 9.73) to obtain compound 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 001 (19.18 mg, 27.23%).

[0152] LCMS: (ESI, m / z): 534.25[M+H] + .

[0153] 1H NMR (400MHz, DMSO) δ8.62 (t, J=5.5Hz, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.28 (t, J=8.2Hz, 1H), 7.02 (d, J=8.7Hz, 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), 4.34 (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).

[0154] Example 2

[0155] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-propyl]-1H-pyrazole-4-carboxamide (Compound 003)

[0156] At room temperature, a 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (40 mg, 0.106 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred for 30 minutes. 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 40 mg, 0.104 mmol, 1 eq) was added and the reaction was stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with water at room temperature and 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 HPLC under the following conditions (chromatographic 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: 27% to 54% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.48) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-propyl]-1H-pyrazole-4-carboxamide 003 (16.65 mg, 36.45%).

[0157] LCMS: (ESI, m / z): 520.15[M+H] + .

[0158] 1H NMR (400MHz, DMSO-d6) δ8.65 (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).

[0159] Example 3

[0160] Step 1: Synthesis of 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 004)

[0161] To a solution of 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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) in N,N-dimethylformamide (0.8 mL) was added N,N-diisopropyl benzoate at room temperature. Ethylamine (56.65 mg, 0.440 mmol, 5 eq) was stirred for 1 hour, and then O-(7-azabenzotriazole-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) was added and stirred for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to quench the reaction. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 31% B to 54% B in 10 min; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.63) to obtain compound 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 004 (21.27 mg, 47.61%).

[0162] LCMS: (ESI, m / z): 506.10[M+H] + .

[0163] 1H NMR (400MHz, DMSO-d6) δ8.65 (t, J=5.6Hz, 1H), 8.22 (d, J=0.7Hz, 1H), 7.89 (d, J=0.7Hz, 1H), 7.28 (d d, 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=11.3Hz, 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).

[0164] Example 4

[0165] Step 1: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 005)

[0166] Under nitrogen 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), N, N-diisopropylethylamine (50.57 mg, 0.390 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-amino)-1-nitropropane-2-ol was added. The mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and backwashed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 33% B to 60% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.95) to obtain compound 1-cyclopropyl-N-[3-(7-[[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 005 (17.74 mg, 43.63%).

[0167] LCMS: (ESI, m / z): 517.85[M+H] + .

[0168] 1H NMR (400MHz, DMSO-d6) δ8.63 (t, J=5.6Hz, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.28 (dd, J=8.7, 7.6H z, 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).

[0169] Example 5

[0170] Step 1: Synthesis of Compound 006-2

[0171] To the reaction flask were added 1H-pyrazole-4-carboxylic acid ethyl ester (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), dissolved in N,N-dimethylformamide (10 mL), and reacted at 80°C for 3 hours. After the reaction was completed, the reaction solution was poured into water and 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 crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 006-2 (1.5 g, 97.40%).

[0172] LCMS: (ESI, m / z): 195.10[M+H] + .

[0173] Step 2: Synthesis of Compound 006-3

[0174] 1-Cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (compound 006-2, 200 mg, 1.030 mmol, 1 eq) was added to the reaction flask and dissolved with ethanol (2 mL). Then, sodium hydroxide (10 M, 2 mL, 10 mmol, 10 eq) was added and reacted at 50 ° C for 2 hours. After the reaction, the solvent was dried, some 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), and 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 crude compound 006-3 (190 mg).

[0175] Step 3: Synthesis of 1-cyclobutyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 006)

[0176] The reaction flask was added with 1-cyclobutyl-1H-pyrazole-4-carboxylic acid (compound 006-3, 30 mg, 0.181 mmol, 1 eq), 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 69. The mixture was dissolved in 1% paraformaldehyde (21 mg, 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), N,N-diisopropylethylamine (116.66 mg, 0.905 mmol, 5 eq), and N,N-dimethylformamide (3 mL). 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 HPLC using the following conditions (column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), B: acetonitrile; flow rate: 60 ml / min; gradient: 36% B to 56% B over 10 minutes; wavelength: UV 254 nm / 220 nm; retention time (min): 9.2) to obtain compound 1-cyclobutyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 006.

[0177] LCMS: (ESI, m / z): 531.85[M+H] + .

[0178] 1H NMR (400MHz, DMSO-d6) δ8.64 (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), 4.95-4.7 9 (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=1 1.5Hz, 1H), 2.49-2.29 (m, 5H), 2.20 (s, 3H), 2.13 (t, J=10.8Hz, 1H), 1.96-1.72 (m, 4H).

[0179] Example 6

[0180] Step 1: Synthesis of Compound 007-1

[0181] Under nitrogen, ethyl 1H-pyrazole-4-carboxylate (compound 006-1, 500 mg, 3.568 mmol, 1 eq), bromocyclopentane (1063.43 mg, 7.136 mmol, 2 eq), and cesium carbonate (3487.38 mg, 10.704 mmol, 3 eq) were added to a reaction flask and dissolved in N,N-dimethylformamide (5 mL). 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%).

[0182] LCMS: (ESI, m / z): 209.05[M+H] + .

[0183] Step 2: Synthesis of Compound 007-2

[0184] Under nitrogen, ethyl 1-cyclopentyl-1H-pyrazole-4-carboxylate (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. Dissolved in tetrahydrofuran (1 mL) / water (1 mL) / anhydrous methanol (1 mL) was added. The mixture was heated to 50°C and stirred for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 1 mol / L aqueous hydrochloric acid to pH 7. The mixture was concentrated under reduced pressure. The resulting residue was added with 10 mL of tetrahydrofuran, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to afford Compound 007-2 (95 mg, 54.29%).

[0185] LCMS: (ESI, m / z): 181.00[M+H] + .

[0186] Step 3: Synthesis of 1-cyclopentyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 007)

[0187] Under nitrogen protection, 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), N, N-diisopropylethylamine (33.7 mg, 0.260 mmol, 5 eq) were added to the reaction bottle, and N, N-dimethylformamide (2 mL) was added to dissolve the mixture, and the mixture was stirred at room temperature for 10 minutes. 2-(3-Aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.052 mmol, 1 eq) was added and reacted for 1 hour. After the reaction was completed, 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 crude product was purified by high performance liquid chromatography under the following conditions (XBridge BEH C18 OBD Prep Column 5μm, 30mm×150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 34% B to 60% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.02) to obtain compound 1-cyclopentyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 007 (7.1 mg, 24.37%).

[0188] LCMS: (ESI, m / z): 545.90[M+H] + .

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.62 (t, J=5.6Hz, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.28 (dd, J=8.8, 7.6Hz, 1H), 7.0 2 (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).

[0190] Example 7

[0191] Step 1: Synthesis of Compound 009-1

[0192] Under nitrogen, 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 and dissolved in N,N-dimethylformamide (5 mL). 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 crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 18:1) to obtain compound 009-1 (480 mg, 64.25%).

[0193] LCMS: (ESI, m / z): 197.00[M+H] + .

[0194] Step 2: Synthesis of Compound 009-2

[0195] Under nitrogen protection, 1-(oxetane-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 009-1, 200 mg, 0.960 mmol, 1 eq) and lithium hydroxide (115.00 mg, 4.800 mmol, 5 eq) were added to the reaction flask, and tetrahydrofuran (1 mL) / water (1 mL) / anhydrous methanol (1 mL) were added to dissolve the mixture. The mixture was heated to 50° C. and stirred for 1 hour. After the reaction was completed, the mixture was neutralized with 1 mol / L aqueous hydrochloric acid to pH = 7. The mixture was concentrated under reduced pressure, and 10 mL of tetrahydrofuran was added to the residue, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to give compound 009-2 (95 mg, 54.29%).

[0196] LCMS: (ESI, m / z): 169.00[M+H] + .

[0197] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide (Compound 009)

[0198] Under nitrogen protection, 1-(oxetane-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), N,N-diisopropylethylamine (33.7 mg, 0.078 mmol, 1.5 eq) were added to the reaction bottle. The product was dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 10 minutes. 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 20 mg, 0.052 mmol, 1 eq) was added and stirred at room temperature for 1 hour. The desired product was found in the liquid. 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 over 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 (HPLC) under the following conditions (chromatographic 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: 5% B to 29% B in 10 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 8.53) to give compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide 009 (5.79 mg, 20.80%).

[0199] LCMS: (ESI, m / z): 534.05[M+H] + .

[0200] 1H NMR (400MHz, DMSO-d6) δ8.75-8.70 (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), 4.9 2(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, 1 H), 2.41-2.28 (m, 1H), 2.22 (d, J=2.1Hz, 3H), 2.14 (m, 1H), 1.94-1.83 (m, 2H).

[0201] Example 8

[0202] Step 1: Synthesis of Compound 010-1

[0203] At room temperature, 1H-pyrazole-4-carboxylic acid ethyl ester (compound 006-1, 1 g, 7.136 mmol, 1 eq), potassium isopropenyl trifluoroborate (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 the reaction flask, and the mixture was diluted with dichloroethane (10 mL), oxygen was introduced, and the reaction was carried out at 70 ° C overnight. After the reaction was completed, the reaction mixture was quenched with a saturated solution of ethylenediaminetetraacetic acid disodium salt, filtered, and the filtrate was extracted with ethyl acetate (3×30 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (3×20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 010-1 (900 mg, 69.99%).

[0204] LCMS: (ESI, m / z): 180.95[M+H] + .

[0205] Step 2: Synthesis of Compound 010-2

[0206] Under nitrogen protection, diethylzinc (2.74 g, 22.195 mmol, 5 eq) was added to a solution of trifluoroacetic acid (2.53 g, 22.195 mmol, 5 eq) in dichloromethane (10 mL) at 0°C. After stirring and reacting for 20 minutes, diiodomethane (11.89 g, 44.390 mmol, 10 eq) was added dropwise at 0°C. After stirring and reacting for 20 minutes, a solution of 1-(prop-1-en-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 010-1, 800 mg, 4.439 mmol, 1 eq) in dichloromethane (3 mL) was added dropwise at 0°C. The reaction was stirred at 20°C for 16 hours. After the reaction was completed, the reaction mixture was quenched with water 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 crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 2% to 55% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 9.73) to obtain compound 010-2 (90 mg, 10.44%).

[0207] LCMS: (ESI, m / z): 195.45[M+H] + .

[0208] Step 3: Synthesis of compound 010-3

[0209] Under nitrogen protection, a solution of 1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (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 at room temperature. After the reaction, the reaction mixture was diluted with water at room temperature, acidified to pH = 5 with 1 mol / L hydrochloric acid solution, and 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 without further purification to obtain compound 010-3 (50 mg, 83.49%).

[0210] LCMS: (ESI, m / z): 167.40[M+H] + .

[0211] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide (Compound 010)

[0212] 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazole)-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 for 30 minutes, and 2-( 3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 27.46 mg, 0.060 mmol, 1 eq) was stirred for 2 hours. After the reaction, the reaction mixture was quenched with water 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 crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 35% to 57% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.52) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide 010 (15.49 mg, 48.18%).

[0213] LCMS: (ESI, m / z): 532.10[M+H] + .

[0214] 1H NMR (400MHz, DMSO-d6) δ8.63 (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).

[0215] Example 9

[0216] Step 1: Synthesis of Compound 012-2

[0217] Under nitrogen, tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (compound 012-1, 300 mg, 0.928 mmol, 1 eq) was added to a reaction flask and dissolved in 1,4-dioxane (4 mL). A 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was basified to pH 8 with saturated sodium carbonate solution. The mixture was concentrated under reduced pressure, water was added, and extraction with dichloromethane (20 mL x 2) was performed. 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%).

[0218] LCMS: (ESI, m / z): 224.45[M+H] + .

[0219] Step 2: Synthesis of compound 012-3

[0220] Under nitrogen protection, 1-(piperidin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 012-2, 150 mg, 0.672 mmol, 1 eq), sodium cyanoborohydride (84.43 mg, 1.344 mmol, 2 eq), 37% formaldehyde aqueous solution (40.34 mg, 1.344 mmol, 2 eq), acetic acid (0.04 mL, 0.067 mmol, 0.1 eq) were added to the reaction flask, methanol (5 mL) was added for dissolution, and the mixture was heated to 60 ° C and stirred for 1 hour. After the reaction was completed, saturated ammonium chloride (10 mL) was added to the reaction mixture at 0 ° C to quench the reaction mixture. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography under the following conditions: C18 chromatography column, mobile phase: water (0.1% ammonium bicarbonate) and acetonitrile, 10% to 20% gradient 10 minutes, detection wavelength: UV 254 nm. Compound 012-3 (50 mg, 30.64%) was obtained.

[0221] LCMS: (ESI, m / z): 238.00[M+H] + .

[0222] Step 3: Synthesis of Compound 012-4

[0223] Under nitrogen protection, 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 012-3, 50 mg, 0.211 mmol, 1 eq) and lithium hydroxide (10 mg, 0.422 mmol, 2 eq) were added to the reaction flask, dissolved with water (1.0 mL) and tetrahydrofuran (1.0 mL), and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give compound 012-4 (45 mg, 94.51%).

[0224] LCMS: (ESI, m / z): 210.05[M+H] + .

[0225] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide (Compound 012)

[0226] Under nitrogen protection, 1-(1-methylpiperidin-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), N, N-diisopropylethylamine (33.7 mg, 0.260 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and added. 2-(3-Aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.052 mmol, 1 eq) was stirred at room temperature for 1 hour. After the reaction, water was added and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and backwashed with saturated sodium chloride solution (10 mL × 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 (chromatographic 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 per minute; elution gradient: 5% B to 35% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 4.5) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide 012 (2.24 mg, 8.69%).

[0227] 1H NMR (400MHz, Chloroform-d) δ8.01 (s, 1H), 7.81 (s, 1H), 7.18 (t, J=7.8Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.33 (t, J=5.5Hz, 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).

[0228] Example 10

[0229] Step 1: Synthesis of Compound 013-1

[0230] A solution of 1H-pyrazole-4-carboxylic acid ethyl ester (Compound 006-1, 400 mg, 2.854 mmol, 1 eq), 4-methylbenzenesulfonic acid oxalanyl ester (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 at 80°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with water at room temperature and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were 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 afford Compound 013-1 (300 mg, 46.87%). LCMS: (ESI, m / z): 224.85 [M+H]. + .

[0231] Step 2: Synthesis of Compound 013-2

[0232] At 50 ° C, 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (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) were stirred for 1 hour. After the reaction, the reaction mixture was diluted with water at room temperature, acidified to pH = 5 with 1 M hydrochloric acid solution, and 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 without further purification to give compound 013-2 (160 mg, 73.15%). LCMS: (ESI, m / z): 197.05 [M+H] + .

[0233] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (Compound 013)

[0234] 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (32.56 mg, 0.085 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred for 30 minutes, and 2 -(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 32.56 mg, 0.071 mmol, 1 eq) was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was quenched with water 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 crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 31% to 61% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.45) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide 013 (28.05 mg, 70.00%).

[0235] LCMS: (ESI, m / z): 562.15[M+H] + .

[0236] 1H NMR (400MHz, DMSO-d6) δ8.67 (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=9.0 Hz, 1H), 4.94 (s, 0.5H), 4.81 (s, 0.5H), 4.44 (m, 1H), 4.34 (d, J=5.4Hz, 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).

[0237] Example 11

[0238] Step 1: Synthesis of Compound 014-2

[0239] Under nitrogen protection, a solution of 1H-pyrazole-4-carboxylic acid methyl ester (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, the reaction mixture was concentrated in vacuo and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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 (min): 7.08) to give compound 014-2 (120 mg, 12.00%).

[0240] LCMS: (ESI, m / z): 211.05[M+H] + .

[0241] Step 2: Synthesis of 3-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 014)

[0242] 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (33.38 mg, 0.088 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred for 30 minutes, and then the mixture was added. 2-(3-Aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 40.06 mg, 0.088 mmol, 1.2 eq) was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and 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 (chromatographic 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: 24% to 50% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 8.8) to obtain compound 3-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 014.

[0243] LCMS: (ESI, m / z): 576.15[M+H] + .

[0244] 1H NMR (400MHz, DMSO-d6) δ8.64 (t, J=5.6Hz, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.2 8 (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, 5 H), 3.45 (ddd, J=11.5, 8.0, 3.2Hz, 2H), 3.06 (t, J=9.7Hz, 1H), 2.78 (d, J=11.6 Hz, 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).

[0245] Example 12

[0246] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-phenyl-1H-pyrazole-4-carboxamide (Compound 015)

[0247] Under nitrogen 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), N, N-diisopropylethylamine (33.71 mg, 0.260 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropyl)-1-nitropropane was added. The mixture was stirred for 1 hour, and after the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm*150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 41% B to 67% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.55) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-phenyl-1H-pyrazole-4-carboxamide 015 (11.42 mg, 39.47%).

[0248] LCMS: (ESI, m / z): 553.90[M+H] + .

[0249] 1H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.85 (t, J=5.5Hz, 1H), 8.19 (s, 1H), 7.87 (d, J=7.9Hz, 2H), 7.54 (t, J=7.9H z, 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=1 1.7Hz, 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).

[0250] Example 13

[0251] Step 1: Synthesis of Compound 022-2

[0252] 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 to the reaction flask in sequence, dissolved in N, N-dimethylformamide (10 mL), and reacted at 80°C for 5 hours. After the reaction, the reaction solution was poured into water and 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 give compound 022-2 (1.4 g, 79.11%).

[0253] LCMS: (ESI, m / z): 246.85[M+H] + .

[0254] Step 2: Synthesis of compound 022-3

[0255] 2-(4-bromo-1H-pyrazol-1-yl)-2-isobutyric acid methyl ester (compound 022-2, 1.15 g, 4.654 mmol, 1 eq) was added to the reaction flask and dissolved with ethanol (23.0 mL). Sodium borohydride (528.2 mg, 13.962 mmol, 3 eq) was added at 0°C, and the reaction was continued at room temperature for 2 hours. Water was added to quench the reaction mixture, and 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%).

[0256] LCMS: (ESI, m / z): 218.95[M+H] + .

[0257] Step 3: Synthesis of Compound 022-4

[0258] 2-(4-Bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol (compound 022-3, 900 mg, 4.108 mmol, 1 eq) was added to the reaction flask and dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (821.54 mg, 20.540 mmol, 5 eq, 60%) was added at 0°C and stirred for 30 minutes. Methyl iodide (1166.19 mg, 8.216 mmol, 2 eq) was then added. The reaction was warmed to room temperature and the reaction was continued for 2 hours. 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 022-4 (900 mg, 89.28%).

[0259] LCMS: (ESI, m / z): 232.90[M+H] + .

[0260] Step 4: Synthesis of compound 022-5

[0261] Under nitrogen, 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). n-Butyl lithium (2.4 mL, 2 eq, 2.5 M) was added dropwise at -78°C and stirred for 30 minutes. Propyl chloroformate (331.2 mg, 2.703 mmol, 0.9 eq) was then added and stirring continued for 1 hour. After the reaction was complete, the reaction solution was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×150 mL). The organic phases were combined, 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 give compound 022-5 (220 mg, 27.44%).

[0262] LCMS: (ESI, m / z): 241.30[M+H] + .

[0263] Step 5: Synthesis of Compound 022-6

[0264] To the reaction flask was added 1-(1-methoxy-2-methylpropane-2-yl)-1H-pyrazole-4-carboxylic acid propyl ester (compound 022-5, 200 mg, 0.832 mmol, 1 eq), dissolved with methanol (2 mL), and then sodium hydroxide (10 M) (1.6 mL, 8.32 mmol, 10 eq) was added. The reaction was continued at 50 ° C for 1 hour. After the reaction, the solvent was directly dried, water was added, and the pH was adjusted to 4 with 1 M hydrochloric acid. 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 022-6 (180 mg, 98.20%).

[0265] LCMS: (ESI, m / z): 199.10[M+H] + .

[0266] Step 6: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methoxy-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide (Compound 022)

[0267] The reaction flask was added with 1-(1-methoxy-2-methylpropane-2-yl)-1H-pyrazole-4-carboxylic acid (compound 022-6, 30 mg, 0.151 mmol, 1 eq), 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 58.03 mg, 0.151 mmol, 1 eq), 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 dissolved in N, N-dimethylformamide (3 mL) and reacted at room temperature for 1 hour. After the reaction, water was added to the reaction solution and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic 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; gradient: 36% B to 58% B in 8 minutes; wavelength: UV 254 nm / 220 nm; retention time (minute): 8.12) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxamide 022 (12.28 mg, 14.14%).

[0268] LCMS: (ESI, m / z): 564.25[M+H] + .

[0269] 1H NMR (400MHz, DMSO-d6) δ8.62 (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 =11.1Hz, 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).

[0270] Example 14

[0271] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 024)

[0272] 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 A solution of 2-(7-azobenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (35.7 mg, 0.094 mmol, 1.2 eq) in N,N-dimethylformamide (1 mL) was stirred for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 30 mg, 0.078 mmol, 1 eq) was added. The mixture was stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and 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 (chromatographic 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 254 nm / 220 nm; retention time (min): 9.08), to give compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide 024 (14.57 mg, 33.97%).

[0273] LCMS: (ESI, m / z): 546.05[M+H] + .

[0274] 1H NMR (400MHz, DMSO-d6) δ9.04 (t, J=5.5Hz, 1H), 8.97 (s, 1H), 8.33 (3, 1H), 7.28 (dd, J=8.7, 7.6Hz, 1 H), 7.02 (d, J=8.6Hz, 1H), 6.32 (d, J=7.4Hz, 1H), 6.20 (d, J=9.1Hz, 1H), 4.87 (d, J=49.4Hz, 1H), 4.3 8 (d, J=5.5Hz, 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=1 1.5Hz, 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).

[0275] Example 15

[0276] Step 1: Synthesis of Compound 029-1

[0277] Under nitrogen protection, 1H-pyrazole-4-carboxylic acid ethyl ester (compound 006-1, 100 mg, 0.714 mmol, 1 eq), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 2,2,2-trifluoro-1-methylethyl ester (565.36 mg, 1.428 mmol, 2 eq) and cesium carbonate (697.48 mg, 2.142 mmol, 3 eq) were added to the reaction flask at room temperature, dissolved with N,N-dimethylformamide (2 mL), and stirred for overnight. After the reaction, the reaction mixture was poured into water (10 mL) and 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 give compound 029-1 (120 mg, 71.20%).

[0278] LCMS: (ESI, m / z): 237.00[M+H] + .

[0279] Step 2: Synthesis of Compound 029-2

[0280] At room temperature, 1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 029-1, 100 mg, 0.423 mmol, 1 eq) and lithium hydroxide (15.21 mg, 0.634 mmol, 1.5 eq) were added to the reaction flask, dissolved with tetrahydrofuran (2 mL) and water (1 mL), and the reaction was stirred overnight. The residue was concentrated under reduced pressure to give compound 029-2 (80 mg, 90.78%).

[0281] LCMS: (ESI, m / z): 209.35[M+H] + .

[0282] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxamide (Compound 029)

[0283] At room temperature, 1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxylic acid 029-2 (18.25 mg, 0.088 mmol, 2 eq), O-(7-azabenzotriazole-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) were added to the reaction bottle, dissolved in N,N-dimethylformamide (1 mL), stirred for 20 minutes, and then 2-(3-aminoprop-1-yne-1- The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was poured into water (10 mL) and 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. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 37% B to 67% B in 10 minutes; wavelength: UV 254nm / 220nm; retention time (minute): 8.22) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1,1,1-trifluoropropyl-2-yl)-1H-pyrazole-4-carboxamide 029 (5.01 mg, 19.89%).

[0284] LCMS: (ESI, m / z): 573.85[M+H] + .

[0285] 1H NMR (400MHz, DMSO-d6) δ8.81 (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=11.5 Hz, 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).

[0286] Example 16

[0287] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrido[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (Compound 030)

[0288] At room temperature, 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3- The mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL × 3), 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 (chromatographic column specifications: XBridge BEH Shield RP18 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: 32% B to 57% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.83) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrido[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide 030 (5.06 mg, 13.56%).

[0289] LCMS: (ESI, m / z): 559.85[M+H] + .

[0290] 1H NMR (400MHz, Methanol-d4) δ8.17 (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=11.6Hz, 1H), 2.33 (dd, J=37.4, 13.3Hz, 1H), 2.20-2.16 (m, 4H), 1.96-1.88 (m, 2H).

[0291] Example 17

[0292] Step 1: Synthesis of 1-(difluoromethyl)-N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 035)

[0293] Under nitrogen protection, 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), N, N-diisopropylethylamine (50.57 mg, 0.390 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (2 mL), and stirred at room temperature. Stir for 10 minutes, then add 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 30 mg, 0.078 mmol, 1 eq), stir and react for 1 hour. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL×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 (HPLC) under the following conditions (chromatographic column specifications: XBridge BEH Shield RP18 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: 30% B to 57% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.79) to give compound 1-(difluoromethyl)-N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 035 (19.49 mg, 47.08%).

[0294] LCMS: (ESI, m / z): 527.85[M+H] + .

[0295] 1H NMR (400MHz, DMSO-d6) δ8.97 (t, J=5.5Hz, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 7.87 (t, J=58.8Hz, 1H), 7.2 9 (dd, J=8.8, 7.6Hz, 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).

[0296] Example 18

[0297] Step 1: Synthesis of Compound 082-2

[0298] Under nitrogen protection, ethyl 2-isocyanate (compound 082-1, 5 g, 44.202 mmol, 1 eq) was added to the reaction flask and dissolved in anhydrous ethanol (50.0 mL). (Dimethoxymethyl)dimethylamine (10.53 g, 88.404 mmol, 2 eq) was added dropwise at 0°C and stirred at room temperature overnight. After the reaction was completed, the solvent was directly dried and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 082-2 (5.6 g, 71.56%).

[0299] LCMS: (ESI, m / z): 169.10[M+H] + .

[0300] 1 H NMR (400MHz, DMSO-d6) δ7.31 (s, 1H), 4.11 (q, J=7.1Hz, 2H), 3.19 (s, 6H), 1.20 (t, J=7.1Hz, 3H).

[0301] Step 2: Synthesis of Compound 082-3

[0302] To the reaction flask were added (2E)-3-(dimethylamino)-2-isocyanopropyl-2-enoic acid ethyl ester (compound 082-2, 1 g, 5.945 mmol, 1 eq) and tert-butylamine (2.5 mL, 0.034 mmol, 4 eq) and stirred overnight at 140°C. After the reaction was completed, the reaction solution 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 residue was purified by silica gel column chromatography (ethyl acetate) to give compound 082-3 (600 mg, 48.85%).

[0303] LCMS: (ESI, m / z): 196.90[M+H] + .

[0304] Step 3: Synthesis of Compound 082-4

[0305] 1-tert-Butyl-1H-imidazole-4-carboxylic acid ethyl ester (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 the reaction flask and reacted at 50 ° C for 2 hours. After the reaction, 3 M dilute hydrochloric acid was added to adjust the pH to neutral, and the solvent was dried to obtain compound 082-4 (50 mg, 27.71%).

[0306] LCMS: (ESI, m / z): 169.05[M+H] + .

[0307] Step 4: Synthesis of 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-imidazole-4-carboxamide (Compound 082)

[0308] The reaction flask was added with 1-tert-butyl-1H-imidazole-4-carboxylic acid (compound 082-4, 35 mg, 0.208 mmol, 1 eq), 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 79.78 mg, 0.208 mmol, 1 eq), O-(7-aza Benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (118.68 mg, 0.312 mmol, 1.5 eq), N,N-diisopropylethylamine (134.48 mg, 1.040 mmol, 5 eq), dissolved in N,N-dimethylformamide (4 mL), reacted at room temperature for 2 hours, quenched with water after the reaction was completed, extracted with ethyl acetate (3× 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 (chromatographic column specifications: Kinetex 5 μm EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 27% B to 58% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (min): 7.02), to give compound 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-imidazole-4-carboxamide 082 (19.97 mg, 17.95%).

[0309] LCMS: (ESI, m / z): 533.95[M+H] + .

[0310] 1H NMR (400MHz, DMSO-d6) δ8.45 (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).

[0311] Example 19

[0312] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]cyclopropylcarboxamide (Compound 135)

[0313] At room temperature, cyclopropylcarboxylic acid (4.53 mg, 0.053 mmol, 1.2 eq), N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20.0 mg, 0.053 mmol, 1.2 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (1 mL), stirred for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R )-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1 eq) was stirred and reacted for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and 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 (chromatographic column specifications: Sunfire C18 5μm, 30mm×150mm; mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 27% to 57% in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.93) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]cyclopropylcarboxamide 135 (4.46 mg, 22.43%).

[0314] LCMS: (ESI, m / z): 452.05[M+H] + .

[0315] 1H NMR (400MHz, DMSO-d6) δ8.64 (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, 2 H), 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).

[0316] Example 20

[0317] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-4-(2-hydroxyprop-2-yl)benzamide (Compound 230)

[0318] Under nitrogen protection, 4-(2-hydroxypropan-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 the reaction bottle, dissolved in N, N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropan-1-yl)carbodiimide was added. -alkyn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1 eq) was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL×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 (chromatographic 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: 10% B to 35% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.78) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-4-(2-hydroxypropan-2-yl)benzamide 230 (15.33 mg, 63.40%).

[0319] LCMS: (ESI, m / z): 546.20[M+H] + .

[0320] 1H NMR (400MHz, DMSO-d6) δ8.99 (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).

[0321] Example 21

[0322] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (Compound 231)

[0323] Under nitrogen protection, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 40 mg, 0.088 mmol, 1 eq) and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl were added to the mixture at room temperature. To a solution of formamide (23.66 mg, 0.156 mmol, 1.5 eq) in N, N-dimethylformamide (0.8 mL) were added N, N-diisopropylethylamine (56.65 mg, 0.440 mmol, 5 eq) and O-(7-azabenzotriazole-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), and stirring was continued at room temperature for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to the reaction mixture to quench the reaction mixture. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 30% B to 53% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.67) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide 231 (4.78 mg, 8.49%).

[0324] LCMS: (ESI, m / z): 517.85[M+H] + .

[0325] 1H NMR (400MHz, DMSO-d6) δ8.45 (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=7.5Hz, 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=7.3H z, 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=1 1.4Hz, 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).

[0326] Example 22

[0327] Step 1: Synthesis of compound 232-1

[0328] To the reaction flask, 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-1-ol (compound 022-3, 1.1 g, 5.021 mmol, 1 eq), palladium acetate (112.7 mg, 0.502 mmol, 0.1 eq), 1,3-bis(diphenylphosphino)propane (207.1 mg, 0.502 mmol, 0.1 eq), triethylamine (5.5 mL) were added, followed by N,N-dimethylformamide (13.2 mL) and anhydrous methanol (13.2 mL). ), carbon monoxide was passed to 0.4 MPa, and the reaction was carried out at 140°C overnight. After the reaction was completed, it was filtered, water was added, and the mixture was extracted with ethyl acetate (3×50 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 residue was purified by reverse phase column chromatography under the following conditions (80 g C18 reverse phase chromatography column, mobile phase: water (0.1% ammonium bicarbonate) and acetonitrile, 5% to 30% gradient 30 minutes, flow rate: 60 ml per minute, detection wavelength: UV 254 nm) to obtain compound 232-1 (300 mg, 28.64%).

[0329] LCMS: (ESI, m / z): 199.05[M+H] + .

[0330] Step 2: Synthesis of compound 232-2

[0331] Under nitrogen, sodium hydroxide (40.36 mg, 1.008 mmol, 2 eq) was added to a solution of 1-(1-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid methyl ester (compound 232-1, 100 mg, 0.504 mmol, 1 eq) in methanol (1.0 mL) and water (1.0 mL) at room temperature and stirred at 50°C for 1 hour. After the reaction was completed, the reaction mixture was acidified to pH = 6 with dilute hydrochloric acid solution and extracted with ethyl acetate and dichloromethane (3:1) (5×20 mL). The organic phases were combined, backwashed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 232-2 (50 mg, 53.81%).

[0332] LCMS: (ESI, m / z): 184.95[M+H] + .

[0333] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-1-(1-hydroxy-2-methylpropyl-2-yl)-1H-pyrazole-4-carboxamide (Compound 232)

[0334] To a solution of 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) in N,N-dimethylformamide (1.0 mL) was added 1-(1-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (compound 232-2, 12.11 mg, 0.044 mmol, 1 eq) at room temperature under nitrogen. 066mmol, 1.5eq) and N, N-diisopropylethylamine (28.32mg, 0.220mmol, 5eq), stirred for 30 minutes, and then O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.67mg, 0.044mmol, 1eq) was added at room temperature and stirred for 1 hour. After the reaction was completed, methanol (1.0mL) was added to the mixture at room temperature to quench the reaction. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 5-5% B to 65% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.8) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-hydroxy-2-methylpropyl-2-yl)-1H-pyrazole-4-carboxamide 232 (6.43 mg, 26.37%).

[0335] LCMS: (ESI, m / z): 550.25[M+H] + .

[0336] 1H NMR (400MHz, DMSO-d6) δ8.62 (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).

[0337] Example 23

[0338] Step 1: Synthesis of compound 236-2

[0339] 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 with tetrahydrofuran (0.5 mL) and water (0.5 mL), and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 236-2. The resulting mixture was not further purified and directly used in the next step.

[0340] LCMS: (ESI, m / z): 182.00[M+H] + .

[0341] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6-(2-hydroxyprop-2-yl)pyridine-3-carboxamide (Compound 236)

[0342] 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 the reaction bottle, dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-nitropropanol)-2-nitropropanol)-3-nitropropanol)-1-nitropropanol)-2-nitropropanol)-3-nitropropanol)-4-nitropropanol)-2-nitropropanol)-3-nitropropanol)-1-nitropropanol)-2-nitropropanol)-3-nitropropanol)-4-nitropropanol)-3-nitropropanol)-3-nitropropanol)-1-nitropropanol)-2-nitropropanol)-3-nitropropanol)-3-nitropropanol)-4-nitropropanol)-3 ... 1-(2 ...2-(2-(2-(2-(2-(2-2-(2-(2-(2-2-(2-(2-(2-2-(2-(2-(2-2-(2-(2-(2-2-(2-(2-2-(2-(2-2-(2-(2-2-(2-(2-2-(2-(2-2-(2-2-(2-(2-2-(2-(2-2-(2-(2-2-(2-2-(2-(2-2 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: 5% B to 32% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.05) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6-(2-hydroxypropan-2-yl)pyridine-3-carboxamide 236 (4.77 mg, 10.32%).

[0343] LCMS: (ESI, m / z): 546.90[M+H] + .

[0344] 1H NMR (400MHz, DMSO-d6) δ9.24 (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=9.1 Hz, 1H), 5.34 (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=11.6H z, 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).

[0345] Example 24

[0346] Step 1: Synthesis of compound 261-2

[0347] A solution of (E)-2-cyano-3-ethoxyacrylate (compound 261-1, 25.44 g, 150.353 mmol, 1.00 eq), ethylhydrazine dihydrochloride (20 g, 150.353 mmol, 1 eq) and sodium acetate (12.33 g, 150.304 mmol, 1.00 eq) in anhydrous ethanol (200 mL) was stirred at 80°C overnight. After the reaction was completed, the reaction solution was spin-dried, 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%).

[0348] LCMS: (ESI, m / z): 183.95[M+H] + .

[0349] Step 2: Synthesis of compound 261-3

[0350] At 60°C, 5-amino-1-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester (compound 261-2, 8 g, 43.666 mmol, 1 eq) and lithium hydroxide (5.23 g, 218.330 mmol, 5 eq) were added to the reaction flask, and then methanol (24 mL), tetrahydrofuran (24 mL) and water (24 mL) were added to dissolve. The reaction was stirred overnight. After the reaction was completed, the organic phase was removed by vortexing, acidified to pH = 5 with hydrochloric acid solution (2 M), filtered, and the filter cake was collected and washed with water (20 mL × 2) to obtain compound 261-3 (3.2 g, 47.23%).

[0351] LCMS: (ESI, m / z): 155.85[M+H] + .

[0352] Step 3: Synthesis of 5-amino-1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 261)

[0353] At room temperature, a solution of 5-amino-1-ethyl-1H-pyrazole-4-carboxylic acid (compound 261-3, 2 g, 12.890 mmol, 1 eq) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.90 g, 12.890 mmol, 1.00 eq) and N,N-diisopropylethylamine (6.66 g, 51.560 mmol, 4 eq) in N,N-dimethylformamide (80.00 mL) was stirred for reaction. After 20 minutes, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 5.88 g, 12.890 mmol, 1 eq) was added and stirring was continued for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 15% B to 30% B in 20 minutes; detection wavelength: 254nm / 220nm; retention time (minutes): 18.5) to give the formate salt of 5-amino-1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 261 (748 mg, 10.13%).

[0354] LCMS: (ESI, m / z): 521.10[M+H] + .

[0355] 1H NMR (400MHz, DMSO-d6, ppm) δ8.26 (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=5.6H z, 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), 2.39-2.2 3 (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).

[0356] Example 25

[0357] Step 1: Synthesis of compound 268-1

[0358] Under nitrogen protection, 1H-pyrazole-4-carboxylic acid ethyl ester (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 the reaction flask and dissolved with N, N-dimethylformamide (5 mL, 64.608 mmol). The temperature was raised to 80 ° C. and stirred for 1 hour. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, backwashed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 268-1 (400 mg, 53.97%).

[0359] LCMS: (ESI, m / z): 195.00[M+H] + .

[0360] Step 2: Synthesis of compound 268-2

[0361] Under nitrogen protection, 1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 268-1, 200 mg, 1.030 mmol, 1 eq) and lithium hydroxide (49.32 mg, 2.060 mmol, 2 eq) were added to the reaction flask, dissolved with anhydrous ethanol (1 mL) and water (1 mL), and the temperature was raised to 50°C and stirred for 1 hour. After the reaction, the reaction mixture was concentrated under reduced pressure, 10 mL of tetrahydrofuran was added to the crude product, stirred for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to give compound 268-2 (50 mg, 27.76%).

[0362] LCMS: (ESI, m / z): 167.05[M+H] + .

[0363] Step 3: Synthesis of 1-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 268)

[0364] Under nitrogen protection, 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), N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (1.33 mL, 17.296 mmol), stirred at room temperature for 10 minutes, and 2-(3-amino)-1,2-dextrose ... The mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (20 mL × 2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: Kinetex 5μm EVO C18, 30mm*150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 31% B to 51% B in 8 min; detection wavelength: UV 254nm / 226nm; retention time (minutes): 7.03) to obtain compound 1-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 268.

[0365] LCMS: (ESI, m / z): 532.20[M+H] + .

[0366] 1H NMR (400MHz, DMSO-d6, ppm) δ8.69 (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=7.1H z, 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, 1H), 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).

[0367] Example 26

[0368] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (Compound 270)

[0369] Under nitrogen protection, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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 the reaction bottle, and N,N-dimethylformamide (0.8 mL) was used to prepare the mixture. To the solution, N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise. After stirring for 2 hours, O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added at room temperature and continued to stir for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to quench the reaction. The solvent was dried and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: Kinetex 5 μm EVO C18, 30 mm × 150 mm; mobile phase A: water (10 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 (min): 7.12) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide 270 (8.18 mg, 38.05%), LCMS: (ESI, m / z): 491.20 [M+H] + .

[0370] 1H NMR (400MHz, DMSO-d6, ppm) δ8.31 (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).

[0371] Example 27

[0372] Step 1: Synthesis of compound 271-2

[0373] Under nitrogen 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(diphenylphosphino)ferrocene (27.07 mg, 0.049 mmol, 0.1 eq), zinc powder (6.41 mg, 0.09 8mmol, 0.2eq), dissolved in N,N-dimethylacetamide (2mL, 21.510mmol), heated to 120°C and stirred for reaction for 1 hour. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate (10mL), and the filtrate was washed with saturated sodium chloride solution (20mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol=12:1) to give compound 271-2 (40mg, 27.34%).

[0374] LCMS: (ESI, m / z): 149.25[M+H] + .

[0375] Step 2: Synthesis of 5-cyano-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (Compound 271)

[0376] Under nitrogen 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), N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (1 mL, 12.922 mmol), stirred at room temperature for 10 minutes, and 2-(3-aminopropyl)-1,2-dimethylformamide (1 mL, 12.922 mmol) was added. -1-alkyn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1.00 eq) was stirred at room temperature for 1 hour. After the reaction, it was extracted with ethyl acetate (20 mL×2). The organic phases were combined, backwashed with saturated sodium chloride solution (10 mL×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 (chromatographic 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 254nm / 220nm; retention time (minutes): 7.02) to obtain compound 5-cyano-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide 271.

[0377] LCMS: (ESI, m / z): 516.05[M+H] + .

[0378] 1H NMR (400MHz, DMSO-d6, ppm) δ8.69 (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, 7.6Hz, 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 = 49.4Hz, 1H), 4.33 (d, J = 5.6Hz, 2H), 3.82-3.70 (m, 6H), 3.06 (t, J = 11.5Hz, 1H), 2.7 8 (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).

[0379] Example 28

[0380] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methyl-1H-pyrrole-3-carboxamide (Compound 272)

[0381] 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminoprop-1-yne-1-yl)-2-nitropropane-3-ol was added. The mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 6% B to 32% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.03), to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methyl-1H-pyrrole-3-carboxamide 272 (5.4 mg, 16.68%).

[0382] LCMS: (ESI, m / z): 491.05[M+H] + .

[0383] 1H NMR (400MHz, DMSO-d6, ppm) δ10.93 (s, 1H), 8.19 (t, J=5.7Hz, 1H), 7.28 (dd, J=8.7, 7.6Hz, 1H), 7.18 (d d, 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).

[0384] Example 29

[0385] Step 1: Synthesis of compound 273-2

[0386] To a reaction flask at room temperature was added 5-methyl-1H-pyrrole-3-carboxylic acid (compound 273-1, 200 mg, 1.598 mmol, 1 eq) and dissolved in dimethyl sulfoxide (3 mL). Potassium hydroxide (717.42 mg, 12.784 mmol, 8 eq) was then added and stirred for 50 minutes. Methyl iodide (181.5 mg, 1.278 mmol, 0.8 eq) was then added dropwise. Stirring was continued for 4 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The aqueous phase was retained and acidified to pH 1 with 4 mol / L hydrochloric acid. The extract was backwashed with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 273-2 (170 mg, 61.15%). The crude product was directly used in the next step.

[0387] LCMS: (ESI, m / z): 140.45[M+H] + .

[0388] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1,5-dimethyl-1H-pyrrole-3-carboxamide (Compound 273)

[0389] At room temperature, 1,5-dimethyl-1H-pyrrole-3-carboxylic acid (compound 273-2, 9.15 mg, 0.066 mmol, 1 eq), O-(7-azabenzotriazole-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 the reaction bottle, dissolved in N,N-dimethylformamide (1 mL), and stirred for 30 minutes before adding 2-(3-aminoprop-1-yn-1-yl)-N -((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1 eq), after reacting for 1 hour, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3×20 mL), the organic phases were combined, backwashed with saturated brine (3×20 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 (chromatographic column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm*150 mm; 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 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 5.98) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1,5-dimethyl-1H-pyrrole-3-carboxamide 273 (8.81 mg, 26.21%).

[0390] LCMS: (ESI, m / z): 505.10[M+H] + .

[0391] Example 30

[0392] Step 1: Synthesis of compound 274-2

[0393] At room temperature, 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(diphenylphosphino)propane (40.63 mg, 0.099 mmol, 0.1 eq), palladium acetate (22.11 mg, 0.099 mmol, 0.1 eq), anhydrous methanol (200 mg, 0.985 mmol, 1 eq) were added to a 50 mL autoclave. .0mL), N,N-dimethylformamide (2.0mL) and triethylamine (1.0mL). After the addition was completed, carbon monoxide (3-4MPa) was introduced into the system and stirring was continued at 140°C overnight. The resulting mixture was concentrated under reduced pressure and the crude product was purified by reverse phase column chromatography under the following conditions: (40gC18 reverse phase chromatography column, mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, 5% to 30% gradient over 30 minutes, detection wavelength: UV 254nm) to obtain compound 274-2 (110mg, 61.30%).

[0394] LCMS: (ESI, m / z): 183.05[M+H] + .

[0395] Step 2: Synthesis of compound 274-3

[0396] Under nitrogen protection, sodium hydroxide (21.95 mg, 0.548 mmol, 2 eq) was added to a solution of methyl 6,7-dihydro-4H-pyrazolo[3,2-c][1,4]oxazine-3-carboxylate (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 completed, the reaction mixture was acidified with hydrochloric acid solution to pH = 6, and the resulting residue was concentrated under reduced pressure. The reaction mixture was dissolved with tetrahydrofuran (2 mL), filtered, and the filter cake was washed with tetrahydrofuran (3×1 mL). The filtrate was concentrated under reduced pressure to give compound 274-3 (40 mg, 86.67%).

[0397] LCMS: (ESI, m / z): 169.05[M+H] + .

[0398] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide (Compound 274)

[0399] Under nitrogen protection, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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) were added to the N,N -dimethylformamide (0.8 mL) solution, N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise, and the reaction was stirred for 1 hour, and then O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added and the stirring was continued for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to quench the reaction, and the solvent was dried by spin drying. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm × 150 mm; 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 (min): 6.98) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide 274.

[0400] LCMS: (ESI, m / z): 534.10[M+H] + .

[0401] 1H NMR (400MHz, DMSO-d6, ppm) δ8.71 (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=4 9.4Hz, 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).

[0402] Example 31

[0403] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-(6-morpholin-4-yl)pyridine-3-carboxamide (Compound 275)

[0404] Under nitrogen protection, a solution of 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) and 6-(morpholin-4-yl)pyridine-3-carboxylic acid (13.69 mg, 0.066 mmol, 1.5 eq) in N,N-dimethylformamide (0.8 mL) was added. N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise to the mixture, and the reaction was stirred for 1 hour. O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added at room temperature and the stirring was continued for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to the reaction mixture to quench the reaction. The solvent was dried and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: XBridge BEH Shield RP18 5μm, 30mm×150mm; mobile phase A: water (10mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 34% B to 54% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.65) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-(6-morpholin-4-yl)pyridine-3-carboxamide 275 (14.07 mg, 55.63%).

[0405] LCMS: (ESI, m / z): 574.10[M+H] + .

[0406] 1H NMR (400MHz, DMSO-d6, ppm) δ8.88 (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=49.5H z, 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), 3.0 5 (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).

[0407] Example 32

[0408] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide (Compound 276)

[0409] At room temperature, 4,5,6,7-tetrahydropyrazolo[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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) were added to the reaction bottle, and the mixture was stirred at room temperature for 10 minutes, and 2-(3-amino)-1,2-dextrin was added. The mixture was stirred for 1 hour. After the reaction, it was diluted with ethyl acetate (5 mL). The reaction mixture was washed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm×150 mm; mobile phase A: water (17 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 33% B to 53% B in 7 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.07) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide 276 (5.43 mg, 22.33%).

[0410] LCMS: (ESI, m / z): 531.85[M+H] + .

[0411] 1H NMR (400MHz, DMSO-d6, ppm) δ8.50 (t, J=5.6Hz, 1H), 7.91 (s, 1H), 7.29 (t, J=8.2Hz, 1H), 7.03 (d, J=8.7 Hz, 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=6.4 Hz, 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).

[0412] Example 33

[0413] Step 1: Synthesis of Compound 039-1

[0414] Under nitrogen protection, to a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (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) were added cesium carbonate (2.09 g, 6.423 mmol, 3 eq) and potassium iodide (177.68 mg, 1.071 mmol, 0.5 eq) in batches, and the mixture was stirred at 80°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and filtered. The filter cake was washed with acetonitrile (3×10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 10:1) to give compound 039-1 (450 mg, 84.89%).

[0415] LCMS: (ESI, m / z): 213.00[M+H] + .

[0416] Step 2: Synthesis of Compound 039-2

[0417] Under nitrogen protection, sodium hydride (45.23 mg, 1.884 mmol, 2 eq) was added 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) at 0°C. The reaction was stirred for 30 minutes, and then iodomethane (267.5 mg, 1.884 mmol, 2 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, ice water (20 mL) was added to the reaction mixture at room temperature to quench it, and the mixture was extracted 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 crude product was purified by silica gel column chromatography (dichloromethane / anhydrous methanol = 20:1) to give compound 039-2 (130 mg, 60.97%). LCMS: (ESI, m / z): 227.00[M+H] + .

[0418] Step 3: Synthesis of Compound 039-3

[0419] Under nitrogen protection, to a solution of 1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 039-2, 130 mg, 0.575 mmol, 1 eq) in ethanol (1.5 mL) was added dropwise a solution of sodium hydroxide (45.96 mg, 1.150 mmol, 2 eq) in water (0.5 mL) at room temperature, and stirring was continued at 50°C for 1 hour. After the reaction was completed, the reaction mixture was acidified with hydrochloric acid solution to pH = 5, and the obtained residue was concentrated under reduced pressure, dissolved with tetrahydrofuran (3.0 mL), filtered, and the filter cake was washed with tetrahydrofuran (3×3 mL). The filtrate was concentrated under reduced pressure to give compound 039-3 (100 mg, 87.81%).

[0420] LCMS: (ESI, m / z): 199.00[M+H] + .

[0421] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxamide (Compound 039)

[0422] Under nitrogen protection, at room temperature, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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 added to an N,N-dimethyl-1H-pyrazole-4-carboxylic acid solution. N, N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) was added dropwise to the formamide (0.8 mL) solution. After stirring for 1 hour, O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) was added at room temperature and continued to stir for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to the reaction mixture at room temperature to quench the reaction mixture. The mixture was concentrated under reduced pressure and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 33% B to 63% B in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 7.1) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo-11,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrazole-4-carboxamide 039 (20.93 mg, 83.80%).

[0423] LCMS: (ESI, m / z): 564.15[M+H] + .

[0424] 1H NMR (400MHz, DMSO-d6, ppm) δ8.70 (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).

[0425] Example 34

[0426] Step 1: Synthesis of Compound 277-1

[0427] Under nitrogen protection, sodium hydride (76.72 mg, 3.196 mmol, 2 eq) was added to a solution of methyl pyrazole-4-carboxylate (compound 014-1, 200 mg, 1.598 mmol, 1 eq) in tetrahydrofuran (5 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes, and then bromoethane (348.34 mg, 3.196 mmol, 2 eq) dissolved in tetrahydrofuran (2 mL) was added dropwise at 0°C. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with saturated aqueous ammonium chloride at room temperature and 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to give compound 277-1 (240 mg, 98.02%). LCMS: (ESI, m / z): 154.10[M+H] + .

[0428] Step 2: Synthesis of Compound 277-2

[0429] At 50°C, a solution of 1-ethyl-1H-pyrrole-3-carboxylic acid methyl ester (compound 277-1, 20 mg, 0.131 mmol, 1 eq) and sodium hydroxide (5.22 mg, 0.131 mmol, 1 eq) in methanol (1 mL) and water (1 mL) was added to the reaction flask and stirred for 1 hour. After the reaction, the reaction mixture was adjusted to pH = 5 with 1 mol / L hydrochloric acid solution and concentrated in vacuo to give compound 277-2 (15 mg, 82.56%).

[0430] LCMS: (ESI, m / z): 140.15[M+H] + .

[0431] Step 3: Synthesis of 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrrole-3-carboxamide (Compound 277)

[0432] At room temperature, a solution of 1-ethyl-1H-pyrrole-3-carboxylic acid (compound 277-2, 6.1 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazole-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 added to the reaction flask and stirred for 30 minutes. Then, 2-(3-aminoprop-1-yn-1-yl)-N-(( 3S, 4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1 eq) was stirred at room temperature for 2 hours. After the reaction, 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 crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 36% to 51% in 7 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 6.22) to obtain compound 1-ethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrrole-3-carboxamide 277 (13.84 mg, 62.27%).

[0433] LCMS: (ESI, m / z): 505.15[M+H] + .

[0434] 1H NMR (400MHz, DMSO-d6, ppm) δ8.31 (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), 4.2 9 (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=11.4 Hz, 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).

[0435] Example 35

[0436] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methylfuran-3-carboxamide (Compound 278)

[0437] At room temperature, 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 O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) in N,N-dimethylformamide (1 mL) were added to the reaction flask and stirred at room temperature for 10 minutes. Then, 2-(3-aminoprop-1-yne-1-yl)-2-nitroprop-1-yne) was added to the above system. The mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL × 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 (chromatographic column specifications: Kinetex 5μm EVO C18, 30mm*150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 31% B to 51% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.98) to obtain compound N-13-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methylfuran-3-carboxamide 278 (5.2 mg, 23.87%).

[0438] LCMS: (ESI, m / z): 492.05[M+H] + .

[0439] 1H NMR (400MHz, DMSO-d6, ppm) δ8.70 (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), 3.98-3.82(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).

[0440] Example 36

[0441] Step 1: Synthesis of Compound 021-1

[0442] Under nitrogen protection, 1H-pyrazole-4-carboxylic acid ethyl ester (compound 006-1, 500 mg, 3.568 mmol, 1 eq), concentrated sulfuric acid (220 uL, 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 the reaction bottle at room temperature and stirred at 90°C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase column chromatography under the following conditions (C18 chromatography column, mobile phase: petroleum ether and ethyl acetate, 0% to 30% gradient 15 minutes, detection wavelength: UV 254 nm) to give compound 021-1 (270 mg, 41.53%), LCMS: (ESI, m / z): 211.00 [M+H] + .

[0443] Step 2: Synthesis of compound 021-2

[0444] At room temperature, a solution of 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) in tetrahydrofuran (2 mL) and water (1 mL) was added to a reaction flask. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated in vacuo, and the residue was dissolved in tetrahydrofuran (10 mL), filtered, and the filtrate was concentrated in vacuo to give Compound 021-2 (240 mg, 93.44%). LCMS: (ESI, m / z): 183.00 [M+H] + .

[0445] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methylbutan-2-yl)-1H-pyrazole-4-carboxamide (Compound 021)

[0446] At room temperature, a solution of 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) in N,N-dimethylformamide (1.2 mL) was added to the reaction flask and stirred for 10 minutes. 2-(3-aminopropane-1-yl)pyrazole-4-carboxylic acid was added. -alkyn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1.00 eq), stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated sodium chloride solution (10 mL×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 (chromatographic column specifications: Kinetex 5μm EVO C18, 30mm×150mm; mobile phase A: water (10mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 35% B to 54% B in 7 minutes; detection wavelength: UV 254nm / 226nm; retention time (minutes): 6.55) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo11,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methylbutan-2-yl)-1H-pyrazole-4-carboxamide 021 (14.31 mg, 39.55%).

[0447] LCMS: (ESI, m / z): 548.25[M+H] + .

[0448] 1H NMR (400MHz, DMSO-d6, ppm) δ8.63 (t, J=5.5Hz, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.29 (dd, J=8.8, 7.6Hz, 1H), 7.0 3(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).

[0449] Example 37

[0450] Step 1: Synthesis of compound 248-2

[0451] To a solution of tert-butyl 1H-pyrazole-4-carboxylate (compound 248-1, 200 mg, 1.189 mmol, 1 eq) in acetonitrile (2 mL) were added bromoacetonitrile (171.16 mg, 1.427 mmol, 1.2 eq) and potassium carbonate (493.01 mg, 3.567 mmol, 3 eq) at room temperature and stirred at 85°C for 2 hours. After the reaction was completed, the mixture was filtered and the filter cake was washed with acetonitrile (3×50 mL). The filtrate was concentrated under reduced pressure, the crude product was diluted with water (50 mL), and 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 give crude compound 248-2 (265 mg), which was directly used in the next step without further purification.

[0452] LCMS: (ESI, m / z): 208.00[M+H] + .

[0453] Step 2: Synthesis of compound 248-3

[0454] To a solution of tert-butyl 1-(cyanomethyl)-1H-pyrazole-4-carboxylate (compound 248-2, 260 mg, 1.255 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) was added iodomethane (890.4 mg, 6.275 mmol, 5 eq) at 0°C, and then lithium bistrimethylsilylamide (629.81 mg, 3.765 mmol, 3 eq) was slowly added dropwise. The mixture was warmed to room temperature and reacted for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride at 0°C, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography under the following conditions (chromatographic column specifications: 40 g, mobile phase: 0.001% trifluoroacetic acid and acetonitrile, 10% to 80% gradient over 15 minutes, detection wavelength: UV 254 nm) to give compound 248-3 (190 mg, 61.79%).

[0455] LCMS: (ESI, m / z): 236.00[M+H] + .

[0456] Step 3: Synthesis of Compound 248-4

[0457] To a solution of tert-butyl 1-(1-cyano-1-methylethyl)-1H-pyrazole-4-carboxylate (compound 248-3, 30 mg, 0.128 mmol, 1 eq) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature and the mixture was stirred for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude compound 248-4 (30 mg, 59.70%). The crude product was not further purified and was directly used in the next step.

[0458] LCMS: (ESI, m / z): 180.00[M+H] + .

[0459] Step 3: Synthesis of 1-(1-cyano-1-methylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 248)

[0460] 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) were added O-(7-azabenzotriazole-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) at room temperature. The reaction was stirred for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N -((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1 eq), the reaction was continued for 1 hour. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic phases were combined, backwashed with saturated brine (3×20 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 (chromatographic column specifications: XBridge BEH Shield RP185μm, 30mm*150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 36% B to 54% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.17) to obtain compound 1-(1-cyano-1-methylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 248 (15.7 mg, 43.41%).

[0461] LCMS: (ESI, m / z): 545.25[M+H] + .

[0462] 1H NMR (4()()MHz, DMSO-d6) δ8.81(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, 3H), 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).

[0463] Example 38

[0464] Step 1: Synthesis of compound 146-2

[0465] 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(diphenylphosphino)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 the mixture was added. N, N-dimethylformamide (2 mL) was charged with carbon monoxide, the pressure was 4 MPa, and the reaction was carried out at 140°C overnight. After the reaction was completed, the reaction mixture was quenched with water at room temperature and 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 reverse column chromatography under the following conditions (40 g C18 reverse phase chromatography column, mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, 5% to 30% gradient 10 minutes, detection wavelength: UV 254 nm) to obtain compound 146-2 (100 mg, 44.30%).

[0466] LCMS: (ESI, m / z): 195.05[M+H] + .

[0467] Step 2: Synthesis of compound 146-3

[0468] At room temperature, a solution of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid methyl ester (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 for 2 hours. After the reaction, the reaction mixture was acidified to pH = 5 with 1 mol / L hydrochloric acid solution and 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 obtain compound 146-3 (40 mg, 86.23%).

[0469] LCMS: (ESI, m / z): 181.10[M+H] + .

[0470] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]-1H-pyrazole-3-carboxamide (Compound 146)

[0471] At room temperature, 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) and N,N-diisopropylethylamine were mixed. A solution of amine (28.32 mg, 0.220 mmol, 5 eq) in N,N-dimethylformamide (1 mL) was stirred for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1 eq), and the reaction was continued with stirring for 2 hours. After the reaction was completed, the reaction mixture was quenched with water at room temperature and 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 (chromatographic 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 per minute; elution gradient: 32% to 58% in 8 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (min): 7.63), to give compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide 146 (14.94 mg, 61.91%).

[0472] LCMS: (ESI, m / z): 546.15[M+H] + .

[0473] 1H NMR (400MHz, DMSO-d6, ppm) δ8.47 (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), 6.32 (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), 3.85 (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, 1H), 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).

[0474] Example 39

[0475] Step 1: Synthesis of compound 279-2

[0476] Under air protection, a solution of methyl pyrazole-4-carboxylate (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 overnight. After completion of the reaction, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 279-1 (600 mg, 81.96%).

[0477] LCMS: (ESI, m / z): 170.00[M+H] + .

[0478] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(methoxyethyl)-1H-pyrrole-3-carboxamide (Compound 279)

[0479] To a solution of 1-(2-methoxyethyl)pyrrole-3-carboxylic acid (compound 279-1, 6.62 mg, 0.039 mmol, 1.5 eq) in N,N-dimethylformamide (1 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.84 mg, 0.052 mmol, 2 eq) at room temperature, and the reaction was stirred for 10 minutes. Then, (3S,4R)-N-[2-(3-aminopropyl)-1-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ -1-alkyne-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]-3-fluoro-1-methylpiperidin-4-amine (10 mg, 0.026 mmol, 1.00 eq) was stirred for 90 minutes, and 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 and adjusted as follows (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 17% B to 35% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.42) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(methoxyethyl)-1H-pyrrole-3-carboxamide 279 (6.14 mg, 18.00%).

[0480] LCMS: (ESI, m / z): 535.00[M+H] + .

[0481] 1H NMR (400MHz, DMSO-d6, ppm) δ8.33 (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).

[0482] Example 40

[0483] Step 1: Synthesis of compound 280-1

[0484] Under oxygen protection, at 70°C, a solution of methyl pyrazole-4-carboxylate (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 reacted overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate (3×20 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 = 5:1) to give compound 280-1 (250 mg, 37.87%).

[0485] LCMS: (ESI, m / z): 166.00[M+H] + .

[0486] Step 2: Synthesis of compound 280-2

[0487] To a solution of methyl 1-cyclopropylpyrrole-3-carboxylate (compound 280-1, 50 mg, 0.303 mmol, 1 eq) in methanol (0.5 mL) / water (0.5 mL) was added lithium hydroxide (21.75 mg, 0.909 mmol, 3 eq), and the mixture was stirred at 50°C for 1 hour. After the reaction, the reaction mixture was acidified to pH = 3 with hydrochloric acid solution and 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 give compound 280-2 (43 mg, 93.98%).

[0488] LCMS: (ESI, m / z): 151.00[M+H] + .

[0489] Step 3: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-prop-2-yn-1-yl]-1H-pyrrole-3-carboxamide (Compound 280)

[0490] 1-cyclopropylpyrrole-3-carboxylic acid (compound 280-2, 10 mg, 0.066 mmol, 1.5 eq), 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq), A solution of N, N-diisopropylethylamine (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 for 2 hours. After the reaction was completed, 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 (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm*150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 40% B to 59% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.98) to obtain compound 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(ethyl 2,2,2-trifluoroacetate)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrrole-3-carboxamide 280 (19.36 mg, 47.66%).

[0491] LCMS: (ESI, m / z): 517.00[M+H] + .

[0492] 1 H (400MHz, DMSO-d6, ppm) δ8.32 (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=2.5Hz, 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=49.9 Hz, 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).

[0493] Example 41

[0494] Step 1: Synthesis of compound 260-2

[0495] At room temperature, 2-pyrrolecarboxaldehyde (compound 260-1, 2 g, 21.030 mmol, 1 eq), methyl 3-bromopropionate (7.02 g, 42.060 mmol, 2 eq), and cesium carbonate (20.56 g, 63.090 mmol, 3 eq) were added to the reaction flask and dissolved with N,N-dimethylformamide (20.0 mL, 258.459 mmol, 12.29 eq). The reaction was carried out at 80°C for 1 hour, quenched with water, and extracted with ethyl acetate (3×20 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 260-2 (2.4 g, 59.83%).

[0496] LCMS: (ESI, m / z): 182.05[M+H] + .

[0497] Step 2: Synthesis of compound 260-3

[0498] Methyl 3-(2-formylpyrrol-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 at room temperature and dissolved in ethanol (10.0 mL). The mixture was allowed to react overnight at 50°C. After completion of the reaction, the mixture was quenched with water. 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 give compound 260-3 (210 mg, 22.15%). LCMS: (ESI, m / z): 164.10 [M+H] + .

[0499] Step 3: Synthesis of compound 260-4

[0500] At room temperature, 3H-pyrrolizine-6-carboxylic acid methyl ester (compound 260-3, 100 mg, 0.613 mmol, 1 eq) and rhodium on carbon (25.23 mg, 0.245 mmol, 0.4 eq) were added to the reaction flask, dissolved with ethanol (5 mL), placed in a hydrogen environment, and stirred at room temperature for 4 hours. After the reaction, the reaction solution 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%).

[0501] LCMS: (ESI, m / z): 166.05[M+H] + .

[0502] Step 4: Synthesis of compound 260-5

[0503] At room temperature, 2,3-dihydro-1H-pyrrolizine-6-carboxylic acid methyl ester (compound 260-4, 50 mg, 0.303 mmol, 1 eq) was added to the reaction flask, dissolved with methanol (1 mL, 24.699 mmol, 81.60 eq), and then a solution of sodium hydroxide (48.42 mg, 1.212 mmol, 4 eq) in water (2 mL) was added. The reaction was allowed to proceed at 50°C overnight. After the reaction was completed, the mixture was adjusted to neutral with 3M hydrochloric acid solution. The residue was concentrated under reduced pressure, dissolved with tetrahydrofuran (5 mL), filtered, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 260-5 (35 mg, 72.59%).

[0504] LCMS: (ESI, m / z): 152.00[M+H] + .

[0505] Step 5: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-2,3-dihydro-1H-pyrrolazine-6-carboxamide (Compound 260)

[0506] At room temperature, 2,3-dihydro-1H-pyrrolizine-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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (1 mL), stirred for 10 minutes, and then 2-(3-aminoprop-1-yne) was added. -1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1.00 eq), stirring was continued for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL×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 (chromatographic 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 34% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.48) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-2,3-dihydro-1H-pyrrolizine-6-carboxamide 260 (9.86 mg, 39.71%).

[0507] LCMS: (ESI, m / z): 517.15[M+H] + .

[0508] Example 42

[0509] Step 1: Synthesis of compound 281-2

[0510] Under nitrogen protection, 4-bromo-1H-pyrrole-2-carbaldehyde (compound 281-1, 5 g, 28.736 mmol, 1 eq), 2-bromoethanol (5.39 g, 43.104 mmol, 1.5 eq), and cesium carbonate (18.73 g, 57.472 mmol, 2 eq) were added to the reaction flask and dissolved with N,N-dimethylformamide (10 mL). The mixture was stirred at 80°C for 1 hour. After the reaction, the reaction mixture was extracted with ethyl acetate (50 mL×2), the organic phases were combined, backwashed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 281-2 (4 g, 63.65%).

[0511] LCMS: (ESI, m / z): 219.95[M+H] + .

[0512] Step 2: Synthesis of compound 281-3

[0513] Under nitrogen protection, 4-bromo-1-(2-hydroxyethyl)-1H-pyrrole-2-carbaldehyde (compound 281-2, 3.3 g, 15.134 mmol, 1 eq) and triethylamine (6.31 mL, 45.402 mmol, 3 eq) were added to the reaction flask and dissolved in dichloromethane (20 mL). p-Toluenesulfonyl chloride (3.46 g, 18.161 mmol, 1.2 eq) was added at 0°C and stirred at room temperature for overnight. After the reaction was completed, ice water (15 mL) was added to the reaction mixture at 0°C to quench the reaction mixture. The mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, backwashed with saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 281-3 (3 g, 42.44%).

[0514] Step 3: Synthesis of compound 281-4

[0515] Under nitrogen protection, 2-(4-bromo-2-formyl-1H-pyrrol-1-yl)ethyl-4-methylbenzenesulfonate (compound 281-3, 2 g, 5.373 mmol, 1 eq) was added to the reaction flask and dissolved with anhydrous ethanol (10 mL). Sodium borohydride (101.63 mg, 2.687 mmol, 0.5 eq) was added at 0°C and stirred at room temperature for 1 hour. After the reaction was completed, ice water (10 mL) was added to the reaction mixture at 0°C to quench the reaction mixture. The mixture was concentrated under reduced pressure, 20 mL of dichloromethane was added, stirred for 5 minutes, and filtered to give compound 281-4 (1.5 g, 62.21%).

[0516] Step 4: Synthesis of compound 281-5

[0517] Under nitrogen protection, 2-(4-bromo-2-(hydroxymethyl)-1H-pyrrol-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 stirred at room temperature for 1 hour. After the reaction, 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 (chromatographic column specifications: mobile phase: water and acetonitrile, 10% to 45% gradient 20 minutes, detection wavelength: UV 254 nm) to give compound 281-5 (160 mg, 22.05%).

[0518] LCMS: (ESI, m / z): 201.95[M+H] + .

[0519] Step 5: Synthesis of compound 281-6

[0520] To a 20 mL autoclave were added 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(diphenylphosphino)propane (65.32 mg, 0.158 mmol, 0.2 eq), triethylamine (560.93 mg, 5.54 4mmol, 7eq), dissolved in anhydrous methanol (3mL, 74.096mmol, 93.57eq) and N,N-dimethylformamide (3mL, 38.765mmol), filled with 4MPa of carbon monoxide into the kettle, heated to 140°C and stirred to react overnight. After the reaction, the reaction mixture was purified by reverse phase column chromatography under the following conditions (chromatographic column specifications: mobile phase: water and acetonitrile, 5% to 20% gradient 15 minutes, detection wavelength: UV 254nm) to obtain compound 281-6 (90mg, 62.66%).

[0521] LCMS: (ESI, m / z): 182.00[M+H] + .

[0522] Step 6: Synthesis of compound 281-7

[0523] Under nitrogen, methyl 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylate (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 stirred at 50°C overnight. After the reaction, the reaction mixture was acidified to pH = 3 with 1 mol / L hydrochloric acid solution, the mixture was concentrated under reduced pressure, 10 mL of dichloromethane was added, 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] + .

[0524] Step 7: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxamide (Compound 281)

[0525] Under nitrogen 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), N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.5 mg, 0.073 mmol, 1.1 eq) was added. 3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1.00 eq) was stirred and reacted for 1 hour. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic 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: 10% B to 32% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.05) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxamide 281 (13.62 mg, 38.08%).

[0526] LCMS: (ESI, m / z): 533.15[M+H] + .

[0527] 1H NMR (400MHz, DMSO-d6, ppm) δ8.34 (t, J=5.7Hz, 1H), 7.31-7.25 (m, 2H), 7.02 (d, J=8.6Hz, 1H), 6.3 1 (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).

[0528] Example 43

[0529] Step 1: Synthesis of compound 282-2

[0530] 2-Acetyl-3-(dimethylamino)ethyl 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 the reaction flask, dissolved in ethanol (8 mL), and reacted at 80°C for 2 hours. After the reaction, 10 mL of dichloromethane was added to dilute the mixture, washed with saturated sodium chloride solution (1×20 mL), dried over anhydrous sodium sulfate, and the solvent was dried. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 282-2 (454 mg, 41.13%).

[0531] LCMS: (ESI, m / z): 195.10[M+H] + .

[0532] Step 2: Synthesis of compound 282-3

[0533] 1-Cyclopropyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (compound 282-2, 100 mg, 0.515 mmol, 1 eq) was added to the reaction flask and dissolved with methanol (3 mL). Then, sodium hydroxide (1 M) (1 mL, 1.0 mmol, 2 eq) was added and reacted at 50 ° C for 10 hours. After the reaction, the solvent was dried and hydrochloric acid (1 M) was added to adjust the pH to acidic. 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%).

[0534] LCMS: (ESI, m / z): 167.05[M+H] + .

[0535] Step 3: Synthesis of 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)-pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methyl-1H-pyrazole-4-carboxamide (Compound 282)

[0536] The reaction flask was added with 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylic acid (compound 282-3, 30 mg, 0.181 mmol, 1 eq), 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 69.21 mg, 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), N, N-diisopropylethylamine (116.66 mg, 0.905 mmol, 5 eq), dissolved in N, N-dimethylformamide (2 mL), reacted at room temperature for 1 hour, quenched with water after the reaction, extracted with ethyl acetate (3×10 mL), combined the organic phases, 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 (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 10% B to 33% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.8), to obtain compound 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)-pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methyl-1H-pyrazole-4-carboxamide 282 (34.25 mg, 35.58%).

[0537] LCMS: (ESI, m / z): 532.55[M+H] + .

[0538] 1H NMR(4()()MHz, DMSO-d6, ppm) δ8.53(t, J=5.6Hz, 1H), 7.83(s, 1H), 7.28(t, J=8.2Hz, 1H), 7.03(d, J=8.7 Hz, 1H), 6.32 (d, J=7.6Hz, 1H), 6.25 (d, J=9.0Hz, 1H), 4.89 (d, J=49.4Hz, 1H), 4.30 (d, J=5.6Hz, 2H), 3.9 5-3.81 (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=11.3H z, 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).

[0539] Example 44

[0540] Step 1: Synthesis of Compound 047-2

[0541] 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 with stirring, followed by ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (Compound 047-1, 20 g, 94.67 mmol, 1 equiv). The temperature was raised to 60°C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and the pH was adjusted to 2-2.5 with 4 mol / L hydrochloric acid. 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] + .

[0542] Step 2: Synthesis of 5-amino-1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 047)

[0543] 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-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 41.85 mg, 0.109 mmol, 1.0 eq) were added. ), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (45.66 mg, 0.120 mmol, 1.1 eq), N,N-diisopropylethylamine (70.25 mg, 0.545 mmol, 5 eq) in N,N-dimethylformamide (2 mL) were stirred for 1 hour. After the reaction was completed, 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 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: 15% B to 31% B in 7 minutes; detection wavelength: 254nm / 220nm; retention time (minutes): 6.43) to obtain compound 5-amino-1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 047 (9.3 mg, 15.42%).

[0544] LCMS: (ESI, m / z): 549.15[M+H] + .

[0545] 1H NMR (4()()MHz, DMSO-d6) δ8.31(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=7.6Hz, 1H), 6.25 (d, J=9.0Hz, 1H), 6.18 (s, 2H), 4.87 (d, J=49.5Hz, 1H), 4.28 (d, J=5.6H z, 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).

[0546] Example 45

[0547] Step 1: Synthesis of compound 304-1

[0548] Under nitrogen protection, a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (compound 006-1, 180 mg, 1.284 mmol, 1 eq), 1-(phenylsulfonyl)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 at room temperature. After the reaction was completed, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 304-1 (150 mg, 59.52%).

[0549] LCMS: (ESI, m / z): 197.05[M+H] + .

[0550] Step 2: Synthesis of compound 304-2

[0551] Under nitrogen protection, a solution of ethyl 1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxylate (compound 304-1, 130 mg, 0.663 mmol, 1 eq) and diethylaminosulfur trifluoride (160.20 mg, 0.995 mmol, 1.5 eq) in dichloromethane (2 mL) was stirred and reacted for 1 hour at -78°C. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate (10 mL) at room temperature and extracted 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 give compound 304-2 (110 mg, 83.77%).

[0552] LCMS: (ESI, m / z): 199.35[M+H] + .

[0553] Step 3: Synthesis of compound 304-3

[0554] At 50°C, a solution of 1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (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, 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 (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%).

[0555] LCMS: (ESI, m / z): 171.35[M+H] + .

[0556] Step 4: Synthesis of N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxamide (Compound 304)

[0557] At room temperature, 1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxylic acid (compound 304-3, 20 mg, 0.118 mmol, 1 eq) and 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 45 mg, 0.118 mmol, 1 eq) were added. q), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (44.7 mg, 0.118 mmol, 1 eq), diisopropylethylamine (75.96 mg, 0.590 mmol, 5 eq) in N,N-dimethylformamide (1.66 mL) were stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the crude product was purified by high performance liquid chromatography under the following conditions (Column: XBridge BEH Shield RP185μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 15% B to 31% B in 7 minutes; detection wavelength: 254nm / 220nm; retention time (minutes): 6.43) to obtain compound N-(3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-fluorocyclopropyl)-1H-pyrazole-4-carboxamide 304 (10.06 mg, 15.28%).

[0558] LCMS: (ESI, m / z): 535.85[M+H] + .

[0559] 1 H NMR (400MHz, DMSO-d6) δ8.86 (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, 1H), 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, 2H), 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, 1H), 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).

[0560] Example 46

[0561] Step 1: Synthesis of compound 286-2

[0562] Under nitrogen protection, sodium acetate (197.5 mg, 2.408 mmol, 1 eq) was added to a solution of (2-methylpropyl)hydrazine hydrochloride (compound 286-1, 300 mg, 2.408 mmol, 1 eq) and ethyl (2E)-2-cyano-3-ethoxyacrylate (448.03 mg, 2.649 mmol, 1.1 eq) in anhydrous ethanol (6.0 mL) at room temperature. The mixture was stirred at 80°C for 2 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with anhydrous ethanol (3×4 mL), 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 give compound 286-2 (250 mg, 49.15%).

[0563] LCMS: (ESI, m / z): 211.90[M+H] + .

[0564] Step 2: Synthesis of compound 286-3

[0565] Under nitrogen, 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 at room temperature. The mixture was stirred at 50°C overnight. After completion of the reaction, 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. The filtrate was concentrated under reduced pressure to obtain compound 286-3 (100 mg). The crude product was used directly in the next step without further purification.

[0566] LCMS: (ESI, m / z): 184.05[M+H] + .

[0567] Step 3: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-1-isobutyl-1H-pyrazole-4-carboxamide (Compound 286)

[0568] Under nitrogen protection, at room temperature, 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) were added N-hydroxybenzotriazole (35.54 mg, 0.262 mmol, 1.5 eq) and N,N-diisopropylethylamine (113.3 mg, 0.262 mmol, 1.5 eq) in portions. 875mmol, 5eq), after reacting for 1 hour, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 80mg, 0.175mmol, 1eq) was added at room temperature and the reaction was continued for 1 hour. After the reaction was completed, methanol (1.0mL) was added to the reaction mixture, and the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 17% B to 30% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 5.67) to give 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-1-isobutyl-1H-pyrazole-4-carboxamide 286 as a formate salt (26.9 mg, 25.75%).

[0569] LCMS: (ESI, m / z): 549.15[M+H] + .

[0570] 1H NMR (400MHz, DMSO-d6, ppm) δ8.27 (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, 1H), 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).

[0571] Example 47

[0572] Step 1: Synthesis of compound 263-2

[0573] Under nitrogen protection, 1-methylcyclopropane-1-carboxylic acid (compound 263-1, 3 g, 29.965 mmol, 1 eq) was added to the reaction flask and dissolved in tert-butanol (10 mL). Then, diphenylphosphoryl azide (6.5 mL, 30.067 mmol, 1.00 eq) and triethylamine (4 mL) were added. The temperature was raised to 80°C and stirred to react overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to give compound 263-2 (2 g, 35.12%).

[0574] 1 H NMR (400MHz, DMSO-d6, ppm) δ7.04 (s, 1H), 1.36 (s, 9H), 1.22 (s, 3H), 0.57 (q, J=4.4Hz, 2H), 0.46-0.42 (m, 2H).

[0575] Step 2: Synthesis of compound 263-3

[0576] Under nitrogen 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 in dichloromethane (20 mL). The nitrogen in the reaction flask was replaced three times, and tert-butyl nitrite (2.29 g, 22.192 mmol, 2 eq) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 12:1) to give compound 263-3 (1.2 g, 53.96%).

[0577] 1 H NMR (400MHz, DMSO-d6, ppm) δ1.59 (s, 9H), 1.09 (s, 3H), 0.87-0.83 (m, 2H), 0.64 (s, 2H).

[0578] Step 3: Synthesis of compound 263-4

[0579] Under nitrogen 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, and the nitrogen was replaced 3 times. The temperature was cooled to 0°C, and 4 mol / L aqueous hydrochloric acid solution (8 mL) was added. The temperature was returned to room temperature and stirred to react overnight. After the reaction was completed, the mixture was filtered, the filter cake was washed with water (5 mL×2), and the filtrate was concentrated under reduced pressure to obtain compound 263-4 (1.2 g, 89.09%).

[0580] Step 4: Synthesis of compound 263-5

[0581] Under nitrogen protection, (1-methylcyclopropyl)hydrazine hydrochloride (compound 263-4, 1 g, 8.157 mmol, 1 eq), (E)-2-cyano-3-ethoxyacrylate ethyl ester (1.38 g, 8.157 mmol, 1 eq), sodium acetate (669.12 mg, 8.157 mmol, 1 eq) were added to the reaction flask and dissolved in anhydrous ethanol (10 mL). The mixture was stirred at 80°C and reacted overnight. After the reaction was completed, 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 (chromatographic 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) to give compound 263-5 (70 mg, 4.10%).

[0582] LCMS: (ESI, m / z): 210.05[M+H] + .

[0583] Step 5: Synthesis of compound 263-6

[0584] Under nitrogen protection, 5-amino-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 263-5, 60 mg, 0.287 mmol, 1 eq) and sodium hydroxide (22.94 mg, 0.574 mmol, 2 eq) were added to the reaction flask, dissolved with anhydrous ethanol (5 mL) and water (2 mL), and stirred at 80°C overnight. After the reaction, the reaction mixture was acidified to pH ~ 3 with 1 mol / L hydrochloric acid solution, and the mixture was concentrated under reduced pressure to obtain a 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%).

[0585] LCMS: (ESI, m / z): 181.95[M+H] + .

[0586] Step 6: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide (Compound 263)

[0587] Under nitrogen 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), N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminobenzotriazole)-N,N',N'-tetramethyluronium hexafluorophosphate (25.0 mg, 0.066 mmol, 1 eq) was added. The mixture was stirred at room temperature for 1 hour, and then water was added and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic 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: 10% B to 34% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 5.88) to obtain the formate salt of compound 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrazole-4-carboxamide 263 (13.4 mg, 36.47%).

[0588] LCMS: (ESI, m / z): 547.05[M+H] + .

[0589] 1H NMR (400MHz, DMSO) δ8.25 (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), 3.0 5(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).

[0590] Example 48

[0591] Step 1: Synthesis of compound 305-2

[0592] Under nitrogen protection, cyclopropylhydrazine hydrochloride (compound 305-1, 1 g, 9.211 mmol, 1 eq), (E)-2-cyano-3-ethoxyacrylate ethyl ester (1.56 g, 9.211 mmol, 1 eq), and sodium acetate (0.76 g, 9.211 mmol, 1 eq) were added to the reaction flask, dissolved in anhydrous ethanol (10 mL), and the temperature was raised to 80°C with stirring to react overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give compound 305-2 (900 mg, 49.50%).

[0593] LCMS: (ESI, m / z): 196.05[M+H] + .

[0594] Step 2: Synthesis of compound 305-3

[0595] Under nitrogen protection, 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (compound 305-2, 300 mg, 1.537 mmol, 1 eq) and sodium hydroxide (122.93 mg, 3.074 mmol, 2 eq) were added to the reaction flask, dissolved with anhydrous ethanol (5 mL) and water (2 mL), and the temperature was raised to 80°C with stirring to react overnight. After the reaction was completed, the reaction mixture was acidified to pH ~ 3 with 1 mol / L hydrochloric acid solution, and 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%).

[0596] LCMS: (ESI, m / z): 167.95[M+H] + .

[0597] Step 3: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-1-(cyclopropyl)-1H-pyrazole-4-carboxamide (Compound 305)

[0598] Under nitrogen 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), N,N-diisopropylethylamine (141.62 mg, 1.095 mmol, 5 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (5 mL, 64.608 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropyl)-1H-pyrazole-4-carboxylic acid was added. -1-alkyne-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 100 mg, 0.219 mmol, 1.00 eq) was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic 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: 35% B to 55% B in 9 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.05) to obtain a crude product of compound 305. The crude product was prepared a second time and purified by HPLC under the following conditions (chromatographic column specifications: Xselect CSHTM Prep C18 5μm30*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 254nm / 220nm; retention time (min): 5.75), to give the formate salt of compound 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-1-(cyclopropyl)-1H-pyrazole-4-carboxamide 305 (52.16 mg, 44.47%).

[0599] LCMS: (ESI, m / z): 533.55[M+H] + .

[0600] 1H NMR (400MHz, DMSO-d6, ppm) δ8.24 (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=11.1H z, 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).

[0601] Example 49

[0602] Step 1: Synthesis of 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-isopropyl-1H-pyrazole-4-carboxamide (Compound 306)

[0603] 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (833.28 mg, 2.191 mmol, 1 eq) were added to the reaction bottle, and the mixture was diluted with N,N-dimethylformamide (20 mL) and stirred at room temperature for 10 minutes. Then, 2-(3-aminoprop-1-yn-1-yl)-N-((3 S, 4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 1 g, 2.191 mmol, 1 eq) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated sodium chloride solution (20 mL×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 crude compound 306. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 14% B to 26% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.3) to give the formate salt of compound 5-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-isopropyl-1H-pyrazole-4-carboxamide 306 (31.21 mg, 2.64%).

[0604] LCMS: (ESI, m / z): 534.90[M+H] + .

[0605] 1H NMR (400MHz, DMSO-d6, ppm) δ8.27 (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, 1H), 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).

[0606] Example 50

[0607] Step 1: Synthesis of compound 283-2

[0608] Ethyl 2-cyanoacetate (compound 283-1, 5 g, 44.202 mmol, 1 eq) was added to the reaction flask and dissolved in aqueous acetic acid (45 w / w%, 20 mL). The mixture was reacted at 0°C for 15 minutes. Sodium nitrite (9.15 g, 132.606 mmol, 3 eq) was then added and the mixture was stirred at room temperature and reacted overnight. After the reaction was complete, ether and water were added to the reaction solution until the reaction solution was clarified. The mixture was extracted with 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 (5.5 g, 83.18%).

[0609] 1 H NMR (400MHz, DMSO-d6, ppm) δ15.07 (s, 1H), 4.31 (q, J=7.1Hz, 2H), 1.28 (t, J=7.1Hz, 3H).

[0610] Step 2: Synthesis of compound 283-3

[0611] To the reaction flask, ethyl 2-cyano-2-(hydroxyimino)acetate (compound 283-2, 3 g, 21.110 mmol, 1 eq) and platinum oxide (239.68 mg, 1.056 mmol, 0.05 eq) were added, dissolved in ethanol (15.0 mL), and then placed in a hydrogen environment of 0.4 MPa. The reaction was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered through celite, the filter cake was washed with dichloromethane, and the filtrate was dried to directly obtain compound 283-3 (2.2 g, 77.27%).

[0612] 1 H NMR (400MHz, DMSO-d6, ppm) δ4.80 (s, 1H), 4.20 (q, J=7.1, 2H), 1.24 (t, J=7.1Hz, 3H).

[0613] Step 3: Synthesis of compound 283-4

[0614] To the reaction flask, ethyl 2-amino-2-cyanoacetate (compound 283-3, 1 g, 7.805 mmol, 1 eq) and triethyl orthoformate (2.08 g, 14.049 mmol, 1.8 eq) were added and dissolved in acetonitrile (20.0 mL). The mixture was reacted at 90°C for 35 minutes, and the solvent was dried to an oily state. Tert-butylamine (970.38 mg, 13.268 mmol, 1.7 eq) was added and dissolved in acetonitrile (20.0 mL). The mixture was refluxed for 30 minutes. After the reaction was completed, the solvent was dried and the residual liquid was dissolved in chloroform (30 mL). The mixture was washed with 2 mol / L sodium hydroxide solution (10 mL) and water (10 mL) in that order. The organic phase was dried to give compound 283-4 (300 mg, 17.29%).

[0615] LCMS: (ESI, m / z): 212.05[M+H] + .

[0616] Step 4: Synthesis of compound 283-5

[0617] To the reaction flask, 5-amino-1-tert-butyl-1H-imidazole-4-carboxylic acid ethyl ester (compound 283-4, 100 mg, 0.473 mmol, 1 eq) and 1 mol sodium hydroxide aqueous solution (0.94 mL, 0.946 mmol, 2 eq) were added, dissolved with ethanol (2 mL), and reacted at 80°C overnight. After the reaction, the reaction mixture was acidified to pH = 3 with 1 mol hydrochloric acid solution, and the solvent was dried to directly obtain compound 283-5 (90 mg, 98.59%).

[0618] LCMS: (ESI, m / z): 184.05[M+H] + .

[0619] Step 5: Synthesis of 5-amino-1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 283)

[0620] To the reaction flask were added 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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), O-(7-azabenzotriazol-1-yl)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (99.97 mg, 0.263 mmol, 1.2 eq) and N,N-diisopropylethylamine (141.59 mg, 1.095 mmol, 5 eq) were dissolved in N,N-dimethylformamide (3 mL) and reacted at room temperature for 2 hours. After the reaction was completed, water 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 (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 (chromatographic 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: 13% B to 29% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.4) to obtain compound 5-amino-1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 283 (35.0 mg, 28.94%).

[0621] LCMS: (ESI, m / z): 549.20[M+H] + .

[0622] 1H NMR (400MHz, DMSO-d6) δ7.97 (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).

[0623] Example 51

[0624] Step 1: Synthesis of compound 292-2

[0625] Under nitrogen protection, (cyclopropylmethyl)hydrazine dihydrochloride (compound 292-1, 500 mg, 3.144 mmol, 1 eq), (2E)-2-cyano-3-ethoxyacrylate ethyl ester (531.85 mg, 3.144 mmol, 1 eq), and sodium acetate (257.89 mg, 3.144 mmol, 1 eq) were added to the reaction flask and dissolved in anhydrous ethanol (5 mL). The temperature was raised to 80° C. and the reaction was stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give compound 292-2 (250 mg, 37.97%).

[0626] LCMS: (ESI, m / z): 210.10[M+H] + .

[0627] Step 2: Synthesis of compound 292-3

[0628] Under nitrogen protection, 5-amino-1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 292-2, 200 mg, 0.956 mmol, 1 eq) and sodium hydroxide (76.46 mg, 1.912 mmol, 2 eq) were added to the reaction flask, dissolved with anhydrous ethanol (5 mL, 86.067 mmol) and water (2 mL, 111.019 mmol), and the temperature was raised to 50°C with stirring for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, 20 mL of water was added to the crude product, and the pH was adjusted to 3 with 1 mol / L hydrochloric acid solution, and then extracted with ethyl acetate (20 mL×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%).

[0629] LCMS: (ESI, r / z): 182.05[M+H] + .

[0630] Step 3: Synthesis of 5-amino-4-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 292)

[0631] Under nitrogen protection, 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), N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and 2-(3-aminopropyl- The mixture was stirred at room temperature for 1 hour. After the reaction, 20 mL of the mixture was added and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 7% B to 33% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.1), to obtain the formate salt of compound 5-amino-4-(cyclopropylmethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 292 (15.92 mg, 44.17%).

[0632] LCMS: (ESI, m / z): 547.10[M+H] + .

[0633] 1H NMR (4()()MHz, DMSO-d6, ppm) δ8.26(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).

[0634] Example 52

[0635] Step 1: Synthesis of compound 307-1

[0636] Under nitrogen protection, ethyl 5-amino-1-(tert-butyl)-1H-pyrazole-4-carboxylate (compound 047-1, 300 mg, 1.420 mmol, 1 eq) was added to the reaction flask and dissolved in tetrahydrofuran (3 mL, 37.028 mmol). Sodium hydride (51.12 mg, 2.130 mmol, 1.5 eq) was added at 0°C and 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 with stirring for 2 hours. After the reaction was complete, 2 mL of water was added and the mixture was extracted with ethyl acetate (3 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 307-1, which was directly used in the next step without further purification.

[0637] LCMS: (ESI, m / z): 226.00[M+H] + .

[0638] Step 2: Synthesis of compound 307-2

[0639] Under nitrogen, a crude mixture of ethyl 1-(tert-butyl)-5-(methylamino)-1H-pyrazole-4-carboxylate (compound 307-1, 300 mg, 1.332 mmol, 1 eq) and sodium hydroxide (106.52 mg, 2.664 mmol, 2 eq) was added to a reaction flask, dissolved in anhydrous ethanol (2 mL, 34.427 mmol) and water (0.5 mL, 27.755 mmol), and the mixture was heated to 50°C and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude mixture of compound 307-2 (220 mg, 53.02%).

[0640] LCMS: (ESI, m / z): 198.05[M+H] + .

[0641] Step 3: Synthesis of 1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide (Compound 307)

[0642] Under nitrogen protection, 1-(tert-butyl)-5-(methylamino)-1H-pyrazole-4-carboxylic acid (compound 307-2, 64.84 mg, 0.329 mmol, 1.50 eq) and tetramethyl chlorouronium hexafluorophosphate (245.96 mg, 0.876 mmol, 4 eq) were added to the reaction flask and dissolved in acetonitrile (5 mL). Then, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001- 12, 100 mg, 0.219 mmol, 1.00 eq), N-methylimidazole (179.93 mg, 2.190 mmol, 10 eq), stirred at room temperature for 4 hours. After the reaction, 10 mL of water was added and extracted with dichloromethane (20 mL × 2). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL × 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 a crude product of compound 307. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 17% B to 33% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.52) to obtain the formate salt of compound 1-(tert-butyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide 307 (11.34 mg, 9.16%).

[0643] LCMS: (ESI, m / z): 563.10[M+H] + .

[0644] 1H NMR (400MHz, DMSO-d6, ppm) δ8.38 (t, J=5.7Hz, 1H), 7.68 (s, 1H), 7.28 (dd, J=8.8, 7.6Hz, 1H), 7.02 (d, J=8.6 Hz, 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).

[0645] Example 53

[0646] Step 1: Synthesis of 6-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]nicotinamide (Compound 296)

[0647] 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 for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 5 mg, 0.011 mmol, 1 eq) was stirred and reacted for 2 hours. After the reaction was completed, 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 (chromatographic 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: 15% B to 35% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.22) to obtain the formate salt of compound 6-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]nicotinamide 296 (19.37 mg, 63.82%).

[0648] LCMS: (ESI, m / z): 504.00[M+H] + .

[0649] 1H NMR (400MHz, DMSO-d6, ppm) δ8.75 (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=49.4Hz, 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).

[0650] Example 54

[0651] Step 1: Synthesis of 2-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6-methylnicotinamide (Compound 295)

[0652] At room temperature, 2-amino-6-methylnicotinic acid (6.67 mg, 0.044 mmol, 1 eq), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol, 1 eq), N,N-diisopropylethylamine (28.32 mg, 0.220 mmol, 5 eq) were added to the reaction bottle, and N,N-dimethylformamide (1 mL) solution was stirred for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoromethyl)-1-[ ...3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoromethyl)-1-[3-aminoprop-1-yn-1-yl)-N-(3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoromethyl)-1-[3-aminoprop-1-yn-1-yl)-N-(3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoromethyl)-1- [1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 20 mg, 0.044 mmol, 1 eq) was stirred for 2 hours. After the reaction, the reaction mixture was quenched with water at room temperature and 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 (chromatographic 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: 15% B to 35% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 7.22) to obtain the formate salt of compound 2-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6-methylnicotinamide 295 (18.89 mg, 83.03%).

[0653] LCMS: (ESI, m / z): 518.10[M+H] + .

[0654] 1H NMR (400MHz, DMSO-d6, ppm) δ8.91 (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=49.4H z, 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).

[0655] Example 55

[0656] Step 1: Synthesis of 4-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)propyl-2-yn-1-yl]-6-methylnicotinamide (Compound 294)

[0657] Under nitrogen 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), N, N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction bottle, dissolved in N, N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-1-ol was added. -N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1 eq), stirred for 1 hour. After the reaction, the reaction mixture was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic column specifications: Xselect 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 254nm / 220nm; retention time (minutes): 6.27) to obtain the formate salt of compound 4-amino-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-6-methylnicotinamide 294 (20.3 mg, 59.36%).

[0658] LCMS: (ESI, m / z): 518.05[M+H] + .

[0659] 1H NMR (400MHz, DMSO-d6, ppm) δ8.95 (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=5.4Hz, 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, 1H), 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).

[0660] Example 56

[0661] Step 1: Synthesis of compound 269-2

[0662] Under nitrogen protection, at 0°C, to a solution of 1-cyclopropylethanol (compound 269-1, 614.62 mg, 7.136 mmol, 2.00 eq), 1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 3.568 mmol, 1.00 eq) and triphenylphosphine (1.87 g, 7.136 mmol, 2.00 eq) in tetrahydrofuran (40 mL) was added dropwise diisopropyl azodicarboxylate (1.44 g, 7.136 mmol, 2.00 eq). After the addition was complete, the mixture was stirred at room temperature overnight. The resulting residue was concentrated under reduced pressure and then ether was added. The mixture was cooled to 0°C, filtered, and the filtrate was spin-dried. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 269-2 (700 mg, 94.21%).

[0663] LCMS: (ESI, m / z): 208.90[M+H] + .

[0664] Step 2: Synthesis of compound 269-3

[0665] At room temperature, a solution of (1-cyclopropylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (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 residue was concentrated under reduced pressure and acidified to pH ~ 5 with hydrochloric acid solution (2 M). The residue was concentrated under reduced pressure, and the mixture was washed with tetrahydrofuran / methanol (3 / 1 mL), filtered, and the filter cake was washed with tetrahydrofuran (1×4 mL). The filtrate was concentrated under reduced pressure to give compound 269-3 (100 mg, 72.23%).

[0666] LCMS: (ESI, m / z): 181.05[M+H] + .

[0667] Step 3: Synthesis of 1-(1-cyclopropylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide (Compound 269)

[0668] 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 for 20 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N- ((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 80 mg, 0.175 mmol, 1 eq) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic phases were combined, backwashed with saturated sodium chloride (2×20 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 (chromatographic 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: 16% B to 32% B in 7 minutes; detection wavelength: UV 254nm / 225nm; retention time (minutes): 6.42) to obtain the formate salt of compound 1-(1-cyclopropylethyl)-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide 269 (2.07 mg, 1.98%).

[0669] LCMS: (ESI, m / z): 545.95[M+H] + .

[0670] 1H NMR (400MHz, DMSO-d6, ppm) δ8.67 (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).

[0671] Example 57

[0672] Step 1: Synthesis of compound 300-1

[0673] Under nitrogen protection, to a solution of 1H-pyrrole-3-carboxylic acid methyl ester (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) 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 added in batches and stirred at 80°C overnight. After the reaction was completed, the mixture was filtered, the filter cake was washed with acetonitrile (3×10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 300-1 (320 mg, 40.60%).

[0674] LCMS: (ESI, m / z): 197.95[M+H] + .

[0675] Step 2: Synthesis of compound 300-2

[0676] Under nitrogen protection, sodium hydride (65.7 mg, 2.738 mmol, 2 eq) was added to a solution of 1-(2-hydroxy-2-methylpropyl)-1H-pyrrole-3-carboxylic acid methyl ester (compound 300-1, 270 mg, 1.369 mmol, 1 eq) in N,N-dimethylformamide (4.0 mL) at 0°C. The mixture was stirred for 30 minutes, and iodomethane (388.61 mg, 2.738 mmol, 2 eq) was added dropwise at 0°C. The mixture was naturally restored to room temperature and stirred for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction mixture to quench the mixture, 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 300-2 (250 mg, 86.44%).

[0677] LCMS: (ESI, m / z): 212.00[M+H] + .

[0678] Step 3: Synthesis of compound 300-3

[0679] Under nitrogen, a solution of methyl 1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxylate (compound 300-2, 100 mg, 0.473 mmol, 1 eq) in methanol (1.0 mL) was added dropwise with sodium hydroxide (37.87 mg, 0.946 mmol, 2 eq) in water (0.5 mL) at room temperature. The mixture was stirred at 50°C overnight. After completion of the reaction, the reaction mixture was acidified to pH 5 with hydrochloric acid solution. The resulting residue was concentrated under reduced pressure and dissolved in tetrahydrofuran (3 mL). The resulting residue was filtered through a filter membrane and concentrated again under reduced pressure to afford compound 300-3 (60 mg, 64.27%). The crude product was not further purified and was directly used in the next step.

[0680] LCMS: (ESI, m / z): 198.00[M+H] + .

[0681] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxamide (Compound 300)

[0682] Under nitrogen protection, at room temperature, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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, To a solution of 1,4-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) in N,N-dimethylformamide (0.8 mL) was added dropwise. After stirring for 1 hour, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.5 mg, 0.073 mmol, 1.1 eq) was added at room temperature. After the addition was complete, the system was stirred at room temperature for 1 hour. After the reaction was complete, methanol (1.0 mL) was added to the reaction mixture at room temperature to quench the reaction. The crude product was purified by high performance liquid chromatography (HPLC) under the following conditions (column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm × 150 mm; 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 in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (min): 6.6), to give compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxamide 300 (5.81 mg, 15.64%).

[0683] LCMS: (ESI, m / z): 563.15[M+H] + .

[0684] 1H NMR (400MHz, DMSO-d6, ppm) δ8.35 (t, J=5.7Hz, 1H), 7.32-7.24 (m, 2H), 7.02 (d, J=8.7Hz, 1H), 6.69 (t, J=2.5H z, 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, 2H), 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).

[0685] Example 58

[0686] Step 1: Synthesis of compound 302-2

[0687] Under nitrogen protection, proline (compound 302-1, 1 g, 8.686 mmol, 1 eq) was added to the reaction flask and dissolved with formic acid (8.5 mL). Acetic anhydride (5.75 mL, 60.802 mmol, 7 eq) was added at 0°C and stirred at room temperature for 1 hour. After the reaction, the reaction mixture was quenched with ice water at 0°C, and the residue was concentrated under reduced pressure to give compound 302-2 (1.2 g, 88.60%).

[0688] LCMS: (ESI, m / z): 144.00[M+H] + .

[0689] Step 2: Synthesis of compound 302-3

[0690] Under nitrogen, formylproline (compound 302-2, 500 mg, 3.493 mmol, 1 eq) and ethyl propiolate (2.40 g, 24.451 mmol, 7 eq) were added to the reaction flask and dissolved in acetic anhydride (5 mL, 52.895 mmol). The temperature was raised to 120°C and stirred for overnight. After the reaction was completed, the reaction mixture was quenched with water at room temperature and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, backwashed with saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give compound 302-3 (200 mg, 23.96%).

[0691] LCMS: (ESI, m / z): 180.05[M+H] + .

[0692] Step 3: Synthesis of compound 302-4

[0693] Under nitrogen, ethyl 2,3-dihydro-1H-pyrrolazine-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 and dissolved with anhydrous ethanol (5 mL, 86.067 mmol) and water (2 mL, 111.019 mmol). The temperature was raised to 50°C and stirred to react overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was added with 20 mL of ethyl acetate and 20 mL of water. The product was in the aqueous phase. The aqueous phase was adjusted to pH 3 with 1 mol / L hydrochloric acid solution and extracted with ethyl acetate (20 mL×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.

[0694] LCMS: (ESI, m / z): 152.05[M+H] + .

[0695] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-2,3-dihydro-1H-pyrrolazine-7-carboxamide (Compound 302)

[0696] Under nitrogen protection, 2,3-dihydro-1H-pyrrolazine-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), N,N-diisopropylethylamine (42.49 mg, 0.330 mmol, 5 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL, 25.843 mmol), stirred at room temperature for 10 minutes, and then 2-(3-aminopropane-1- The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, backwashed with saturated sodium chloride solution (30 mL × 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 (chromatographic column specifications: Xselect Crude compound 302 was obtained using a CSHTM Prep C18 5 μm 30*150 mm OBD column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 16% B to 33% B in 8 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.28. The mixture was chirally resolved under the following conditions (chromatographic column specifications: CHIRALPAK-IA 2*25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol:DCM = 1:1; flow rate: 20 ml / min; elution gradient: isocratic 45; detection wavelength: UV 254 / 220nm; retention time (min): 6.097; post-peak retention time (min): 8.463; dissolving solvent: methanol; single injection volume: 2.0mL; number of injections: 1), to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-2,3-dihydro-1H-pyrrolizine-7-carboxamide 302 (4.7 mg, 13.76%).

[0697] LCMS: (ESI, m / z): 517.15[M+H] + .

[0698] 1H NMR (400MHz, DMSO-d6, ppm) δ8.10 (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), 6.31 (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=1 1.1Hz, 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).

[0699] Example 59

[0700] Step 1: Synthesis of compound 148-2

[0701] Benzoyl hydrazide (5 g, 36.723 mmol, 1 eq) and acetic acid (44.11 mg, 0.734 mmol, 0.02 eq) were added to the reaction flask and dissolved with acetone (22 mL). The mixture was reacted at room temperature overnight. After the reaction, it was diluted with water and the reaction mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and 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%).

[0702] LCMS: (ESI, m / z): 176.70[M+H] + .

[0703] Step 2: Synthesis of compound 148-3

[0704] N-(prop-2-ylidene)benzohydrazide (compound 148-2, 1 g, 5.675 mmol, 1 eq) was added to the reaction flask and dissolved in 1,2-dichloroethane (10 mL). Allyltrimethylsilane (972.6 mg, 8.512 mmol, 1.5 eq) and boron trifluoride etherate (1.21 g, 8.512 mmol, 1.5 eq) were added and reacted at 85 ° C for 5 minutes. The solvent was dried and the residue was dissolved in N, N-dimethylformamide (10 mL). (Trifluoromethyl)trimethylsilane (1.61 g, 11.350 mmol, 2eq), sodium acetate (1.86 g, 22.700 mmol, 4eq), reacted at 55 ° C for 3 hours. After the reaction, the reaction solution was cooled to room temperature, saturated sodium carbonate was added to quench the reaction, stirred for 5 minutes, diluted with water, extracted with ethyl acetate (3×20 mL), and 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 residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 1) to give compound 148-3 (1.1 g, 74.79%).

[0705] LCMS: (ESI, m / z): 246.85[M+H] + .

[0706] Step 3: Synthesis of Compound 148-4

[0707] N-(1,1,1-trifluoro-2-methylprop-2-yl)benzohydrazide (compound 148-3, 1.1 g, 4.467 mmol, 1 eq) was added to the reaction flask, dissolved with methanol (6.6 mL), and then hydrochloric acid (6 mL) was added. The reaction was allowed to proceed at 80°C overnight. After the reaction, the reaction solution was cooled to room temperature, the solvent was dried, and ether was added to precipitate the product. The product was filtered and the filter cake was washed with ether to obtain the hydrochloride salt of compound 148-4 (570 mg, 85.29%).

[0708] 1 H NMR (400MHz, DMSO-d6, ppm) δ9.44 (s, 2H), 6.02 (s, 1H), 1.33 (s, 6H).

[0709] Step 4: Synthesis of compound 148-5

[0710] To the reaction flask, (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazine hydrochloride (compound 148-4, 2.2 g, 15.479 mmol, 1 eq) and 2-bromomalonaldehyde (2.80 g, 18.575 mmol, 1.2 eq) were added and dissolved in acetic acid (33 mL). The mixture was stirred at room temperature overnight. After the reaction was completed, 1 mol / L sodium hydroxide aqueous solution was added to adjust the pH to 7. 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 residue was purified by reverse phase column chromatography under the following conditions (C18 chromatography column 120 g, mobile phase: water and acetonitrile, 10% to 80% gradient 10 minutes, UV 220 nm detection) to give compound 148-5 (200 mg, 4.27%).

[0711] LCMS: (ESI, m / z): 256.85[M+H] + .

[0712] Step 5: Synthesis of compound 148-6

[0713] Under nitrogen protection, 4-bromo-1-(1,1,1-trifluoro-2-methylprop-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). A 2.5 mol / L n-butyllithium n-hexane solution (0.373 mL, 0.934 mmol, 2 eq) was added dropwise at -78 ° C. The mixture was reacted at this temperature for 30 minutes, and then propyl chloroformate (62.93 mg, 0.514 mmol, 1.1 eq) was added. The reaction was continued for 30 minutes, then the temperature was raised to room temperature and the reaction was continued for 72 hours. After the reaction was completed, saturated ammonium chloride solution 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 resulting residue was purified by reverse phase column chromatography under the following conditions (chromatographic column specifications: C18; mobile phase: water and acetonitrile, 10% to 90% gradient 10 minutes, UV220 nm) to obtain compound 148-6 (25 mg, 19.25%).

[0714] LCMS: (ESI, m / z): 265.00[M+H] + .

[0715] Step 6: Synthesis of compound 148-7

[0716] 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole-4-carboxylic acid propyl ester (compound 148-6, 25 mg, 0.094 mmol, 1 eq) and 1 mol sodium hydroxide aqueous solution (0.188 mL, 0.188 mmol, 2 eq) were added to the reaction flask, dissolved with methanol (1 mL), and reacted at 50°C overnight. After the reaction, the reaction mixture was acidified to pH = 3 with 1 mol hydrochloric acid solution, and the solvent was dried to obtain compound 148-7 (20 mg, 95.15%).

[0717] LCMS: (ESI, m / z): 222.95[M+H] + .

[0718] Step 7: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1,1,1-trifluoro-2-methylprop-2-yl)-1H-pyrazole-4-carboxamide (Compound 148)

[0719] To the reaction flask were added 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 35 mg, 0.091 mmol, 1 eq), 1-(1,1,1-trifluoro-2-methylprop-2-yl)-1H-pyrazole-4-carboxylic acid (compound 148-7, 20.28 mg, 0.091 mmol, 1 eq), 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 dissolved in N, N-dimethylformamide (1 mL) and reacted at room temperature for 2 hours. After the reaction, 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 (chromatographic 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: 18% B to 36% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.05) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1,1,1-trifluoro-2-methylprop-2-yl)-1H-pyrazole-4-carboxamide 148 (4.51 mg, 8.34%).

[0720] LCMS: (ESI, m / z): 588.10[M+H] + .

[0721] 1H NMR (400MHz, DMSO-d6, ppm) δ8.77 (t, J=5.6Hz, 1H), 8.60 (s, 1H), 8.02 (s, 1H), 7.29 (dd, J=8.7, 7.6 Hz, 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=11.5Hz, 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).

[0722] Example 60

[0723] Step 1: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methylindole-3-carboxamide (Compound 308)

[0724] At room temperature, 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) were added to the reaction bottle, and the mixture was diluted with N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 10 minutes, and 2-(3-aminoprop-1-yn-1-yl)-2-nitropropane-3-ol was added. )-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1 eq) was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL×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 (chromatographic column specifications: Sunfire C18 5μm, 30mm*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 19% B to 33% B in 1 min; detection wavelength: UV 254nm / 220nm) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methylindole-3-carboxamide 308 (13.82 mg, 38.65%).

[0725] LCMS: (ESI, m / z): 541.20[M+H] + .

[0726] 1H NMR (400MHz, DMSO-d6, ppm) δ8.46 (t, J=5.6Hz, 1H), 8.17 (d, J=7.9Hz, 1H), 8.03 (s, 1H), 7.50 (d, J=8.1Hz, 1 H), 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=9.1H z, 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=11.8 Hz, 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).

[0727] Example 61

[0728] Step 1: Synthesis of compound 301-2

[0729] Under nitrogen protection, 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 at 0°C for 1 hour. After the reaction, the reaction mixture was quenched with water at room temperature, and the residue was concentrated under reduced pressure to give compound 301-2 (1.5 g).

[0730] LCMS: (ESI, m / z): 159.95[M+H] + .

[0731] Step 2: Synthesis of compound 301-3

[0732] Under nitrogen protection, a solution of 4-formylmorpholine-3-carboxylic acid (compound 301-2, 1.5 g, 9.426 mmol, 1 eq) and ethyl propiolate (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 completed, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 301-3 (600 mg, 32.61%).

[0733] LCMS: (ESI, m / z): 196.05[M+H] + .

[0734] Step 3: Synthesis of compound 301-4

[0735] Under air protection, at 60°C, a solution of ethyl 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylate (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 completed, the reaction solution was concentrated under reduced pressure to obtain compound 301-4 (182 mg, 92.41%).

[0736] LCMS: (ESI, m / z): 168.00[M+H] + .

[0737] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide (Compound 301)

[0738] At room temperature, compound 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (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) were dissolved in N,N-dimethylformamide (1 mL) and stirred for 20 minutes. Then, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 27.3 mg, 0.060 mmol, 1 eq) was stirred overnight. After the reaction was completed, the reaction mixture was quenched with water (5 mL) and 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 crude compound 301. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 15% B to 29% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.77) to obtain the formate salt of compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide 301 (2.81 mg, 8.05%).

[0739] LCMS: (ESI, m / z): 533.15[M+H] + .

[0740] Example 62

[0741] Step 1: Synthesis of compound 303-2

[0742] Under nitrogen protection, triethylamine (132.36 mg, 1.308 mmol, 1.1 eq) was added dropwise to a solution of tert-butyl 1H-pyrazole-4-carboxylate (compound 303-1, 200 mg, 1.189 mmol, 1 eq) and 1-(phenylsulfonyl)cyclopropane-1-ol (259.3 mg, 1.308 mmol, 1.1 eq) in acetonitrile (3.0 mL) at room temperature. After the addition, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, methanol (2.0 mL) was added to the reaction mixture at room temperature to quench the reaction mixture. The resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 303-2 (200 mg, 75.00%).

[0743] LCMS: (ESI, m / z): 225.00[M+H] + .

[0744] Step 2: Synthesis of compound 303-3

[0745] Under nitrogen protection, trifluoroacetic acid (0.5 mL) was added dropwise to a solution of tert-butyl 1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxylate (compound 303-2, 100 mg, 0.446 mmol, 1 eq) in dichloromethane (1.0 mL) at room temperature. After the addition, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give compound 303-3 (100 mg). The resulting mixture was not further purified and was directly used in the next step.

[0746] LCMS: (ESI, m / z): 168.95[M+H] + .

[0747] Step 3: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxamide (Compound 303)

[0748] Under nitrogen protection, at room temperature, 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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. 3eq) in N, 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 stirred at room temperature for 1 hour. After the reaction was completed, methanol (1.0 mL) was added to the reaction mixture to quench it. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic column specifications: YMC Triart C18 ExRs 5μm, 30mm×150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 28% B to 52% B in 10 min; detection wavelength: UV 254nm / 220nm; retention time (minutes): 9.5) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-hydroxycyclopropyl)-1H-pyrazole-4-carboxamide 303 (2.14 mg, 8.51%).

[0749] LCMS: (ESI, m / z): 534.05[M+H] + .

[0750] 1H NMR-PH-CCJS-P-477-0: (400MHz, DMSO-d6, ppm) δ8.73 (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).

[0751] Example 63

[0752] Step 1: Synthesis of compound 309-2

[0753] 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) was slowly added dropwise under argon at -50°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight under argon. 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 afford compound 309-2 (300 mg, 20.12%).

[0754] LCMS: (ESI, m / z): 191.05[M+H] + .

[0755] Step 2: Synthesis of compound 309-3

[0756] At room temperature, 2-(difluoromethyl)-1-methyl-1H-imidazole-4-carboxylic acid methyl ester (compound 309-2, 100 mg, 0.526 mmol, 1 eq) and lithium hydroxide (25.19 mg, 1.052 mmol, 2 eq) were added to the reaction flask, dissolved with tetrahydrofuran (5 mL) and water (1 mL), and stirred at room temperature for 2 hours. After the reaction, it was adjusted to neutral with 3 mol / L hydrochloric acid solution. The residue was concentrated under reduced pressure, dissolved with tetrahydrofuran (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 309-3 (90 mg, 97.17%).

[0757] LCMS: (ESI, m / z): 176.95[M+H] + .

[0758] Step 3: Synthesis of 2-difluoromethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-imidazole-4-carboxamide (Compound 309)

[0759] At room temperature, 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-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-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, 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. The crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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 33% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.2) to obtain compound 2-difluoromethyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-imidazole-4-carboxamide 309 (5.94 mg, 15.22%).

[0760] LCMS: (ESI, m / z): 542.05[M+H] + .

[0761] 1H NMR (400MHz, DMSO-d6, ppm) δ8.61 (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, 1 H), 2.37-2.21 (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).

[0762] Example 64

[0763] Step 1: Synthesis of compound 310-2

[0764] To a solution of 2-hydrazinoethanol (compound 310-1, 76.1 mg, 1.000 mmol, 1 eq) in ethanol (100 mL) was added dropwise a solution of ethyl 2-formyl-3-oxopropanoate (144.13 mg, 1.000 mmol, 1 eq) in ethanol (100 mL) at 0°C. The mixture was returned to room temperature and stirred overnight. After completion of the reaction, the mixture was concentrated in vacuo to give compound 310-2 (180 mg, 97.8%).

[0765] LCMS: (ESI, m / z): 184.95[M+H] + .

[0766] Step 2: Synthesis of compound 310-3

[0767] At room temperature, 1-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (compound 310-2, 100 mg, 0.543 mmol, 1 eq) and lithium hydroxide (26.01 mg, 1.086 mmol, 2 eq) were added to the reaction flask, and then tetrahydrofuran (5 mL, 61.714 mmol, 113.67 eq) and water (1 mL, 55.509 mmol, 102.25 eq) were added to dissolve the mixture. The mixture was stirred at 50°C overnight. After the reaction was completed, the reaction solution was adjusted to neutral with 3 mol / L hydrochloric acid solution. The resulting residue was concentrated under reduced pressure, dissolved with tetrahydrofuran (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give compound 310-3 (80 mg, 94.37%).

[0768] LCMS: (ESI, m / z): 157.00[M+H] + .

[0769] Step 2: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide (Compound 310)

[0770] At room temperature, 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.066 mmol, 1 eq) were added to the reaction bottle, dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then 2-(3-aminopropyl)-1H-pyrazole-4-carboxylic acid was added. -1-alkyne-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 30 mg, 0.066 mmol, 1 eq) was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated sodium chloride solution (10 mL×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 (chromatographic column specifications: XBridge BEH C18 OBD Prep Column 130, 5 μm, 30 mm*150 mm; 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 min; detection wavelength: UV 254 nm / 220 nm; retention time (min): 6.95) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide 310 (9.4 mg, 26.89%).

[0771] LCMS: (ESI, m / z): 522.00[M+H] + .

[0772] 1H NMR (400MHz, DMSO-d6, ppm) δ8.67 (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, 1 H), 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).

[0773] Example 65

[0774] Step 1: Synthesis of compound 312-1

[0775] Under nitrogen, a solution of 1H-pyrrole-3-carboxylic acid methyl ester (compound 014-1, 1 g, 7.992 mmol, 1 eq) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (4.25 g, 11.988 mmol, 1.5 eq) in acetonitrile (20.0 mL) was stirred at 50°C for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford compound 312-1 (58 mg, 5.07%). LCMS: (ESI, m / z): 144.00 [M+H]. + .

[0776] Step 2: Synthesis of compound 312-2

[0777] A solution of 5-fluoro-1H-pyrrole-3-carboxylic acid methyl ester (compound 312-1, 48 mg, 0.335 mmol, 1 eq), cesium carbonate (327.83 mg, 1.005 mmol, 3 eq) and iodomethane (95.21 mg, 0.670 mmol, 2 eq) in N,N-dimethylformamide (3 mL) was stirred at 80°C for 1 hour. After the reaction, the reaction mixture was quenched with water at room temperature and 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 give crude compound 312-2 (40 mg, 75.89%) without further purification.

[0778] LCMS: (ESI, m / z): 158.00[M+H] + .

[0779] Step 3: Synthesis of compound 312-3

[0780] A solution of 5-fluoro-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (compound 312-2, 80 mg, 0.509 mmol, 1 eq) and sodium hydroxide (40.72 mg, 1.018 mmol, 2 eq) in methanol (2 mL) and water (2 mL) was stirred at 50°C for 1 hour. After the reaction, the reaction mixture was acidified to pH 5 with 1 mol / L hydrochloric acid solution and concentrated in vacuo to give crude compound 312-3 (35 mg, 48.04%) without further purification.

[0781] LCMS: (ESI, m / z): 144.00[M+H] + .

[0782] Step 4: Synthesis of 5-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide (Compound 312)

[0783] 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 for 30 minutes, and then 2-(3-aminoprop-1-yn-1-yl)-N-((3 S, 4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (Compound 001-12, 20 mg, 0.044 mmol, 1 eq) was added and the reaction was continued with stirring for 2 hours. After the reaction was completed, the reaction mixture was quenched with water at room temperature and 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 (chromatographic 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: 15% to 30% in 10 minutes; detection wavelength: UV 254 nm / 220 nm; retention time (minutes): 9.08) to give compound 5-fluoro-N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]-1-methyl-1H-pyrrole-3-carboxamide 312 (12.59 mg, 56.15%).

[0784] LCMS: (ESI, m / z): 509.05[M+H] + .

[0785] 1H NMR (400MHz, DMSO-d6, ppm) δ8.48 (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).

[0786] Example 66

[0787] Step 1: Synthesis of compound 313-2

[0788] Under argon protection, a solution of 2,5-dimethoxytetrahydrofuran (compound 313-1, 500 mg, 3.783 mmol, 1 eq) and 1-methylcyclopropylamine (269.08 mg, 3.783 mmol, 1 eq) in acetic acid (2 mL) / dichloroethane (10 mL) / water (6 mL) was stirred at 90°C for 4 hours. After the reaction, the reaction mixture was quenched with 2 mol / L sodium hydroxide solution at room temperature and extracted with dichloromethane (3×30 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 to give compound 313-2 (480 mg). The resulting mixture was not further purified and directly used in the next step.

[0789] 1 H NMR (400MHz, DMSO-d6, ppm) δ6.79 (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).

[0790] Step 2: Synthesis of compound 313-3

[0791] 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 reacted overnight. After the reaction, the reaction mixture was quenched with saturated aqueous sodium carbonate at 0°C and 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 (chromatographic column C18 specifications: mobile phase: water and acetonitrile (0.1% formic acid), 20% to 60% gradient 15 minutes, detection wavelength; UV 254 nm) to give compound 313-3 (450 mg, 42.62%).

[0792] LCMS: (ESI, m / z): 267.85[M+2+H] + .

[0793] Step 3: Synthesis of compound 313-4

[0794] Under nitrogen protection, 2,2,2-trichloro-1-(1-(1-methylcyclopropyl)-1H-pyrrol-3-yl)ethan-1-one (compound 313-3, 200 mg, 0.750 mmol, 1 eq) and 10 mol / L sodium hydroxide (0.1 mL, 5 eq) in tetrahydrofuran (10.0 mL) were stirred at room temperature for 2 hours. After the reaction, 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 give compound 313-4 (120 mg, 96.81%). The resulting mixture was not further purified and directly used in the next step.

[0795] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.70 (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).

[0796] Step 4: Synthesis of N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxamide (Compound 313)

[0797] At room temperature, 1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxylic acid (compound 313-4, 20 mg, 0.121 mmol, 1 eq) and 2-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-amine dihydrochloride (compound 001-12, 46.42 mg, 0.121 mmol, 1eq), N, N-diisopropylethylamine (78.24 mg, 0.605 mmol, 5eq), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (46.04 mg, 0.121 mmol, 1eq) in N, N-dimethylformamide (2 mL) was stirred for 1 hour. After the reaction was completed, the residue was concentrated under reduced pressure and the crude product was purified by high performance liquid chromatography under the following conditions (chromatographic 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: 18% B to 34% B in 8 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 6.9) to obtain compound N-[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)pyrazolo[1,5a]pyridin-2-yl)prop-2-yn-1-yl]-1-(1-methylcyclopropyl)-1H-pyrrole-3-carboxamide 313 (6.12 mg, 9.44%).

[0798] LCMS: (ESI, m / z): 531.20[M+H] + .

[0799] 1H NMR (400MHz, DMSO-d6, ppm) δ8.32 (t, J=5.8Hz, 1H), 7.44 (t, J=2.0Hz, 1H), 7.28 (t, J=8.2Hz, 1H), 7.02 (d, J=8.7Hz, 1H), 6.86 (t, J=2.6Hz, 1H), 6.44 (t, J=2.2Hz, 1H), 6.31 (d, J=7.6Hz, 1H), 6.23 (d, J=9.0Hz, 1H), 4.87 (d, J=49.5Hz, 1H), 4.29 (d, J=5.7Hz, 2H) , 3.93-3.83 (m, 1H), 3.75 (q, J=11.1Hz, 2H), 3.05 (t, J=11.6Hz, 1H), 2.78 (d, J=11.5Hz, 1H), 2.40-2.22 (m, ...

Claims

1. A compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: in, R1 and R2 are the same or different and are independently selected from H, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; R3 is selected from H, C 1-12 alkyl; R4 is selected from H, halogen, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, halogenated C 3-12 Cycloalkyl, cyano C 1-12 Alkyl, cyano C 1-12 Alkoxy; W is selected from C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, C 6-10 Arylene, 5-10 membered heteroarylene; Ring A is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R a is selected from H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)N(R a11 )(R a12 )、-N(R a13 )(R a14 )、-S(O)2-R a15 、-S(O)(=NR a16 )(R a17 )、-P(O)(R a18 )(R a19 ); each R a1 are the same or different and are independently selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R a2 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NH2, -S(O)2-C 1-12 Alkyl; each R a2 are the same or different and are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 The same or different, independently selected from H, C 1-12 Alkyl, C 3-7 Cycloalkyl, 3-8 membered heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5; Z is absent or selected from NH, S, O, C 1-6 Alkylene, C 1-6 Alkylene-NH; Ring E is selected from 3-14 membered heterocyclic group, C 3-12 Cycloalkyl; R e is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R e1 Substituted with the following groups: C 1-12 Alkyl, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 1-12 Alkyl-NH-, (C 1-12 Alkyl)2-N-; each R e1 are the same or different and are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; or, two R attached to the same carbon atom e With their respective attached atoms form C 3-12 Cycloalkane ring, 3-14 membered heterocyclic ring; or, two R connected to different carbon atoms e The atoms to which they are attached form a 3-14 membered heterocyclic ring; p is selected from 0, 1, 2, 3, 4, 5; X1, X2, X3 are the same or different, independently selected from CH or N, and at least two of X1, X2, X3 are CH; R x Selected from H, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy; n is selected from 0, 1, 2 or 3; Y is selected from C(O), C(O)NH, C(S), SO2.

2. The compound according to claim 1 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3 are the same or different and are independently selected from H, C 1-6 alkyl; Preferably, R1, R2, and R3 are all H; Preferably, R4 is selected from C 1-6 Alkyl, C 2-6 Alkenyl, halogenated C 1-6 Alkyl, cyano C 1-6 alkyl; Preferably, R4 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano C 1-6 alkyl; Preferably, R4 is selected from methyl, ethyl, propyl, isopropyl, vinyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; Preferably, R4 is selected from methyl, ethyl, propyl, isopropyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

3. The compound according to claim 1 or 2, and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: W is selected from C 2-4 Alkenylene, C 2-4 Alkynylidene, C 3-6 Cycloalkylene, C 6-10 Arylene, 5-6 membered heteroarylene; Preferably, W is selected from:

4. The compound according to any one of claims 1 to 3 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 6-10 membered heterocyclyl, C 3-6 cycloalkyl; Preferably, ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 8-9 membered heterocyclyl, C 3-6 cycloalkyl; Preferably, ring A is selected from: Preferably, R a is selected from H, CN, oxo (=O), halogen, OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)(NHC 1-6 Alkyl), -S(O)2-C 1-6 Alkyl, -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 are the same or different and are independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, cyano 1-6 Alkyl, cyano C 1-6 Alkoxy, C 1-6 Alkyl-NH-, (C 1-6 Alkyl)2-N-, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, hydroxyl C 1-6 alkyl; Preferably, R a is selected from H, F, Cl, CN, oxo (=O), OH, unsubstituted or optionally substituted with one, two or more R a1 Substituted from the following groups: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, isopropoxy, propoxy, phenyl, pyridyl, benzyl, piperidyl, -C(O)NHCH3, -S(O)2-CH3, -S(O)(=NH)(CH3), -P(O)(CH3)(CH3), -NH2; each R a1 are the same or different and are independently selected from H, CN, OH, F, Cl, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2OCH3, -CH2CH2OCH3, -CH2OH, -CH2CN, -N(CH3)2, -S(O)2-CH3, Preferably, R a is selected from H, F, Cl, CN, oxo (=O), OH, NH2, methylamino, dimethylamino, methyl, ethyl, isopropyl, tert-butyl, -C(CH3)2CH2CH3, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, benzyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, isopropyloxy, 2- Hydroxyethyl, Preferably, Selected from 5. The compound according to any one of claims 1 to 4 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Z is absent or selected from NH, S, O, CH2, CH2NH; Preferably, ring E is selected from a 5-9 membered heterocyclic group or a C 5-6 Cycloalkyl; Preferably, ring E is selected from a 6-9 membered heterocyclic group or a C 5-6 Cycloalkyl; Preferably, ring E is selected from Preferably, ring E is selected from Preferably, R e is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R e1 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, (C 1-6 Alkyl)2-N-; each R e1 are the same or different and are independently selected from OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy; or, two R e With their respective attached atoms form C 3-6 Cycloalkane ring; Preferably, R e Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, (C 1-6 Alkyl)2-N-; or, two R e With their respective attached atoms form C 3-6 Cycloalkane ring; Preferably, R e is selected from H, F, Cl, methyl, deuterated methyl (CD3), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, Alternatively, two R attached to the same carbon atom e The atoms to which they are attached form a cyclopropane ring, Alternatively, two R attached to different carbon atoms e With their respective attached atoms Preferably, R e is selected from H, F, Cl, methyl, deuterated methyl (CD3), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, Alternatively, two R attached to the same carbon atom e The atoms to which they are attached form a cyclopropane ring, Alternatively, two R attached to different carbon atoms e With their respective attached atoms Preferably, X1, X2, and X3 are all CH, or one of X1, X2, and X3 is N; Preferably, R x Selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, R x Selected from H, F, Cl, CN, methoxy, methyl.

6. The compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has the structure shown below: Among them, ring A, ring E, X1, X2, X3, Y, R1, R2, R3, R4, R a , R e , R x , m, n, p have any one of claims 1-5 the definitions stated; Preferably, the compound represented by formula (I) has the structure shown below: Among them, ring A, ring E, X1, X2, X3, Y, R1, R2, R3, R4, R a , R e , R x , m, n, p have the definitions as described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R a , R x , m, n have the definitions as described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the structure shown below: Among them, ring A, R a , R x , m, n have the definitions as described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the structure shown below: Among them, R a , R e It has the definition as described in any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from the following structures:

8. A method for preparing the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, comprising the following step: reacting compound 1 with compound 2 to obtain a compound of formula (I); in, 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 as described in any one of claims 1-7.

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

10. Use of at least one of the compound according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof in the preparation of a medicament; Preferably, the use can be in the preparation of anti-tumor drugs containing p53-Y220C mutants, such as in the preparation of p53-Y220C mutants. Use in activator drugs; Preferably, the tumor containing the p53-Y220C mutant includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumors such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive cell tumor, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt's lymphoma, unknown primary cancer, central nervous system lymphoma, cerebellar astrocytoma, uterine Cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative diseases, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, Hodgkin 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 such as non-small cell lung cancer and small cell lung cancer, lymphoma leukemia, macroglobulinemia, malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma, melanoma, mesothelioma, metastatic squamous cell carcinoma with occult primary, oral cancer, multiple endocrine neoplasms syndrome, myelodysplastic syndrome, myeloid leukemia, nasal 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, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic islet cell carcinoma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal gland Astrocytoma, pineal germ cell tumor, pituitary adenoma, pleuropulmonary blastoma, plasmacytoma, primary central nervous system lymphoma, prostate cancer, colorectal cancer, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, Merkel cell carcinoma of the skin, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (pregnancy), cancer of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

Images