Heterocyclic compound

Abstract

The invention relates to a heterocyclic compound, in particular to a compound as shown in a formula (I), and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for preventing and / or treating cancers.

Description

[0001] This application claims priority to an earlier patent application filed by the applicant with the China National Intellectual Property Administration on August 19, 2024, with patent application number 202411137765.X, entitled "FGFR inhibitor compounds, pharmaceutical compositions and methods of preparation thereof and applications thereof". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and specifically relates to a heterocyclic compound. Background Technology

[0003] FGFRs are a subfamily of receptor tyrosine kinases (RTKs), including FGFR1–5, which share high sequence homology. Activation of the FGFR signaling axis primarily depends on binding to the ligand FGF. Upon binding to FGF, FGFRs polymerize into FGFR dimers. These dimers bind intracellularly to fibroblast growth factor receptor substrate 2 (FRS2) and undergo autophosphorylation, thereby activating downstream signaling pathways such as PI3K-AKT and RAS-MAPK, regulating cell proliferation and apoptosis. When FGFRs undergo abnormalities such as gene amplification, activating mutations, or oncogenic fusions, it leads to aberrant activation of downstream signaling pathways, resulting in tumor development, progression, metastasis, and drug resistance.

[0004] A study by Helsten et al. (Helsten T, Elkin S, Arthur E, et al., The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing[J]. Clin Cancer Res, 2016, 22(1):259-267) analyzed 4,853 tumor patients using next-generation sequencing and found that 7.1% of cancers had FGFR alterations, mainly FGFR amplification (66%), FGFR mutation (26%), and FGFR gene rearrangement (8%), with FGFR1 amplification being the most common. FGFR alterations are present in some patients with almost every type of malignant tumor, most commonly urothelial carcinoma (32%), breast cancer (18%), endometrial cancer (13%), squamous cell carcinoma of the lung (13%), and ovarian cancer (9%). FGFR plays an important role in tumor development, progression, and treatment resistance, and targeting FGFR has shown good therapeutic effects in the treatment of various cancers. Erdafitinib is approved for patients with urothelial carcinoma harboring FGFR2 / 3 mutations, while futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harboring FGFR2 fusions or rearrangements. Pemigatinib is also approved for patients with relapsed or refractory myeloid / lymphoma harboring FGFR1 rearrangements. Although FGFR inhibitors have shown great potential in the clinical treatment of malignancies, many cancers with FGFR alterations still lack effective treatment options. Furthermore, FGFR inhibitor resistance is a significant challenge affecting their clinical use, including "gatekeeper" gene mutations such as FGFR1 V559X, V561X, FGFR2 V564X, V565X, FGFR3 V553X, V555X, and FGFR4 V550X, and "kinase brake" gene mutations such as FGFR1 N546X, FGFR2 N549X, and FGFR3 N540X. Therefore, there is an urgent clinical need to develop a new generation of FGFR inhibitors for the treatment of more malignant tumors, while also having inhibitory activity against acquired resistance mutations of FGFR, thereby improving clinical treatment outcomes. Summary of the Invention

[0005] This disclosure provides compounds of formula (I), their tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs:

[0006]

[0007] in,

[0008] A is selected from 5-14 heteroaryl groups;

[0009] B is selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3);

[0010] E does not exist or is selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3);

[0011] Each R a They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl, -OR1, -N(R2)(R3); each R a1 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a2 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl, -OR1, -N(R2)(R3); each R a2 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a3 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3), -C(O)NH2; each R a3 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), -C(O)NH2, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 1-10 Alkyl-3-14-membered heterocyclic groups, -OR1, -N(R2)(R3);

[0012] Each R b They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. b1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkyne group, -OR1, -N(R2)(R3); each R b1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, -OR1, -N(R2)(R3);

[0013] Each R e They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. e1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 6-14 Aryl, -S(O)2-C 1-10 Alkyl, -OR1, -N(R2)(R3); each R e1 They may be the same or different, and are independently selected from halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, 5-14 membered heteroaryl, -OR1, -N(R2)(R3);

[0014] L1 is absent or selected from no substitution or is optionally replaced by one, two or more Rs. L1 The following groups are substituted: C 2-10 alkenyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C3-10 Cycloalkenyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic; each R L1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl groups, -OR1, -N(R2)(R3);

[0015] L2 is absent or selected from O, NH, C(O), -NHC(O)-, -NHC(O)NH-, N(C 1-6 alkyl);

[0016] Each R1, R2, and R3 may be the same or different, and is independently selected from H, without substitution, or arbitrarily determined by one, two, or more Rs. r The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl;

[0017] Each R r They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl;

[0018] m is selected from 0, 1, 2, 3, 4 or 5;

[0019] n is selected from 0, 1, 2, 3, 4 or 5;

[0020] p is selected from 0, 1, 2, 3, 4 or 5.

[0021] According to the embodiments of this disclosure, ring A is selected from 9-12 member heteroaryl groups;

[0022] According to the implementation scheme of this disclosure, ring A is selected from...

[0023] According to the implementation scheme of this disclosure, Selected from

[0024] According to the implementation scheme of this disclosure, each Ra They may be the same or different, and are independently selected from H, halogens, unsubstituted, or optionally composed of one, two, or more R atoms. a1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, OH; each R a1 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a2 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR1, -N(R2)(R3); each R a2 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a3 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, -OR1, -N(R2)(R3), -C(O)NH2; each R a3 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), -C(O)NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 1-6 Alkyl-3-8-membered heterocyclic groups, -OR1, -N(R2)(R3);

[0025] According to the implementation scheme of this disclosure, each R a They may be the same or different, and are independently selected from H, halogens, unsubstituted, or optionally composed of one, two, or more R atoms. a1The following groups are substituted: OH, methyl, methoxy, ethoxy, vinyl, propynyl, cyclopropyl, cyclohexyl, benzyloxy, phenyl, monofluoroethoxy, difluoroethoxy, piperazine, pyrazolyl, pyranyl, tetrahydropyranyl, pyridyl, cyclohexenyl, aziridine, and aziridine.

[0026] According to the implementation scheme of this disclosure, each R a They may be the same or different, and are independently selected from H, Cl, OH, methoxy, ethoxy, cyclopropyl, benzyloxy, phenyl, pyridyl, monofluoroethoxy, difluoroethoxy,

[0027] According to the implementation scheme of this disclosure, B is selected from C. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 5-10 heterocyclic, 5-10 heteroaryl;

[0028] According to embodiments of this disclosure, B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, piperidinyl, cyclohexenyl, benzimidazolyl, indolyl, tetrahydropyranyl, ...

[0029] According to the implementation scheme of this disclosure, B is selected from...

[0030] According to the implementation scheme of this disclosure, each R b They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. b1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OR1, -N(R2)(R3); each R b1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, -OR1, -N(R2)(R3);

[0031] According to the implementation scheme of this disclosure, each R bThey are either the same or different, and are independently selected from H, F, Cl, OH, NH2, methyl, methoxy, trifluoromethyl, ethynyl, -C(O)NH2;

[0032] According to the implementation scheme of this disclosure, when Rb is not H, Selected from

[0033] According to the implementation scheme of this disclosure, E does not exist or is selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-8 membered heteroaryl, -OR1, -N(R2)(R3);

[0034] According to embodiments of this disclosure, E is absent or selected from ethyl, propyl, propenyl, 2-butenyl, pyrimidinyl, cyclobutyl, monoheterocyclic butyl, phenyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyridinyl, morpholinyl,

[0035] According to the implementation scheme of this disclosure, each R e They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. e1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, -S(O)2-C 1-6 Alkyl, -OR1, -N(R2)(R3); each R e1 They may be the same or different, and are independently selected from halogens, OH, CN, NH2, oxo (=O), and C. 1-6 Alkyl, -OR1, -N(R2)(R3), pyrimidinyl.

[0036] According to the implementation scheme of this disclosure, It does not exist or is selected from CN, methyl, isopropyl, tetrahydropyrrolyl, morpholinyl,

[0037] According to the embodiments of this disclosure, L1 is absent or selected from no substitution or optionally replaced by one, two or more R L1 The following groups are substituted: C 2-6 alkenyl, C 1-6 Alkyl, 5-10 heteroaryl; each R L1They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0038] According to the embodiments of this disclosure, L1 is absent or selected from no substitution or optionally replaced by one, two or more R L1 The following groups are substituted: vinyl, ethoxy, pyrazolyl; each R L1 They may be the same or different, and are independently selected from H, F, and methoxy groups;

[0039] According to the implementation scheme of this disclosure, L1 does not exist or is selected from...

[0040] According to the embodiments of this disclosure, L2 is absent or selected from O, NH, C(O), -NHC(O)-, -NHC(O)NH-, N(CH3).

[0041] According to embodiments of this disclosure, the compound represented by formula (I) has the following structure:

[0042]

[0043] Among them, rings B, E, and R a R b R e L1, L2, m, n, and p have the definitions described above.

[0044] According to embodiments of this disclosure, the compound represented by formula (I) has the following structure:

[0045]

[0046] Among them, rings E and R a R b R e L2, n, p have the definitions described above, X1, X2, X3, X4 are the same or different, are independently selected from N or CH, and at most two are selected from N.

[0047] According to embodiments of this disclosure, the compound represented by formula (I) is selected from compounds 1 to 267 in Table 1 of the examples.

[0048] This disclosure also provides a method for preparing the compound represented by formula (I), its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, the method comprising the following steps: reacting compound 1 with compound 2 to obtain the compound represented by formula (I);

[0049]

[0050] Among them, rings A, B, E, and R a R b R e L1, L2, m, n, and p have the definitions described above; X is selected from leaving groups, such as halogens.

[0051] According to embodiments of this disclosure, those skilled in the art may also protect the functional groups (e.g., hydroxyl and / or amino) of compound 1 with suitable protecting groups (e.g., hydroxyl protecting groups and / or amino protecting groups known in the art) before reacting it with compound 2, and then remove the protecting groups.

[0052] Suitable protecting groups can be groups known to those skilled in the art, such as C. 1-10 Alkyl, C 6-14 Aryl C 1-10 Alkyl groups, examples of which can be tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenemethoxycarbonyl (Fmoc), trifluoroacetyl, etc.

[0053] The conditions for removing the protecting group are known to those skilled in the art, for example, removing the protecting group under hydrolytic conditions.

[0054] According to embodiments of this disclosure, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and others. Polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those that may be substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0055] This disclosure also provides a pharmaceutical composition comprising a compound of formula (I), a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug.

[0056] According to embodiments of this disclosure, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0057] This disclosure also provides the use of the compound represented by formula (I), its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition in the preparation of a medicament.

[0058] According to embodiments of this disclosure, the pharmaceutical composition or the drug is used to treat tumors, such as cancer.

[0059] According to the embodiments of this disclosure, the drug is an FGFR inhibitor.

[0060] According to embodiments of this disclosure, the tumor includes, but is not limited to, at least one of the following: sarcoma, myeloma, lymphoma, melanoma, brain tumor, spinal cord tumor, and germ cell tumor.

[0061] According to embodiments of this disclosure, the cancers include, but are not limited to, at least one selected from the following: urothelial carcinoma, breast cancer, endometrial cancer, squamous cell carcinoma of the lung, ovarian cancer, bile duct cancer, lymphoma, blood cancer (such as leukemia), gastric cancer, bladder cancer, blood cancer, bone cancer, brain cancer, lung cancer, central nervous system cancer, cervical cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer.

[0062] This disclosure also provides a compound of formula (I), its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, or pharmaceutical compositions thereof for the prevention and / or treatment of tumors, such as cancer.

[0063] This disclosure also provides a method for preventing and / or treating tumors, such as cancer, comprising administering to a patient a therapeutically effective amount of at least one of the following: a compound of formula (I), a tautomer thereof, a stereoisomer thereof, an isotope label thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the pharmaceutical composition thereof.

[0064] According to embodiments of this disclosure, the tumors include: sarcoma, myeloma, lymphoma, melanoma, brain tumor, spinal cord tumor, and germ cell tumor.

[0065] According to embodiments of this disclosure, the cancers include: urothelial carcinoma, breast cancer, endometrial cancer, squamous cell carcinoma of the lung, ovarian cancer, bile duct cancer, lymphoma, blood cancer (such as leukemia), stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, lung cancer, central nervous system cancer, cervical cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer.

[0066] According to embodiments of this disclosure, the treatment includes inhibiting the proliferation of tumor cells and / or inhibiting the volume of the tumor, such as inhibiting the proliferation of cancer cells and / or inhibiting the volume of cancerous sites.

[0067] Beneficial effects

[0068] The compounds of formula (I) disclosed herein, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs have excellent FGFR inhibitory activity and can be used for the prevention and / or treatment of cancer.

[0069] Terminology Definitions and Explanations

[0070] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0071] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0072] It should be understood that in the description of 1, 2 or more, "more" should refer to an integer greater than 2, such as an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0073] The context of this disclosure is used Represents a chemical bond.

[0074] Term "C" 1-10 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 1-10 Alkyl groups include C 1-3Alkyl, C 1-6 Alkyl, C 3-6 Alkyl groups, etc. "C" 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group 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 their isomers.

[0075] “C 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 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., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable 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)- Pentyl-1-enyl, (Z)-pentyl-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.

[0076] Term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0077] Term "C" 3-10 "Cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups include C 3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, etc. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, 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 tricyclic hydrocarbon groups, such as adamantyl.

[0078] Term "C" 3-10 "Cycloalkenyl" refers to a monocyclic, bicyclic (such as fused, bridged, or spirocyclic) hydrocarbon ring or tricyclic alkane containing at least one carbon-carbon double bond, having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkenyl groups include C3-8 Cycloalkenyl, C 3-5 Cycloalkenyl, C 6-8 Cycloalkenyl, C 3-4 Cycloalkenyl, C 5-6 Cycloalkenyl, C6 cycloalkenyl, etc. The C... 3-10 Cycloalkenyl groups can be monocyclic hydrocarbon groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl, or they can be bicyclic hydrocarbon groups or tricyclic hydrocarbon groups.

[0079] The term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the 3-14-membered heterocyclic group ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine or tetrahydropyrrole, the nitrogen atom or carbon atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta, or para position can be attached to other groups.

[0080] Term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0081] The term "5-14-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein the ring atoms comprise 1-5 heteroatoms independently selected from N, O, and S, and the bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings. The 5-14-membered heteroaryl contains 1-5 heteroatoms, preferably 1-3. Additionally, in each case, the 5-14-membered heteroaryl can be benzofused. The 5-14-membered heteroaryl includes 5-8-membered heteroaryl, 5-9-membered heteroaryl, 5-10-membered heteroaryl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, 6-membered heteroaryl, etc. Examples of heteroaryl groups include, but are not limited to: 5-membered rings, such as oxazolyl, pyrazolyl, thiophene, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzisoxazole, tetrahydrobenzothiazole, tetrahydrobenzisoxazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptazothiazole, tetrahydrocycloheptazofuran. The heterocyclic group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom bonded to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom bonded to a heteroatom on the heteroaryl ring can be substituted.

[0082] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0083] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0084] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] "Halogenation" refers to the substitution of a substance by one or more halogens.

[0087] The term "oxo" refers to the substitution of a non-oxygen atom with a hydrogen atom or a lone pair of electrons by an oxygen atom, for example, After being oxidized, it becomes After being oxidized, it becomes

[0088] The term "halogenated C" 1-10 "Alkyl" refers to an alkyl group as defined above, which is substituted with one or more halogens as defined above, preferably "halogenated C". 1-6 "Alkyl". The halogenated alkyl group includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc.

[0089] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-10 The definition of alkyl also applies to C 1-10 Alkyloxy, C 1-10 Alkyl thio, C 1-10 Alkylamino, C 1-10 Alkyl carbonyl and other groups containing C 1-10 Definition of alkyl groups.

[0090] Crystallization often produces solvates of the compounds disclosed herein. As used herein, a solvate is a combination of one or more molecules of the compounds disclosed and one or more solvent molecules.

[0091] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds disclosed herein can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and their corresponding solvated forms. The compounds disclosed herein can be true solvates, but in other cases, they may simply contain water or a mixture of water and other solvents by chance. The compounds disclosed herein can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds disclosed herein are also included within the scope of this disclosure.

[0092] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it does not have a lasting harmful effect on the overall health of the subject of treatment.

[0093] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds disclosed herein and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition.

[0094] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0095] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0096] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0097] In this application, "pharmaceutical composition" refers to a formulation of the disclosed compound and a medium conventionally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0098] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0099] In this application, the term "solvent" refers to a compound of the present disclosure or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0100] In this application, the term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of the compound of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0101] "Isotope" refers to all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds disclosed herein are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 31 P, 32 P, 35 S, 18 F and 36 C1. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically labeled reagents instead of non-isotopically labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0102] In this article, the term "tumor" includes both benign tumors and malignant tumors (such as cancer).

[0103] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0104] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0105] (ii) To suppress a disease or symptom, that is, to curb its development;

[0106] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0107] (iv) To alleviate the symptoms caused by the disease or condition.

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

[0109] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0110] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0111] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0112] Example 1: Preparation of Compound 1

[0113] Step A: (E)-N-(4-(2-(6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0114]

[0115] Add 6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61 mg, 0.15 mmol), (E)-N-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)vinyl)phenyl)acrylamide (68 mg, 0.23 mmol), potassium carbonate (62 mg, 0.45 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), 1, 4-Dioxane (3 mL), water (0.3 mL), nitrogen purged three times, reacted at 90 °C for 6 h, diluted with 20 mL of water, extracted with 2 × 20 mL of dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 8%) to give (E)-N-(4-(2-(6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide (1.1 mg), m / z = 428 [M+1] + .

[0116] Example 2: Preparation of Compound 2

[0117] 1-(3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one

[0118]

[0119] 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.27 mmol), DCM (10 mL), DIEA (172 mg, 1.33 mmol), and acryloyl chloride (24 mg, 0.27 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of water, extracted with DCM, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 36 mg of the product. m / z = 430 [M+1] + . 1H-NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.59-8.60(m,1H),8.51-8.52(m,1H),8.06-8.09(m,1H),7 .59(s,1H),7.23-7.24(m,1H),6.83-6.86(m,1H),6.44-6.51(m,1H),6.10-6.15(m,1H),5.67-5.70 (m,1H),4.87-4.88(m,1H),4.53-4.54(m,1H),4.14-4.20(m,2H),4.01-4.04(m,1H),3.68-3.77(m, 2H),3.59-3.66(m,1H),2.72-2.77(m,1H),2.50-2.51(m,2H),1.66-1.68(m,1H),1.37-1.43(m,3H).

[0120] Example 3: Preparation of Compound 3

[0121] Step A: N-(1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperazin-4-yl)acrylamide

[0122]

[0123] Add 1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperazine-4-aminohydrochloride (150 mg, 0.3 mmol), DIEA (194 mg, 1.5 mmol), DMF (10 mL), and acryloyl chloride (27 mg, 0.3 mmol) to the reaction flask, react at room temperature for 2 h, and then add 30 mL of the solution. Dilute with water, extract with 2 × 50 mL of dichloromethane, combine organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate, and precipitate by column chromatography (MeOH / DCM = 6%) to give N-(1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperazin-4-yl)acrylamide (20.5 mg), m / z = 446 [M+1] + .

[0124] 1HNMR (400MHz, DMSO-d6): δ12.65(brs,1H),8.57(s,1H),8.51(s,1H),8.02(d,J=8. 8Hz,1H),7.74(s,1H),7.58(s,1H),7.25(s,1H),7.07(d,J=8.8Hz,1H),6.39-6.32 (m,1H),6.09-6.04(m,1H),5.56-5.53(m,1H),4.16(t,J=5.7Hz,2H),4.01-3.98(m ,2H),3.30-3.27(m,2H),2.24-2.21(m,2H),1.59-1.53(m,2H),1.39-1.32(m,6H).

[0125] Example 4: Preparation of Compound 4

[0126] Step A: 1-(4-(4-bromophenyl)piperidin-1-yl)prop-2-en-1-one

[0127]

[0128] 4-(4-bromophenyl)piperidine (240 mg, 0.1 mmol), DCM (3 mL), DIEA (387 mg, 3.0 mmol), and acryloyl chloride (91 mg, 1.0 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of water, extracted with DCM, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (PE:EA = 4:1) to obtain 220 mg of the product. m / z = 294, 296 [M+1] + .

[0129] Step B: 1-(4-(4-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)piperidin-1-yl)propyl-2-en-1-one

[0130]

[0131] 1-(4-(4-bromophenyl)piperidin-1-yl)prop-2-en-1-one (60 mg, 0.2 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (65 mg, 0.2 mmol), Cs2CO3 (196 mg, 0.6 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), 15-crown ether-5 (15 mg, 20% w / w), dioxane (3 mL), and water (0.5 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 16 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 3.9 mg of product, m / z = 416 [M+1]. + .

[0132] 1 H-NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.54-8.55(m,1H),7.79-7.81(m,2H),7.59( s,1H),7.47-7.49(m,2H),7.26-7.27(m,1H),6.83-6.90(m,1H),6.11-6.16(m,1H),5 .67-5.71(m,1H),4.58-4.64(m,1H),4.14-4.22(m,3H),3.15-3.21(m,1H),2.88-2.9 4(m,1H),2.71-2.77(m,1H),1.89-1.92(m,2H),1.62-1.65(m,2H),1.35-1.43(m,3H).

[0133] Example 5: Preparation of Compound 5

[0134] Step A: N-(4-bromophenyl)acrylamide

[0135]

[0136] 4-Bromoaniline (860 mg, 5 mmol), DCM (10 mL), DIEA (1900 mg, 15 mmol), and acryloyl chloride (453 mg, 5 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of water, extracted with DCM, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (PE:EA = 4:1) to obtain 1160 mg of the product. m / z = 226, 228 [M+1] + .

[0137] Step B: N-(4-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide

[0138]

[0139] N-(4-bromophenyl)acrylamide (45 mg, 0.2 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (65 mg, 0.2 mmol), Cs2CO3 (196 mg, 0.6 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), 15-crown-5 (15 mg, 20% w / w), dioxane (3 mL), and water (0.5 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 16 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 3.5 mg of product, m / z = 348 [M+1]. + .

[0140] 1 H-NMR(400MHz,DMSO-d6)δ12.65(s,1H),10.42(s,1H),8.55-8.56(m,1H),7.91-7.94(m,2H),7.84-7.87(m,2H),7.61(s ,1H),7.28-7.29(m,1H),6.47-6.52(m,1H),6.30-6.34(m,1H),5.80-5.83(m,1H),4.18-4.20(m,2H),1.39-1.42(m,3H).

[0141] Example 6: Preparation of Compound 6

[0142] Step A: 4-((4-methoxybenzyl)oxy)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0143]

[0144] Add 6-bromo-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (420 mg, 1.13 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (376.6 mg, 1.72 mmol), tetratetraphenylphosphine palladium (260 mg, 0.23 mmol), potassium carbonate (310.8 mg, 2.25 mmol), 1,4-dioxane (4 mL), and water (1 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 6 hours. After the reaction is complete, extract with water and dichloromethane, and obtain 165 mg of product by silica gel column chromatography, m / z = 390.2 [M+1]. + .

[0145] Step B: 6-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-hydroxytrifluoroacetate

[0146]

[0147] Add 165 mg (0.42 mmol) of 4-((4-methoxybenzyl)oxy)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, 0.5 mL of trifluoroacetic acid, and 2 mL of dichloromethane to a reaction flask. Stir at room temperature for 1 hour. After the reaction is complete, concentrate until no residue appears, add 1 mL of methanol and 10 mL of methyl tert-butyl ether, stir for 0.5 hours, and filter to obtain 120 mg of a pale yellow solid, m / z = 270.1 [M+1]. + .

[0148] Step C: 6-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate

[0149]

[0150] 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-hydroxytrifluoroacetate (120 mg, 0.31 mmol), N-methylpyrrolidone (2 mL), and DIEA (242.5 mg, 1.9 mmol) were added to the reaction flask. PhN(Tf)₂ (112 mg, 0.31 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water and dichloromethane were added for extraction, and silica gel column chromatography was performed to obtain 60 mg of a white solid, m / z = 402 [M+1]. + .

[0151] Step D: (E)-N-(4-(2-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)vinyl)phenyl)acrylamide

[0152]

[0153] Add 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (60 mg, 0.15 mmol) and (E)-N-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)vinyl)phenyl)acrylamide (89.5 mg) to the reaction flask. The reaction mixture consisted of 0.30 mmol Pd(dppf)Cl2 (22 mg, 0.03 mmol), 41.3 mg potassium carbonate (0.33 mmol), 1,4-dioxane (2 mL), and 0.5 mL water. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 6 hours. After the reaction was complete, water and dichloromethane were added for extraction. The product was purified by reverse-phase column chromatography and then lyophilized to obtain 7 mg of product. m / z = 425.1 [M+1] + .

[0154] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),10.30(s,1H),8.70(s,1H),8.22(s,1H),7.92(s,1H),7.80-7.71(m,4H),7.68-7.64(d,1H,J=16.4),7. 52-7.45(m,1H),6.50-6.44(m,2H),6.32-6.27(dd,1H),5.80-5.77(dd ,1H),3.09-3.08(m,2H),2.61(s,3H),2.33-2.67(m,3H),1.23(s,1H).

[0155] Example 7: Preparation of Compound 7

[0156] Step A: N-(5-bromopyridin-2-yl)acrylamide

[0157]

[0158] 5-Bromopyridin-2-amine (520 mg, 3 mmol) and DMF (10 mL) were added to a reaction flask. NaH (40% 140 mg) was added, and the mixture was reacted in an ice-water bath for 0.5 h. Acryloyl chloride (300 mg, 3.3 mmol) was then added, and the reaction was continued for 1 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and stirred. Extraction was performed using EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 500 mg of the product (m / z = 227 [M+1]). + .

[0159] Step B: N-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0160]

[0161] N-(5-bromopyridin-2-yl)acrylamide (100 mg, 0.45 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.3 mmol), PdCl2 (dppf) (20 mg, 0.03 mmol), Cs2CO3 (200 mg, 0.6 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 2 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 7 mg of the product, m / z = 349 [M+1]. + .

[0162] 1 HNMR (400MHz, DMSO-d6): δ12.70(brs,1H),11.02(s,1H),8.83(s,1H),8.61(s,1H),8.43(d,J=8.8Hz,1H),8.34-8.32(m,1H),7 .55(s,1H),7.39(s,1H),6.70-6.66(m,1H),6.39-6.34(m,1H),5.85-5.83(m,1H),4.17(q,J=6.8Hz,2H),1.39(t,J=6.8Hz,3H).

[0163] Example 8: Preparation of Compound 8

[0164] Step A: N-(5-bromopyridin-2-yl)methacrylamide

[0165]

[0166] 5-Bromopyridin-2-amine (520 mg, 3 mmol) and DMF (10 mL) were added to a reaction flask. NaH (40% , 140 mg) was added, and the reaction was carried out in an ice-water bath for 0.5 h. Methacrylamide chloride (350 mg, 3.3 mmol) was then added, and the reaction was continued for 1 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and stirred. Extraction was performed using EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 56 mg of the product, m / z = 227 [M+1]. + .

[0167] Step B: N-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)methacrylamide

[0168]

[0169] N-(5-bromopyridin-2-yl)methacrylamide (56 mg, 0.23 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (50 mg, 0.3 mmol), PdCl2 (dppf) (20 mg, 0.03 mmol), Cs2CO3 (200 mg, 0.6 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 2 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 8 mg of the product, m / z = 349 [M+1]. + .

[0170] 1 HNMR (400MHz, DMSO-d6): δ12.71(brs,1H),10.56(s,1H),8.84(s,1H),8.61(s,1H),8.33(s,1H),7.58(s ,1H),7.41(s,1H),6.01(s,1H),5.61(s,1H),4.17(q,J=6.8Hz,2H),2.00(s,3H),1.39(t,J=6.8Hz,3H).

[0171] Example 9: Preparation of Compound 9

[0172] 1-(3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-2-methylprop-2-en-1-one

[0173]

[0174] 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (75 mg, 0.2 mmol), TEA (100 mg, 1.0 mmol), methacryloyl chloride (40 mg, 0.4 mmol), and DMF (2 mL) were added to a reaction flask and reacted at 0 °C for 1 h. The reaction was monitored by LCMS until complete. Column chromatography yielded 30 mg of the product, m / z = 444 [M+1]. + .

[0175] 1 HNMR (400MHz, DMSO-d6): δ12.65(brs,1H),8.60(s,1H),8.51(s,1H),8.06(s, 1H),7.58(s,1H),7.25(s,1H),6.85(s,1H),5.49-5.46(m,2H),4.75-4.71(m,1 H),4.51-4.46(m,1H),4.15(q,J=6.8Hz,2H),4.10-4.05(m,1H),3.78-3.62(m, 3H), 2.78-2.74 (m, 1H), 1.76 (s, 3H), 1.68-1.65 (m, 1H), 1.39 (t, J = 6.8Hz, 3H).

[0176] Example 10: Preparation of Compound 10

[0177] Step A: 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0178]

[0179] 1-(5-(4,4,5,5-tetramethyl-1,2-dioxorane-2-yl)pyridin-2-yl)piperazine hydrochloride (144 mg, 0.5 mmol), acryloyl chloride (50 mg, 0.55 mmol), DIEA (96 mg, 0.75 mmol), and DMF (25 mL) were added to the reaction flask. The reaction was carried out at 0 °C for 1.5 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the product, m / z = 344 [M+1]. + .

[0180] Step B: 1-(4-(-5-(6-ethoxy-1-hydro-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0181]

[0182] To 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (164 mg, 0.5 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (171 mg, 0.5 mmol), cesium carbonate (1489 mg, 1.5 mmol), 1,4-dioxane (2 mL), and water (0.3 mL), tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol) were added, purged with nitrogen, and reacted at 90 °C for 12 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the product, m / z = 418 [M+1]. + ,

[0183] 1 H NMR (400MHz, DMSO-d6): 12.65(s,1H),8.61(d,J=2.4Hz,1H),8.52(d,J=2.0Hz,1H),8.08(dd,J=8.8,2.4Hz,1H),7.58(s,1H),7.27(d,J=2.1Hz,1H) ,7.13-7.06(m,1H),6.88(m,1H),6.17(dd,J=16.7,2.4Hz,1H),5.74(dd,J =10.4, 2.4Hz, 1H), 4.23-4.06 (m, 2H), 3.71 (m, 8H), 1.40 (t, J = 7.0Hz, 3H).

[0184] Example 11: Preparation of Compound 11

[0185] Step A: 3-(5-(6-ethoxy-1-hydro-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate

[0186]

[0187] 4-(5-chloropyrazin-2-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (200 mg, 0.5 mmol), 3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate (198 mg, 1.0 mmol), DIEA (193 mg, 1.5 mmol), and 3 mL DMSO were added to the reaction flask. The mixture was reacted at 80 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 300 mg of the product, m / z = 477 [M+1]. + .

[0188] Step B: 4-(-5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride

[0189]

[0190] 3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonate tert-butyl ester (340 mg, 0.8 mmol) and 5N hydrochloric acid methanol solution (3 mL, 1.5 mmol) were added to the reaction flask, and the reaction was carried out at 25 °C for 2 h. The product was concentrated under reduced pressure to obtain 340 mg of product, m / z = 377[M+1]+.

[0191] Step C: 1-(3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one

[0192]

[0193] 4-(-5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride (100 mg, 0.26 mmol), acryloyl chloride (24 mg, 0.26 mmol), DIEA (167 mg, 1.3 mmol), and DMF (2 mL) were added to the reaction flask. The reaction was carried out at 0 °C for 1.5 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and stirred. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. The product was obtained at m / z = 431 [M+1]. + ,

[0194] 1 H NMR (400MHz, DMSO-d6): 12.47(s,1H),8.93(d,J=1.5Hz,1H),8.55(d,J=2.1Hz,1H),8.48(d,J=1.5Hz ,1H),8.00(s,1H),7.71(d,J=2.1Hz,1H),6.49(m,1H),6.12(dd,J=16.9,2.1Hz,1H),5.69(dd,J=10.3 ,2.1Hz,1H),4.90(s,1H),4.19(q,J=6.9Hz,2H),4.10(d,J=10.7Hz,1H),3.84(d,J=2.1Hz,2H),3.77( dd,J=11.7,1.7Hz,1H),3.31(s,1H),2.82-2.71(m,1H),1.70(d,J=8.8Hz,1H),1.41(t,J=7.0Hz,3H).

[0195] Example 12: Preparation of Compound 12

[0196] Step A: 3-(5-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylic acid tert-butyl ester

[0197]

[0198] Add 6-(benzyloxy)-4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (840 mg, 2.0 mmol), 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (840 mg, 2.2 mmol), K2CO3 (830 mg, 6.0 mmol), Pd(dppf)Cl2 (150 mg, 0.2 mmol), 15-crown ether-5 (200 mg, 20% w / w), dioxane (10 mL), and water (2 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by column chromatography (PE:EA = 1:4) to obtain 1 g of product, m / z = 622 [M+1]. + .

[0199] Step B: 3-(5-(6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0200]

[0201] 3-(5-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (730 mg, 1.2 mmol), EA (10 mL), anhydrous palladium on carbon (730 mg, 100% w / w), and palladium hydroxide on carbon (150 mg, 20% w / w) were added to the reaction flask. The mixture was purged with hydrogen three times, and the reaction was carried out at 50 °C for 18 h under hydrogen protection. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated and dried under reduced pressure. Column chromatography (methanol / dichloromethane = 8%) yielded 370 mg of the product, m / z = 532 [M+1]. + .

[0202] Step C: 3-(5-(6-((4-methylpyrimidin-2-yl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylic acid tert-butyl ester

[0203]

[0204] 3-(5-(6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (160 mg, 0.30 mmol), Cs₂CO₃ (196 mg, 0.60 mmol), 2-chloro-4-methylpyrimidine (42 mg, 0.33 mmol), and DMF (3 mL) were added to a reaction flask and reacted at 25 °C for 24 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 40 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 150 mg of the product, m / z = 624 [M+1]. + .

[0205] Step D: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((4-methylpyrimidin-2-yl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride

[0206]

[0207] 3-(5-(6-((4-methylpyrimidin-2-yl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (150 mg, 0.24 mmol) and 4N hydrochloric acid-dioxane solution (4 mL) were added to a reaction flask. The reaction was carried out at 25 °C for 2 hours until complete. The mixture was then concentrated to dryness under reduced pressure to obtain 140 mg of the product, m / z = 440 [M+1]. + .

[0208] Step E: 1-(3-(5-(6-((4-methylpyrimidin-2-yl)oxy)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)prop-2-en-1-one

[0209]

[0210] 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((4-methylpyrimidin-2-yl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride (130 mg, 0.24 mmol), DCM (3 mL), and TEA (120 mg, 1.18 mmol) were added to a reaction flask. Acryloyl chloride (21 mg, 0.24 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 hour. The solution was poured into 50 mL of water, extracted with dichloromethane, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 19.9 mg of product, m / z = 494 [M+1]. + .

[0211] Example 13: Preparation of Compound 13

[0212] Step A: 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-((4-methoxyphenyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0213]

[0214] Add 6-bromo-4-((4-methylpyrimidine)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.34 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy)-4-methylpyrimidine (465 mg, 1.40 mmol), Cs2CO3 (555 mg, 4.02 mmol), Pd(dppf)Cl2 (98 mg, 0.134 mmol), dioxane (10 mL), and water (2 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 72 hours. The reaction was monitored by LCMS until it was complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 500 mg of product, m / z = 497 [M+1]+.

[0215] Step B: 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0216]

[0217] 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-((4-methoxyphenyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1 mmol), m-phenylenediamine (414 mg, 3 mmol), and DCM (10 mL) were added to a reaction flask, followed by TFA (5 mL). The reaction was carried out at 25 °C for 1 h, and the reaction was monitored by LCMS to ensure complete reaction. The reaction solution was evaporated to dryness, and the product was slurried with tertiary methyl ether to obtain 130 mg of product, m / z = 377 [M+1]. + .

[0218] Step C: 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-yl trifluoromethanesulfonate

[0219]

[0220] 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (130 mg, 0.35 mmol), DMF (3 mL), DIEA (89 mg, 0.69 mmol), and N-phenylbis(trifluoromethanesulfonylimide) (123 mg, 0.35 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 20 mL of water, extracted with DCM, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (PE:EA = 4:1) to obtain 150 mg of product, m / z = 509 [M+1]. + .

[0221] Step D: 1-(3-(5-(6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one

[0222]

[0223] Add 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (50 mg, 0.1 mmol), 1-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one (40 mg, 0.1 mmol), Cs2CO3 (27 mg, 0.2 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), dioxane (3 mL), and water (0.5 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 7.9 mg of product, m / z = 588 [M+1]. + .

[0224] 1 H-NMR(400MHz,DMSO-d6)δ12.77(s,1H),9.26-9.27(m,1H),8.74-8.75(m,1H),8.50-8.51(m,1H),8.19-8.21 (m,1H),8.02-8.05(m,1H),7.83-7.88(m,2H),7.71(s,1H),7.49-7.53(m,1H),7.21-7.23(m,1H),6.87-6.90 (m,1H),6.45-6.52(m,1H),6.10-6.15(m,1H),5.68-5.71(m,1H),4.89-4.90(m,1H),4.54-4.55(m,1H),4.03 -4.06(m,1H),3.68-3.71(m,2H),3.76-3.77(m,1H),2.66-2.76(m,1H),2.44-2.50(m,3H),1.67-1.69(m,1H).

[0225] Example 14: Preparation of Compound 14

[0226] Step A: 6-ethoxy-4-(6-ethyn-4-methoxypyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0227]

[0228] Add 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (170.2 mg, 0.46 mmol), 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine (100 mg, 0.31 mmol), Pd(dppf)Cl2 (22.4 mg, 0.03 mmol), potassium carbonate (84.7 mg, 0.61 mmol), 1,4-dioxane (1 mL), and water (0.2 mL) to a microwave tube. Purge with nitrogen, stir at 90 °C for 16 hours, extract with water and dichloromethane, and pass the organic phase through a normal-phase column until no more is observed. Use the resulting solution directly for the next step.

[0229] Tetrahydrofuran (1 mL) and TBAF / THF (1 mol / L, 0.2 mL) were added sequentially to the product from the previous rotary evaporation step. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After the reaction was stopped, dichloromethane and water were added for extraction. After the organic phase was stopped, DMF was added, and the mixture was passed through a reversed-phase column and lyophilized to give 10 mg of a white solid, m / z = 334.1 [M+1]. + .

[0230] 1 H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.61(s,1H),8.55-8.52(m,1H),7.63-7.53(m,1 H),7.31-7.27(m,2H),4.54(s,1H),4.20-4.15(q,2H),3.88(s,3H),1.57-1.53(t,3H).

[0231] Example 15: Preparation of Compound 15

[0232] Step A: 2-(tert-butyldimethylsilyl)ethynyl)-5-iodo-4-methoxypyridine

[0233]

[0234] 5-Bromo-2-(tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine (1.0 g, 3.0 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (85 mg, 0.6 mmol), NaI (2.25 g, 15.0 mmol), CuI (57 mg, 0.3 mmol), and DMSO (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. The reaction was monitored by LC-MS until complete. After adding water (80 mL), the mixture was extracted with EA. The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 2-(tert-butyldimethylsilyl)ethynyl)-5-iodo-4-methoxypyridine (780 mg). m / z = 374 [M+H] + .

[0235] Step B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride

[0236]

[0237] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.1 g, 10.0 mmol), 1,4-dioxane (12 mL), and a solution of 1,4-dioxane in hydrogen chloride (4 M, 20 mL, 80.0 mmol) were added sequentially to a reaction flask. The reaction was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until complete, and the solution was concentrated to dryness to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (2.8 g). m / z = 210 [M+H] + .

[0238] Step C: 4-Bromo-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0239]

[0240] 4-Bromo-6-ethoxypyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (1.4 g, 5.0 mmol), DHP (462 mg, 5.5 mmol), TsOH·H₂O (95 mg, 0.5 mmol), and THF (20 mL) were added sequentially to the reaction flask, and the mixture was heated to 60°C and reacted for 5 hours. The reaction was monitored by LCMS until complete, and the concentrate was purified by column chromatography (dichloromethane / methanol = 100 / 1) to give 4-bromo-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (2.0 g). m / z = 365 / 367 [M+H] + .

[0241] Step D: 6-ethoxy-1-(tetrahydropyran-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine

[0242]

[0243] 4-Bromo-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (365 mg, 1.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (368 mg, 1.5 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), Cs2CO3 (73 mg, 0.08 mmol), 1,4-dioxane (12 mL), and water (3 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and reacted for 3 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the organic phase was separated, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give 6-ethoxy-1-tetrahydropyran-2-yl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (290 mg). m / z = 368 [M+H] + .

[0244] Step E: 4-(6'-(tert-butyldimethylsilyl)ethynyl)-4'-methoxy-3,6-dihydro-2H-[1,3'-bipyridine]-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0245]

[0246] The following ingredients were added sequentially to the reaction flask: 6-ethoxy-1-tetrahydropyran-2-yl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (290 mg, 0.8 mmol), 2-(tert-butyldimethylsilyl)ethynyl)-5-iodo-4-methoxypyridine (420 mg, 0.8 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), XantPhos (93 mg, 0.16 mmol), Cs2CO3 (73 mg, 0.08 mmol), and toluene (5 mL). The reaction was carried out at 120°C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the mixture was filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain 4-(6'-(tert-butyldimethylsilyl)ethynyl)-4'-methoxy-3,6-dihydro-2H-[1,3'-bipyridine]-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (180 mg).

[0247] m / z = 613[M+H] + .

[0248] Step F: 6-ethoxy-4-(6-ethynyl-4-methoxy-3,6-dihydro-2H-[1,3'-bipyridin]-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine

[0249]

[0250] Add 180 mg (0.3 mmol) of 4-(6'-(tert-butyldimethylsilyl)ethynyl)-4'-methoxy-3,6-dihydro-2H-[1,3'-bipyridin]-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, 3 mL (1 M), THF, and 3 mmol (1 mL) of TBAF aqueous solution to the reaction flask. Stir the reaction solution at room temperature for 30 min. After the reaction is complete under LCMS monitoring, concentrate to dryness, dissolve in DCM (10 mL), add TFA (4 mL) dropwise to the solution, and stir for 2 hours. After the reaction is complete under LCMS monitoring, concentrate, dilute with DCM (10 mL), and wash with saturated sodium carbonate aqueous solution (5 mL). After the organic phase was concentrated to dryness, it was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 6-ethoxy-4-(6-ethynyl-4-methoxy-3,6-dihydro-2H-[1,3'-bipyridin]-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (25 mg), which was an off-white solid.

[0251] 1 H-NMR(400MHz,DMSO-d6)δ12.61(brs,1H),8.47(s,1H),8.11(s,1H),7.81(s,1H),7.18(s,1H),7.15(s,1H),6.67(s,1H), 4.20(s,1H),4.10-4.19(m,2H),3.95-4.05(m,2H),3.92(s,3H),3.40-3.50(m,2H),2.65-2.75(m,2H),1.36-1.44(m,3H).

[0252] m / z = 415[M+H] + .

[0253] Example 16: Preparation of Compound 16

[0254] Step A: 6-ethoxy-4-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine

[0255]

[0256] 6-ethoxy-1-(tetrahydropyran-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (250 mg, 0.7 mmol), Pd(OH)₂ (30 mg), and methanol (5 mL) were added sequentially to the reaction flask. The reaction was carried out under a hydrogen atmosphere for 16 hours. The reaction was monitored by LCMS until complete, filtered, and concentrated to obtain 250 mg of 6-ethoxy-4-piperidin-4-yl-1-tetrahydro-2H-pyran-2-yl-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine.

[0257] m / z = 370[M+H] + .

[0258] Step B: 4-(1-(6-(tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)piperidin-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0259]

[0260] The following ingredients were added sequentially to the reaction flask: 6-ethoxy-4-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (93 mg, 0.25 mmol), 2-(tert-butyldimethylsilyl)ethynyl)-5-iodo-4-methoxypyridine (100 mg, 0.25 mmol), Pd2(dba)3 (23 mg, 0.03 mmol), XantPhos (29 mg, 0.05 mmol), Cs2CO3 (246 mg, 0.75 mmol), and toluene (2 mL). The reaction was carried out at 120°C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the mixture was filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 4-(1-(6-(tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)piperidin-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (78 mg).

[0261] m / z = 615[M+H] + .

[0262] Step C: 6-ethoxy-4-(1-(6-ethynyl-4-methoxypyridin-3-yl)piperidin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0263]

[0264] Add 78 mg (0.13 mmol) of 4-(1-(6-(tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)piperidin-4-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, 3 mL of THF, and 1 M (1.3 mL, 1.3 mmol) of TBAF aqueous solution to the reaction flask in sequence. Stir the reaction solution at room temperature for 30 min. After the reaction is complete under LCMS monitoring, concentrate to dryness, dissolve in DCM (5 mL), add TFA (2 mL) dropwise to the solution, and stir for 2 hours. After the reaction is complete under LCMS monitoring, concentrate, dilute with DCM (10 mL), and wash with saturated sodium carbonate aqueous solution (5 mL). The organic phase was concentrated to dryness and then purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 4.3 mg of 6-ethoxy-4-(1-(6-ethynyl-4-methoxypyridin-3-yl)piperidin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, as an off-white solid. m / z = 417 [M+H] + .

[0265] 1 H-NMR(400MHz,DMSO-d6)δ12.59(brs,1H),8.40(s,1H),8.09(s,1H),7.95(s,1H),7.17(s,1H),7.06(s,1 H),4.20(s,1H),4.10-4.14(m,2H),3.91(s,3H),3.12-3.20(m,4H),1.95-2.05(m,4H),1.34-1.41(m,3H).

[0266] Example 17: Preparation of Compound 17

[0267] Step A: Ethyl 2-(5-bromo-3-chloropyridin-2-yl)-2-cyanoethyl

[0268]

[0269] 5-Bromo-2,3-dichloropyridine (45.4 g, 0.2 mol), ethyl cyanoacetate (45.2 g, 0.4 mol), cesium carbonate (195 g, 0.6 mol), and DMSO (500 mL) were added to a reaction flask. The reaction was carried out at 90 °C for 15 h, and the reaction was monitored for completeness by LC-MS. The reaction solution was poured into 5 L of water, the pH was adjusted to 5 with hydrochloric acid, filtered, and the filter cake was dried to obtain 50 g of product, m / z = 303 [M+1]. + .

[0270] Step B: 2-(5-bromo-3-chloropyridin-2-yl)acetonitrile

[0271]

[0272] Ethyl 2-(5-bromo-3-chloropyridin-2-yl)-2-cyanoethyl acetate (60 g, 0.2 mol), sodium chloride (3.5 g, 0.06 mol), and DMSO (500 mL) were added to a reaction flask. The reaction was carried out at 160 °C for 2 h, and the reaction was monitored for completeness by LC-MS. The reaction solution was then poured into 5 L of water, stirred for 0.5 h, filtered, and the filter cake was dried to obtain 40 g of product, m / z = 231 [M+1]. + .

[0273] Step C: 2,4,6-Trimethylbenzenesulfonic acid 1-amino-5-bromo-3-chloro-2-(cyanomethyl)pyridine-1-onium

[0274]

[0275] At 0°C, 2-(5-bromo-3-chloropyridin-2-yl)acetonitrile (7.4 g, 32.0 mmol) was added to a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (6.8 g, 31.7 mmol) in dichloromethane (50 mL). The mixture was stirred at 0°C for 3 hours, resulting in the precipitation of a large amount of white solid. After the reaction was complete, diethyl ether (50 mL) was added to the reaction system at 0°C and stirred for 10 minutes. The mixture was then filtered under reduced pressure, washed with diethyl ether, and dried under vacuum to obtain the product (15 g). No further purification was required; the product was directly used in the next reaction. m / z = 246 [M+1] + .

[0276] Step D: 6-Bromo-4-chloropyrazole[1,5-a]pyridine-2-amine

[0277]

[0278] At 0°C, triethylamine (1.1 g, 11.0 mmol) was added to a 30 mL solution of DMF containing 1.0 g (2.2 mmol) of 2,4,6-trimethylbenzenesulfonic acid 1-amino-5-bromo-3-chloro-2-(cyanomethyl)pyridin-1-onium (1.0 g, 2.2 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 350 mg of the product, m / z = 246 [M+1]. + .

[0279] Step E: 1-(2-amino-6-bromo-4-chloropyrazole[1,5-a]pyridin-3-yl)-2-chloroethyl-1-one

[0280]

[0281] 6-Bromo-4-chloropyrazole[1,5-a]pyridine-2-amine (2.5 g, 10.0 mmol), chloroacetonitrile (1.5 g, 20.0 mmol), boron trichloride (12 mL, 12.0 mmol), aluminum trichloride (2.7 g, 20.0 mmol), and chlorobenzene (20 mL) were added to a reaction flask. The mixture was reacted at 120 °C for 12 hours. Then, 30 mL of dilute hydrochloric acid (1 N) was added, and the mixture was reacted at 100 °C for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 1.5 g of the product, m / z = 322 [M+1]. + .

[0282] Step F: 1-(2-amino-6-bromo-4-chloropyrazole[1,5-a]pyridin-3-yl)-2-chloroethyl-1-ol

[0283]

[0284] 1-(2-amino-6-bromo-4-chloropyrazole[1,5-a]pyridin-3-yl)-2-chloroethyl-1-one (2.0 g, 6.2 mmol), dioxane (20 mL), and water (2 mL) were added to a reaction flask. The reaction system was cooled to 0 °C, and sodium borohydride (0.3 g, 7.9 mmol) was added in portions. The mixture was then brought to room temperature and reacted for 5 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 1.0 g of product, m / z = 324 [M+1]. + .

[0285] Step G: 6-Bromo-4-chloro-1H-pyrrole[2',3':3,4]pyrazole[1,5-a]pyridine

[0286]

[0287] 1-(2-amino-6-bromo-4-chloropyrazole[1,5-a]pyridin-3-yl)-2-chloroethyl-1-ol (323 mg, 1.0 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask. The reaction system was cooled to 0 °C, and isopropyl magnesium chloride (1.5 mL, 3.0 mmol) was slowly added dropwise. The reaction was carried out at 80 °C for 1 hour. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 178 mg of product, m / z = 270 [M+1]. + .

[0288] Step H: 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrrole[2',3':3,4]pyrazole[1,5-a]pyridine

[0289]

[0290] To 6-bromo-4-chloro-1H-pyrrole[2',3':3,4]pyrazole[1,5-a]pyridine (650 mg, 2.4 mmol), pinacol diboronate (736 mg, 2.9 mmol), potassium acetate (705 mg, 7.2 mmol), and 1,4-dioxane (10 mL) were added. After nitrogen purging with Pd(dppf)Cl2 (175 mg, 0.24 mmol), the mixture was reacted at 80 °C for 12 h. The mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain 523 mg of the product, m / z = 318 [M+1]. + .

[0291] Step I: 4-Chloro-1-hydro-pyrazole[2',3':3,4]pyrazole[1,5-a]pyridine-6-hydroxy

[0292]

[0293] Add 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrrolo[2',3':3,4]pyrazole[1,5-a]pyridine (634 mg, 2.0 mmol) and tetrahydrofuran (10 mL) to the reaction flask. Cool the reaction system to 0 °C, and slowly add hydrogen peroxide (340 mg, 10.0 mmol). React at 0 °C for 1 hour. After the reaction is complete, quench with saturated sodium metabisulfite aqueous solution, extract with ethyl acetate, combine the organic phases, wash with water, concentrate under reduced pressure, and separate by column chromatography to obtain 500 mg of product, m / z = 208 [M+1]. + .

[0294] Step J: 4-chloro-6-ethoxy-1H-pyrrole[2',3':3,4]pyrazole[1,5-a]pyridine

[0295]

[0296] 4-Chloro-1-hydro-pyrazole[2',3':3,4]pyrazole[1,5-a]pyridine-6-hydroxy (416 mg, 2.0 mmol), iodoethane (374 mg, 2.4 mmol), potassium carbonate (552 mg, 4.0 mmol), and DMF (5 mL) were added to the reaction flask. The reaction system was heated to 50 °C and reacted for 5 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 400 mg of product, m / z = 236 [M+1]. + .

[0297] Step J: 1-(3-(5-(6-ethoxy-1H-pyrrole[2',3':3,4]pyrazol[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one

[0298]

[0299] 4-Chloro-6-ethoxy-1H-pyrrole[2',3':3,4]pyrazole[1,5-a]pyridine (235 mg, 1.0 mmol), 1-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)prop-2-en-1-one (355 mg, 1.0 mmol), Xphos (95.2 mg, 0.2 mmol), palladium acetate (22.4 mg, 0.1 mmol), potassium phosphate (424 mg, 2.0 mmol), and 10 mL of 1,4-dioxane / 2 mL of water were added to the reaction flask. After nitrogen purging, the reaction was carried out at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain 250 mg of the product, m / z = 429 [M+1]. + ,

[0300] 1 H NMR (400MHz, DMSO-d6): 10.82 (s, 1H), 8.57 (d, J = 2.5Hz, 1H), 8.35 (d, J = 2.1Hz, 1H), 8.01 (m, 1H), 7.01-6.9 2(m,2H),6.80(d,J=8.9Hz,1H),6.47(m,1H),6.12(dd,J=17.0,2.2Hz,1H),6.02(dd,J=3.4,1.4Hz,1H),5.6 8(dd,J=10.3,2.1Hz,1H),4.86(d,J=5.9Hz,1H),4.53(s,1H),4.11(q,J=6.9Hz,2H),4.01(d,J=11.5Hz,1H ), 3.76 (s, 2H), 3.66 (d, J = 11.5Hz, 1H), 2.73 (q, J = 7.2Hz, 1H), 1.66 (d, J = 8.7Hz, 1H), 1.38 (t, J = 6.9Hz, 3H).

[0301] Example 18: Preparation of Compound 18

[0302] Step A: 3-(5-(6-((6-methylpyridin-2-yl)methoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0303]

[0304] 3-(5-(6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (175 mg, 0.33 mmol), Cs₂CO₃ (215 mg, 0.66 mmol), 2-(chloromethyl)-6-methylpyridine (47 mg, 0.33 mmol), and DMF (3 mL) were added to a reaction flask and reacted at 25 °C for 16 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 40 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 200 mg of the product, m / z = 637 [M+1]. + .

[0305] Step B: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((6-methylpyridin-2-yl)methoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride

[0306]

[0307] 3-(5-(6-((6-methylpyridin-2-yl)methoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (200 mg, 0.31 mmol), 4N hydrochloric acid-dioxane solution (4 mL) were added to a reaction flask. The reaction was carried out at 25 °C for 2 hours until complete. The solution was concentrated to dryness under reduced pressure to obtain 200 mg of product, m / z = 453 [M+1]. + .

[0308] Step C: 1-(3-(5-(6-((6-methylpyridin-2-yl)methoxy)-11H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)prop-2-en-1-one

[0309]

[0310] 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((6-methylpyridin-2-yl)methoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine hydrochloride (190 mg, 0.34 mmol), DCM (3 mL), and TEA (171 mg, 1.69 mmol) were added to a reaction flask. Acryloyl chloride (31 mg, 0.34 mmol) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 hour. The solution was poured into 50 mL of water, extracted with dichloromethane, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 16.3 mg of product, m / z = 507 [M+1]. + .

[0311] Example 19: Preparation of Compound 19

[0312] Step A: 1-(4-(6-bromopyridin-3-yl)piperazin-1-yl)propyl-2-en-1-one

[0313]

[0314] 1-(6-bromopyridin-3-yl)piperazine (240 mg, 1 mmol) and DCM (10 mL) were added to a reaction flask, followed by DIEA (390 mg, 3 mmol) and acryloyl chloride (90 mg, 1 mmol). The reaction was in an ice-water bath for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 220 mg of the product, m / z = 296 [M+1]. + .

[0315] Step B: 1-(4-(6-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-3-yl)piperazin-1-yl)propyl-2-en-1-one

[0316]

[0317] 1-(4-(6-bromopyridin-3-yl)piperazin-1-yl)propyl-2-en-1-one (149 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 2 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 40 mg of the product, m / z = 418 [M+1]. + .

[0318] 1 HNMR (400MHz, DMSO-d6): δ12.50(brs,1H),8.69(s,1H),8.55(s,1H),8.12-8.05(m,2H),7.69(s,1H),7.52(d,J=6.0Hz,1H),6.93-6. 86(m,1H),6.19-6.15(m,1H),5.75-5.72(m,1H),4.17(q,J=6.8Hz,2H),3.78-3.73(m,4H),3.41-3.36(m,4H),1.39(t,J=6.8Hz,3H).

[0319] Example 20: Preparation of Compound 20

[0320] Step A: 1-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0321]

[0322] 5-Bromo-2-(piperazin-1-yl)pyrimidine (243 mg, 1 mmol) and DCM (10 mL) were added to a reaction flask, followed by DIEA (390 mg, 3 mmol) and acryloyl chloride (90 mg, 1 mmol). The reaction was in an ice-water bath for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 200 mg of the product, m / z = 297 [M+1]. + .

[0323] Step B: 1-(4-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrimidin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0324]

[0325] 1-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)propyl-2-en-1-one (149 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 2 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 46 mg of the product, m / z = 419 [M+1]. + .

[0326] 1 HNMR (400MHz, DMSO-d6): δ12.68(brs,1H),8.88(s,1H),8.73-8.22(m,2H),7.55(s,1H),7.33(s,1H),6.93-6.84(m,1H), 6.19-6.15(m,1H),5.75-5.72(m,1H),4.15(q,J=6.8Hz,2H),3.97-3.83(m,4H),3.82-3.69(m,4H),1.39(t,J=6.8Hz,3H).

[0327] Example 21: Preparation of compound 21

[0328] Step A: 6-ethoxy-4-(5-fluoropyrimidin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0329]

[0330] 2-Bromo-5-fluoropyrimidine (100 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 2 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 150 mg of the product, m / z = 299 [M+1]. + .

[0331] Step B: 4-(2-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrimidin-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0332]

[0333] 6-ethoxy-4-(5-fluoropyrimidin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.5 mmol), DIEA (260 mg, 2.0 mmol), piperazine-1-carboxylic acid tert-butyl ester (186 mg, 1.0 mmol), and DMSO (5 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 2 h under N2 protection, and the reaction was monitored for completeness by LC-MS. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 120 mg of the product, m / z = 465 [M+1]. + .

[0334] Step C: 6-ethoxy-4-(5-(piperazin-1-yl)pyrimidin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0335]

[0336] 120 mg (0.5 mmol) of tert-butyl 4-(2-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrimidin-5-yl)piperazine-1-carboxylate was added to HCl / dioxane (4 M, 5 mL) and reacted at room temperature for 1 h. The reaction was monitored by LC-MS until complete. The product was concentrated under reduced pressure to give 100 mg of product, m / z = 365 [M+1]. + .

[0337] Step D: 1-(4-(2-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyrimidin-5-yl)piperazin-1-yl)propyl-2-en-1-one

[0338]

[0339] 6-ethoxy-4-(5-(piperazin-1-yl)pyrimidin-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.5 mmol), DIEA (260 mg, 2.0 mmol), acryloyl chloride (35 mg, 1.0 mmol), and DMF (2 mL) were added to a reaction flask and reacted for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 4 mg of the product, m / z = 419 [M+1]. + .

[0340] 1 HNMR (400MHz, DMSO-d6): δ12.48(brs,1H),8.86(s,2H),8.66(s,1H),8.27(s,1H),8.05(s,1H),6.93-6.84(m,1H),6.19 -6.15(m,1H),5.75-5.72(m,1H),4.17(q,J=6.8Hz,2H),3.82-3.74(m,4H),3.3.48-3.34(m,4H),1.39(t,J=6.8Hz,3H).

[0341] Example 22: Preparation of compound 22

[0342] Step A: 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)propyl-2-en-1-one

[0343]

[0344] 3-Chloro-6-(piperazin-1-yl)pyridazine (200 mg, 1 mmol) and DCM (10 mL) were added to a reaction flask, followed by DIEA (390 mg, 3 mmol) and acryloyl chloride (90 mg, 1 mmol). The reaction was in an ice-water bath for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 200 mg of the product, m / z = 253 [M+1]. + .

[0345] Step B: 1-(4-(6-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridazin-3-yl)piperazin-1-yl)propyl-2-en-1-one

[0346]

[0347] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)propyl-2-en-1-one (127 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 2 h, and the reaction was monitored by LCMS until complete. The reaction was quenched by stirring with water, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 10 mg of product, m / z = 419 [M+1]. + .

[0348] 1 HNMR (400MHz, DMSO-d6): δ12.51(brs,1H),8.63(s,1H),8.25(s,1H),7.95(s,1H),7.77(s,1H),7.48(d,J=9.6Hz,1H),6 .95-6.85(m,1H),6.20-6.15(m,1H),5.76-5.71(m,1H),4.17(q,J=6.8Hz,2H),3.88-3.61(m,8H),1.39(t,J=6.8Hz,3H).

[0349] Example 23: Preparation of compound 23

[0350] Step A: 1-(4-(4-bromophenyl)piperazin-1-yl)propyl-2-en-1-one

[0351]

[0352] 1-(4-bromophenyl-4-yl)piperazine (240 mg, 1 mmol) and DCM (10 mL) were added to a reaction flask, followed by DIEA (390 mg, 3 mmol) and acryloyl chloride (90 mg, 1 mmol). The reaction was in an ice-water bath for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred. The mixture was extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 230 mg of the product, m / z = 295 [M+1]. + .

[0353] Step B: 1-(4-(4-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)propyl-2-en-1-one

[0354]

[0355] 1-(4-(4-bromophenyl)piperazin-1-yl)propyl-2-en-1-one (148 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 2 h, and the reaction was monitored by LCMS until complete. The reaction was quenched by stirring with water, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 40 mg of product, m / z = 417 [M+1]. + . 1 HNMR (400MHz, DMSO-d6): δ12.61(brs,1H),8.50(s,1H),7.77(s,1H),7.75(s,1H),7.57(s,1H),7.27-7.11(m,3H),6.92-6.85(m ,1H),6.19-6.15(m,1H),5.75-5.72(m,1H),4.15(q,J=6.8Hz,2H),3.76-3.72(m,4H),3.38-3.35(m,4H),1.37(t,J=6.8Hz,3H).

[0356] Example 24: Preparation of compound 24

[0357] Step A: 1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0358]

[0359] 1-(4-bromopyridin-2-yl)piperazine (243 mg, 1 mmol) and DCM (10 mL) were added to a reaction flask, followed by DIEA (390 mg, 3 mmol) and acryloyl chloride (90 mg, 1 mmol). The reaction was in an ice-water bath for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred. The mixture was extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 200 mg of the product, m / z = 296 [M+1]. + .

[0360] Step B: 1-(4-(4-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0361]

[0362] 1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (149 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), Pd(dppf)Cl2 (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 2 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 40 mg of product, m / z = 418 [M+1]. + .

[0363] 1 HNMR (400MHz, DMSO-d6): δ12.69(brs,1H),8.65(s,1H),8.35(s,1H),7.64(s,1H),7.44(s,1H),7.23(s,1H),7.14(d,J=5.2Hz, 1H),6.92-6.85(m,1H),6.18-6.14(m,1H),5.77-5.71(m,1H),4.17(q,J=6.8Hz,2H),3.82-3.54(m,8H),1.37(t,J=6.8Hz,3H).

[0364] Example 25: Preparation of compound 25

[0365] Step A: (1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-yl)tert-butyl carbamate

[0366]

[0367] 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (300 mg, 1.0 mmol), 3-Boc-aminoazacyclobutane (258 mg, 1.5 mmol), DIEA (516 mg, 4.0 mmol), and DMSO (5 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 16 h, cooled to room temperature, poured into 60 mL of water, stirred for 0.5 h, filtered, and the filter cake was subjected to column chromatography (MeOH / DCM = 5%) to obtain (1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-yl)tert-butyl carbamate (390 mg), m / z = 450 [M+1]. + .

[0368] Step B: 1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-aminohydrochloride

[0369]

[0370] (390 mg, 0.87 mmol) of (1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-yl)carbamate tert-butyl ester, methanol (5 mL), and 1,4-dioxane / hydrochloric acid solution (4N) (5 mL) were added to a reaction flask. The mixture was reacted at room temperature for 1 h, concentrated, and slurried with 20 mL of methyl tert-butyl ether. After filtration, 1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-aminohydrochloride (410 g, 100%) was obtained, m / z = 350 [M+1]. + .

[0371] Step C: N-(1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-yl)acrylamide

[0372]

[0373] 1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-aminohydrochloride (150 mg, 0.33 mmol), DIEA (212 mg, 1.65 mmol), and DMF (30 mL) were added to the reaction flask. Then, methacryloyl chloride (30 mg, 0.33 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 1 h. 10 mL of saturated... Quenched with sodium bicarbonate, diluted with 50 mL of water, extracted with 2 × 50 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and concentrated by column chromatography (MeOH / DCM = 5%) to give N-(1-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)azacyclobutane-3-yl)acrylamide (25.1 mg), m / z = 404 [M+1] + .

[0374] 1 HNMR (400MHz, DMSO-d6): δ12.65(brs,1H),8.83(s,1H),8.57-8.52(m,2H),8.03(d,J=8.8Hz,1H),7.55(s,1H),7.21(s,1H),6.65(d,J=8.4Hz, 1H),6.27-6.12(m,2H),5.67-5.64(m,1H),4.76-4.73(m,1H),4.38-4. 34(m,2H),4.15(t,J=5.7Hz,2H),3.92-3.89(m,2H),1.42-1.36(m,3H).

[0375] Example 26: Preparation of Compound 26

[0376] Step A: 4-(6-chloro-4-methylpyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0377]

[0378] Add 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (800 mg, 2.84 mmol), (6-chloro-4-methylpyridin-3-yl)boronic acid (1.46 g, 8.54 mmol), tetrakis(triphenylphosphine)palladium (328.9 mg, 0.28 mmol), potassium carbonate (785.8 mg, 5.69 mmol), 1,4-dioxane (4 mL), and water (1 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 24 hours. After the reaction is complete, extract with water and dichloromethane, and obtain 100 mg of product by silica gel column chromatography, m / z = 328 / 330 [M+1]. + .

[0379] Step B: 4-(6'-((tert-butyldimethylsilyl)ethynyl)-4'-methoxy-4-methyl-[2,3'-bipyridin]-5-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0380]

[0381] Add 4-(6-chloro-4-methylpyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.31 mmol), 2-((tert-butyldimethylsilyl)ethynyl)-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (170 mg, 0.46 mmol), dichloroditriphenylphosphine palladium (21.4 mg, 0.03 mmol), potassium carbonate (84.1 mg, 0.61 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 5 hours. After the reaction is complete, extract with water and dichloromethane, and obtain 60 mg of product by silica gel column chromatography, m / z = 539 [M+1]. + .

[0382] Step C: 6-ethoxy-4-(6'-ethynyl-4'-methoxy-4-methyl-[2,3'-bipyridin]-5-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0383]

[0384] 4-(6'-((tert-butyldimethylsilyl)ethynyl)-4'-methoxy-4-methyl-[2,3'-bipyridinyl]-5-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (60 mg), TBAF / THF (1 mol / L, 1 mL), and THF (1 mL) were added to the reaction flask. The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was concentrated until no product was observed. Water and dichloromethane were added for extraction, and the product was lyophilized after reverse column chromatography to obtain 6.5 mg of product, m / z = 425.1 [M+1]. + .

[0385] 1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.89(s,1H),8.71(s,1H),8.65(s,1H),7.98(s,1H),7.44(s,1H),7.30(s ,1H),7.17(s,1H),4.45(s,1H),4.23-4.18(q,2H,J=7.2),4.02(s,1H),2.27(s,3H),1.43-1.37(t,3H,J=7.2).

[0386] Example 27: Preparation of Compound 27

[0387] Step A: tert-butyl 3-((5-bromopyridin-2-yl)amino)azacyclobutane-1-carboxylate

[0388]

[0389] 3-Aminoazacyclobutane-1-carboxylic acid tert-butyl ester (516 mg, 3.0 mmol) and DMSO (5 mL) were added to a reaction flask. Sodium hydride (60%, 96 mg, 2.4 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. Then, 5-bromo-2-fluoropyridine (350 mg, 2.0 mmol) was added, and the reaction was carried out at 80 °C for 16 h. After cooling to room temperature, the mixture was poured into 60 mL of water, stirred for 0.5 h, filtered, and the filter cake was subjected to column chromatography (EA / PE = 32%) to obtain 3-((5-bromopyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (40 mg), m / z = 328 [M+1]. + .

[0390] Step B: 3-((5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester

[0391]

[0392] 3-((5-bromopyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (40 mg, 0.12 mmol), cesium carbonate (98 mg, 0.3 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol), 1,4 - Dioxane (2 mL), water (0.2 mL), reacted at 100 °C for 16 h, diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 7%) to give tert-butyl 3-((5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)amino)azacyclobutane-1-carboxylic acid (21 mg), m / z = 450 [M+1] + .

[0393] Step C: N-(azacyclobutane-3-yl)-5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridine-2-amino hydrochloride

[0394]

[0395] 3-((5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (21 mg, 0.047 mmol), methanol (2 mL), and 1,4-dioxane / hydrochloric acid solution (4N) (3 mL) were added to a reaction flask. The mixture was reacted at room temperature for 1 h, and then concentrated to give N-(azacyclobutane-3-yl)-5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-amino hydrochloride (24 mg, crude product), m / z = 350 [M+1]. + .

[0396] Step D: 1-(3-((5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)amino)azacyclobutane-1-yl)prop-2-en-1-one

[0397]

[0398] N-(azacyclobutane-3-yl)-5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridine-2-amino hydrochloride (24 mg, crude), DIEA (26 mg, 0.20 mmol), and DMF (1 mL) were added to the reaction flask. Then, methacryloyl chloride (4.7 mg, 0.04 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 1 h. The mixture was then separated by reverse-phase column chromatography (MeOH / NH4HCO3 = 0-60%) and concentrated to obtain 1-(3-((5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)amino)azacyclobutane-1-yl)prop-2-en-1-one (25.1 mg), m / z = 404 [M+1]. + .

[0399] 1 HNMR (400MHz, DMSO-d6): δ12.64(brs,1H),8.50(s,1H),8.48(s,1H),7.96(d,J=8.4H z,1H),7.66(d,J=6.0Hz,1H),7.57(s,1H),7.22(s,1H),6.73(d,J=8.8Hz,1H),6.40-6 .33(m,1H),6.15-6.10(m,1H),5.70-5.67(m,1H),4.76-4.58(m,2H),4.32-4.29(m,1H ),4.16(t,J=5.7Hz,2H),4.08-4.03(m,1H),3.88-3.83(m,1H),1.38(t,J=5.7Hz,3H).

[0400] Example 28: Preparation of Compound 28

[0401] 1-(4-(5-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0402]

[0403] Add 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (80 mg, 0.20 mmol) and 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl))piperazin-1-yl)propyl-2-en-1-one (108 mg) to the reaction flask. 29.2 mg (0.30 mmol), Pd(dppf)Cl2 (29.2 mg, 0.04 mmol), potassium carbonate (55.1 mg, 0.40 mmol), 1,4-dioxane (1 mL), water (0.2 mL), under nitrogen protection, heated to 90 °C and stirred for 16 hours. After the reaction was complete, water and dichloromethane were added for extraction, followed by lyophilization after reverse-phase column chromatography to obtain 6 mg of product, m / z = 469.2 [M+1]. + .

[0404] 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.77(s,1H),8.67(s,1H),8.14-8.12(d,1H),7.78(s,1H),7.15(s,1H),6.92-6.86(dd,1H),6.54-6.4 8(m,2H),6.20-6.15(d,1H,J=2.4),5.76-5.72(d,1H,J=2.4),3.69-3 .37(m,8H),3.36(m,2H),2.61(s,3H),2.33-2.67(m,3H),1.23(s,1H).

[0405] Example 29: Preparation of compound 29

[0406] N-(5-(6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0407]

[0408] Add 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (30 mg, 0.06 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acrylamide (18 mg, 0.06 mmol), K2CO3 (16 mg, 0.12 mmol), Pd(dppf)Cl2 (5 mg, 0.01 mmol), dioxane (3 mL), and water (0.5 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 2.9 mg of product, m / z = 507 [M+1]. + .

[0409] 1 H-NMR(400MHz,DMSO-d6)δ12.83(s,1H),11.06(s,1H),9.36-9.37(m,1H),8.8.94-8.98(m,1H),8.48-8.52(m,3H),8.01-8.09(m,2H),7.87- 7.89(m,1H),7.70-7.71(m,1H),7.51-7.55(m,1H),7.22-7.23(m,1H), 6.66-6.73(m,1H),6.35-6.41(m,1H),5.84-5.87(m,1H),2.45(s,3H).

[0410] Example 30: Preparation of compound 30

[0411] 1-(4-(5-(6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0412]

[0413] Add 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (30 mg, 0.06 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (22 mg, 0.06 mmol), K2CO3 (16 mg, 0.12 mmol), Pd(dppf)Cl2 (5 mg, 0.01 mmol), dioxane (3 mL), and water (0.5 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 5.1 mg of product, m / z = 576 [M+1]. + .

[0414] 1 H-NMR(400MHz,DMSO-d6)δ12.79(s,1H),9.28-9.29(m,1H),8.76-8.78(m,1H),8. 50-8.52(m,1H),8.20-8.23(m,1H),8.03-8.07(m,1H),7.84-7.91(m,2H),7.71-7. 71(m,1H),7.50-7.54(m,1H),7.22-7.23(m,1H),7.14-7.16(m,1H),6.86-6.98(m ,1H),6.16-6.20(m,1H),5.73-5.76(m,1H),3.71-3.74(m,8H),2.45-2.46(m,3H).

[0415] Example 31: Preparation of compound 31

[0416] Step A: 5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine

[0417]

[0418] 2,5-Dibromopyridine (237 mg, 1.0 mmol), PdCl₂(PPh₃)₂ (70 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol), TEA (400 mg, 4.0 mmol), tert-butyl(ethynyl)dimethylsilane (154 mg, 1.1 mmol), and DMF (0.5 mL) were added to a reaction flask. The mixture was reacted under N₂ protection at 50 °C for 2 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 260 mg of the product, m / z = 296 [M+1]. + .

[0419] Step B: 4-(6-((tert-butyldimethylsilyl)ethynyl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0420]

[0421] 5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine (149 mg, 0.5 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (197 mg, 0.6 mmol), PdCl2 (dppf) (40 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 2 h under N2 protection, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 60 mg of the product, m / z = 418 [M+1]. + .

[0422] Step C: 6-ethoxy-4-(6-ethynylpyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0423]

[0424] 4-(6-((tert-butyldimethylsilyl)ethynyl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (60 mg, 0.14 mmol), TBAF (1 mL), and THF (2 mL) were added to a reaction flask and reacted at room temperature for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 4 mg of the product, m / z = 304 [M+1].+ .

[0425] 1 HNMR (400MHz, DMSO-d6): δ12.72(brs,1H),9.03(s,1H),8.66(s,1H),8.33(d,J=8.0Hz,1H),7.81(d ,J=8.4Hz,1H),7.60(s,1H),7.48(s,1H),4.51(s,1H),4.17(q,J=6.8Hz,2H),1.38(t,J=6.8Hz,3H).

[0426] Example 32: Preparation of compound 32

[0427] Step A: 5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-(trifluoromethyl)pyridine

[0428]

[0429] 2,5-Dibromo-4-(trifluoromethyl)pyridine (305 mg, 1.0 mmol), PdCl₂(PPh₃)₂ (70 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol), TEA (400 mg, 4.0 mmol), tert-butyl(ethynyl)dimethylsilane (154 mg, 1.1 mmol), and DMF (0.5 mL) were added to a reaction flask. The mixture was reacted under N₂ protection at 50 °C for 2 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 280 mg of the product, m / z = 364 [M+1]. + .

[0430] Step B: 4-(6-((tert-butyldimethylsilyl)ethynyl)-4-(trifluoromethyl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0431]

[0432] 5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-(trifluoromethyl)pyridine (280 mg, 0.77 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (253 mg, 0.77 mmol), PdCl2(dppf) (60 mg, 0.07 mmol), Cs2CO3 (500 mg, 1.5 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 2 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 300 mg of product, m / z = 486 [M+1]. + .

[0433] Step C: 6-ethoxy-4-(6-ethynyl-4-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0434]

[0435] 4-(6-((tert-butyldimethylsilyl)ethynyl)-4-(trifluoromethyl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.3 mmol), TBAF (1 mL), and THF (2 mL) were added to a reaction flask and reacted at room temperature for 1 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 18 mg of the product, m / z = 372 [M+1]. + .

[0436] 1 HNMR(400MHz,DMSO-d6): δ12.66(brs,1H),8.88(s,1H),8.68(s,1H),8.16(s,1H),7 .25(s,1H),7.10(s,1H),4.74(s,1H),4.16(q,J=6.8Hz,2H),1.37(t,J=6.8Hz,3H).

[0437] Example 33: Preparation of compound 33

[0438] Step A: 4-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)-6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0439]

[0440] Add 6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol), 2-((tert-butyldimethylsilyl)ethynyl)-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)pyridine (28 mg, 0.07 mmol), K2CO3 (19 mg, 0.14 mmol), Pd(dppf)Cl2 (5 mg, 0.01 mmol), dioxane (3 mL), and water (0.5 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until it was complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 40 mg of product, m / z = 606 [M+1]+.

[0441] Step B: 4-(6-ethynyl-4-methoxypyridin-3-yl)-6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0442]

[0443] 4-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)-6-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (40 mg, 0.06 mmol), THF (2 mL), and TBAF (0.2 mL, 1 M in THF) were added to a reaction flask, and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was poured into 50 mL of water, extracted with DCM, the organic phase was dried, the solvent was evaporated, and column chromatography (methanol / dichloromethane = 8%) was performed to give 3.0 mg of product, m / z = 492 [M+1]. + .

[0444] 1H-NMR (400MHz, DMSO-d6) δ12.71(s,1H),9.37-9.37(m,1H),8.68-8.70(m,1H),8.50-8.51(m,1H),8.00-8.03(m,1H),7.90-7. 92(m,1H),7.81-7.83(m,1H),7.51-7.53(m,2H),7.22-7.23(m,1H),4.48-4.50(m,1H),3.87-3.90(m,3H),2.44-2.45(m,3H).

[0445] Example 34: Preparation of compound 34

[0446] Step A: 1-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0447]

[0448] 6-Bromo-4-ethoxy-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (22 mg, 0.08 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (34 mg, 0.1 mmol), PdCl2(dppf) (6 mg, 0.08 mmol), Cs2CO3 (78 mg, 0.24 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the organic phase was separated, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1). Washing with methanol yielded 1-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (5.7 mg), m / z = 418 [M+H]. + .

[0449] 1H-NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.76(s,1H),8.63(s,1H),8.05-8.08(m,1H),7.85(s,1H),7.19(s,1H),6.98-7.01 (m,1H),6.84-6.87(m,1H),6.14-6.19(m,1H),5.71-5.75(m,1H),4.39-4.43(m,2H),3.55-3.75(m,8H),1.48-1.51(m,8H).

[0450] Example 35: Preparation of compound 35

[0451] Step A: 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0452]

[0453] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2-yl)piperazine (5.1 g, 14.1 mmol), DCM (60 mL), and DIEA (5.5 g, 4.5 mmol) were added sequentially to a reaction flask. After cooling in an ice bath, a solution of acryloyl chloride (1.5 g, 16.9 mmol) and DCM (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored for completeness by LCMS. After concentration to dryness, the mixture was slurried with ethyl acetate, filtered, and then slurried with n-hexane to obtain 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2-yl)piperazine-1-yl)prop-2-en-1-one (5.7 g).

[0454] m / z = 457[M+H] + .

[0455] Step B: 6-Bromo-4-(4-methoxybenzyloxy)-1-tetrahydropyran-2-ylpyrazole[3,4:3,4]pyrazole[1,5-a]pyridine

[0456]

[0457] 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (1.1 g, 3.0 mmol), THF (30 mL), DHP (380 mg, 4.5 mmol), and p-toluenesulfonic acid monohydrate (57 mg, 0.3 mmol) were added sequentially to the reaction flask. The reaction solution was heated to 60°C and reacted for 3 hours. The reaction was monitored by LCMS until complete, and the solution was concentrated to dryness and purified by column chromatography (dichloromethane / methanol = 80 / 1) to give 6-bromo-4-(4-methoxybenzyloxy)-1-tetrahydropyran-2-ylpyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (1.2 g).

[0458] m / z = 457[M+H] + .

[0459] Step C: 1-(4-(5-(4-(4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0460]

[0461] 6-Bromo-4-(4-methoxybenzyloxy)-1-tetrahydropyran-2-ylpyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (1.1 g, 2.4 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (992 mg, 2.9 mmol), PdCl2(dppf) (176 mg, 0.24 mmol), Cs2CO3 (2.4 g, 7.2 mmol), 1,4-dioxane (30 mL), and water (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the organic phase was separated, concentrated, and purified by column chromatography (dichloromethane / methanol = 25 / 1) to give 1-(4-(5-(4-(4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (1.0 g).

[0462] m / z = 594[M+H] + .

[0463] Step D: 1-(4-(5-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0464]

[0465] 1-(4-(5-(4-(4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (300 mg, 0.5 mmol), DCM (6 mL) and m-phenylenediamine (345 mg, 2.5 mmol) were added sequentially to the reaction flask. After cooling in an ice bath, TFA (2 mL) was added and the reaction was carried out at room temperature for 16 hours. The reaction was monitored by LCMS until complete, concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 8 / 1) to give 1-(4-(5-(4-hydroxy-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (163 mg).

[0466] m / z = 390[M+H] + .

[0467] Step E: 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0468]

[0469] 1-(4-(5-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (163 mg, 0.42 mmol), DMF (4 mL), DIEA (163 mg, 1.26 mmol), and PhN(Tf)2 (104 mg, 0.29 mmol) were added sequentially to the reaction flask. The reaction solution was reacted at room temperature for 3 hours. The reaction was monitored by LCMS until complete. Water (40 mL) was added, and the mixture was extracted twice with DCM / MeOH (4 / 1). The extracts were combined and concentrated to dryness. The solution was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (150 mg).

[0470] m / z = 522[M+H] + .

[0471] Step F: 1-(4-(4-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0472]

[0473] 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (100 mg, 0.2 mmol), 3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenylboronic acid (65 mg, 0.26 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), TEA (60 mg, 0.6 mmol) and 1,4-dioxane (5 mL) were added sequentially to the reaction flask, and the reaction was carried out at 90 degrees Celsius for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete, and then purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 1-(4-(4-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazol[3,4:3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (11.2 mg).

[0474] 1 H-NMR(400MHz,DMSO-d6)δ12.80(s,1H),9.23(s,1H),8.73(s,1H),8.53(s ,1H),8.17-8.19(m,1H),7.99-8.03(m,1H),7.90-7.95(m,2H),7.72(s,1H ),7.64-7.69(m,1H),7.23-7.25(m,1H),7.00-7.03(m,1H),6.84-6.90(m, 1H),6.14-6.19(m,1H),5.72-5.75(m,1H),3.60-3.75(m,8H),2.46(s,3H).

[0475] m / z = 576[M+H] + .

[0476] Example 36: Preparation of compound 36

[0477] Step A: 3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenylboronic acid

[0478]

[0479] A solution of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy)-4-methylpyrimidine (2.0 g, 6.0 mmol), acetone (30 mL), ammonium acetate (1.4 g, 18.0 mmol), and water (14 mL) and sodium periodate (3.8 g, 18.0 mmol) were added sequentially to a reaction flask. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until complete. The mixture was filtered, diluted with ethyl acetate, and the aqueous layer was separated. The organic phase was washed with saturated sodium sulfite solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 3-fluoro-4-(4-methylpyrimidine-2-yl)oxy)phenylboronic acid (1.2 g).

[0480] m / z = 249[M+H] + .

[0481] Step B: tert-butyl 4-(4-bromopyridin-2-yl)piperazine-1-carboxylate

[0482]

[0483] 4-Bromo-2-fluoropyridine (3.5 g, 20.0 mmol), DMF (50 mL), potassium carbonate (8.28 g, 60.0 mmol), and piperazine-1-carboxylic acid tert-butyl ester (3.72 g, 20.0 mmol) were added sequentially to the reaction flask. The reaction solution was reacted at 100 °C for 16 hours. The reaction was monitored by LCMS until complete. The reaction solution was diluted with ethyl acetate, washed twice with water (40 mL), concentrated to dryness, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 4-(4-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.6 g).

[0484] m / z = 342 / 344[M+H] + .

[0485] Step C: (2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridine-4-boronic acid

[0486]

[0487] 4-(4-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.5 g, 13.2 mmol), bipinnatrol borate ester (3.7 g, 14.5 mmol), Pd(dppf)Cl2 (965 mg, 1.32 mmol), potassium acetate (3.88 g, 39.6 mmol), and 1,4-dioxane (90 mL) were added sequentially to a reaction flask. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. The reaction was monitored for completeness by LC-MS. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the solution was slurried with acetonitrile to obtain 2.4 g of crude product.

[0488] Step D: 2-(piperazin-1-yl)pyridine-4-borate

[0489]

[0490] Add (2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridine-4-boronic acid (1.2 g, 3.9 mmol), 1,4-dioxane (10 mL), and a solution of 1,4-dioxane in hydrogen chloride (4 M, 30 mL, 120.0 mmol) to the reaction flask sequentially. Stir the reaction mixture at room temperature for 1 hour. Monitor the reaction for completeness using LC-MS, and filter out 900 mg of crude product.

[0491] m / z = 208[M+H] + .

[0492] Step E: (2-(4-Acryloylpiperazin-1-yl)pyridine-4-boronic acid

[0493]

[0494] 2-(piperazin-1-yl)pyridine-4-borate salt (900 mg, 3.9 mmol), DCM (60 mL), and DIEA (2.5 g, 19.5 mmol) were added sequentially to the reaction flask. After cooling in an ice bath, a solution of acryloyl chloride (390 mg, 4.3 mmol) and DCM (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored for completeness by LCMS. After concentration to dryness, the mixture was slurried with ethyl acetate, filtered, and then slurried with n-hexane to obtain 750 mg of crude product.

[0495] Step F: 1-(4-(4-(4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0496]

[0497] 2-(4-Acryloylpiperazin-1-yl)pyridine-4-boronic acid (520 mg, 2.0 mmol), 6-bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (750 mg, 2.0 mmol), PdCl2(dppf) (150 mg, 0.2 mmol), Cs2CO3 (2.0 g, 6.0 mmol), 1,4-dioxane (30 mL), and water (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C for 72 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After concentration, the product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 220 mg of product.

[0498] m / z = 510[M+H] + .

[0499] Step G: 1-(4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0500]

[0501] 1-(4-(4-(4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (150 mg, 0.3 mmol), DCM (5 mL), and m-phenylenediamine (207 mg, 1.5 mmol) were added sequentially to the reaction flask. After cooling in an ice bath, TFA (1 mL) was added, and the reaction was carried out at room temperature for 16 hours. The reaction was monitored by LCMS until complete, concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 8 / 1) to obtain 67 mg of product.

[0502] m / z = 390[M+H] + .

[0503] Step H: 6-(2-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0504]

[0505] 1-(4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (67 mg, 0.17 mmol), DMF (3 mL), DIEA (66 mg, 0.51 mmol), and PhN(Tf)2 (49 mg, 0.14 mmol) were added sequentially to the reaction flask. The reaction solution was reacted at room temperature for 3 hours. The reaction was monitored by LCMS until complete. Water (40 mL) was added, and the mixture was extracted twice with DCM / MeOH (4 / 1). The extracts were combined, concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 35 mg of product.

[0506] m / z = 522[M+H] + .

[0507] Step I: 1-(4-(4-(3-fluoro-4-(4-methylpyrimidin-2-oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0508]

[0509] The following ingredients were added sequentially to the reaction flask: 6-(2-(4-acryloylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (30 mg, 0.057 mmol), 3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenylboronic acid (19 mg, 0.075 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), TEA (18 mg, 0.171 mmol), and 1,4-dioxane (3 mL). The reaction was carried out at 90°C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After concentration, the product was purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain 7.7 mg of product. m / z = 576 [M+H] +

[0510] 1H-NMR(400MHz,DMSO-d6)δ12.86(s,1H),9.47(s,1H),8.52-8.54(m,1H),8.00-8.06(m,2H),7.90-7.95(m,1H),7.76(s,1H),7.65-7.71(m,1H) ,7.41(s,1H),7.30-7.32(m,1H),7.24-7.26(m,1H),6.85-6.93(m,1H) ,6.14-6.19(m,1H),5.72-5.75(m,1H),3.65-3.78(m,8H),2.47(s,3H).

[0511] Example 37: Preparation of compound 37

[0512] Step A: 4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-encarboxylic acid ethyl ester

[0513]

[0514] Add 6-bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.34 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)cyclohex-3-carboxylate (413 mg, 1.47 mmol), Cs2CO3 (874 mg, 2.68 mmol), Pd(dppf)Cl2 (98 mg, 0.13 mmol), dioxane (10 mL), and water (2 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 72 hours. The reaction was monitored by LCMS until it was complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 450 mg of product, m / z = 447 [M+1]+.

[0515] Step B: 4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-carboxylic acid

[0516]

[0517] Ethyl 4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-carboxylic acid (430 mg, 0.96 mmol), THF (20 mL), H2O (4 mL), and LiOH (46 mg, 1.93 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. 20 mL of EA and 20 mL of H2O were added to the reaction mixture, and the mixture was separated. The aqueous phase was adjusted to 1-2, extracted with EA, the organic solvent was dried, and the product was concentrated to obtain 440 mg. m / z = 419 [M+1] + .

[0518] Step C: (4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolo-1-yl)methyl ketone

[0519]

[0520] 4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-encarboxylic acid (440 mg, 1.05 mmol), DMF (10 mL), DIEA (407 mg, 3.15 mmol), and pyrrole (82 mg, 1.16 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 20 mL of water, extracted with DCM, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 460 mg of the product. m / z = 472 [M+1] + .

[0521] Step D: (4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolo-1-yl)methyl ketone

[0522]

[0523] (4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolo-1-yl)methyl ketone (460 mg, 1 mmol), m-phenylenediamine (414 mg, 3 mmol), and DCM (10 mL) were added to a reaction flask, followed by TFA (5 mL). The reaction was carried out at 25 °C for 1 h, and the reaction was monitored by LCMS until complete. The reaction solution was evaporated to dryness, and the tertiary methyl ether was slurried to obtain 350 mg of the product. m / z = 351 [M+1] + .

[0524] Step E: 6-(4-(pyrrolo-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0525]

[0526] (4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolo-1-yl) methyl ketone (350 mg, 1.0 mmol), DMF (5 mL), DIEA (388 mg, 3.0 mmol), and N-phenylbis(trifluoromethanesulfonylimide) (350 mg, 1.0 mmol) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic solvent was dried, the solution was concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 200 mg of the product. m / z = 484 [M+1] + .

[0527] Step F: 1-(4-(5-(6-(4-(pyrrolo-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0528]

[0529] Add 6-(4-(pyrrolo-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (200 mg, 0.41 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (213 mg, 0.62 mmol), K2CO3 (114 mg, 0.82 mmol), Pd(dppf)Cl2 (30 mg, 0.04 mmol), dioxane (3 mL), and water (0.5 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 27.6 mg of product, m / z = 551 [M+1]. + .

[0530] 1H-NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.72-8.73(m,1H),8.65-8.66(m,1H),8.10-8.13 (m,1H),7.63-7.65(m,2H),7.10-7.12(m,1H),6.86-6.93(m,1H),6.51(s,1H),6.15-6.20 (m,1H),5.73-5.76(m,1H),3.67-3.75(m,8H),3.52-3.55(m,2H),3.31-3.34(m,2H),2.60 -2.80(m,3H),2.30-2.40(m,2H),1.91-1.93(m,3H),1.81-1.89(m,2H),1.78-1.80(m,1H).

[0531] Example 38: Preparation of compound 38

[0532] Step A: (4-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)(pyrrolidine-1-yl)formamide

[0533]

[0534] 4-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-carboxylic acid (300 mg, 0.76 mmol), tetrahydropyrrole (133 mg, 1.53 mmol), DIEA (294 mg, 2.28 mmol), HATU (346 mg, 0.92 mmol), and DMF (8 mL) were added to the reaction flask. The reaction was carried out at room temperature for 16 h. The mixture was diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA / PE = 90%) to give 170 mg of product, m / z = 446 [M+1]. + .

[0535] Step B: (4-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)(pyrrolidine-1-yl)formamide

[0536]

[0537] (4-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)(pyrrolidine-1-yl)formamide (170 mg, 0.38 mmol), palladium hydroxide (50 mg), and methanol (10 mL) were added to the reaction flask. The mixture was reacted at room temperature for 2 h under hydrogen atmosphere. After filtration, the mixture was washed with 15 mL of tetrahydrofuran. The filtrate was concentrated to obtain 138 mg of the product, m / z = 356 [M+1]. + .

[0538] Step C: 6-(pyrrolidine-1-carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate

[0539]

[0540] (4-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)(pyrrolidine-1-yl)carboxamide (138 mg, crud), DIEA (151 mg, 1.17 mmol), and DMF (5 mL) were added to the reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (180 mg, 0.5 mmol). The reaction was carried out at room temperature for 2 h. The mixture was diluted with 30 mL of water, extracted with 2 × 50 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA / PE = 80%) to give 110 mg of the product, m / z = 488 [M+1]. + .

[0541] Step D: 1-(4-(5-(6-(pyrrolidine-1-carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0542]

[0543] Add 6-(pyrrolidine-1-carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (110 mg, 0.22 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)methacrylamide (117 mg, 0.34 mmol), and cesium carbonate (183 mg) to the reaction flask. The reaction mixture consisted of 16 mg (0.56 mmol), Pd(dppf)Cl2 (16 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.2 mL). The mixture was purged with nitrogen three times and reacted at 110 °C for 3 h. The solution was diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to obtain 20 mg of the product, m / z = 555 [M+1]. + .

[0544] Step E: 1-(4-(5-(6-(pyrrolidine-1-carbonyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0545]

[0546] 1-(4-(5-(6-(pyrrolidine-1-carbonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (20 mg, 0.04 mmol), methanol (2 mL), and 1,4-dioxane / hydrochloric acid solution (4N) (2 mL) were added to a reaction flask. The mixture was reacted at room temperature for 2 h, concentrated, and then 5 mL of methanol and 5 mL of dichloromethane were added. The pH was adjusted to 8 with 1N sodium hydroxide. The mixture was diluted with 10 mL of dichloromethane, extracted, concentrated, and subjected to column chromatography (MeOH / DCM = 10%) to obtain 3.6 mg of the product, m / z = 471 [M+1]. + .

[0547] 1 HNMR (400MHz, DMSO-d6): δ12.82(brs,1H),9.02(s,1H),8.62(s,1H),8.09(d,J=8.8Hz,1H),7.69(s,1H),7.59(s,1H), 7.10(d,J=8.8Hz,1H),6.92-6.85(m,1H),6.19-6.15(m,1H),5.75-5.72(m,1H),3.73-3.61(m,12H),1.91-1.86(m,4H).

[0548] Example 39: Preparation of compound 39

[0549] Step A: 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazole[1,5-a]pyridine

[0550]

[0551] 6-Bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine (7 g, 20 mmol), 1-methylpiperazine (4 g, 40 mmol), Pd2(dba)3 (549 mg, 0.6 mmol), Binap (746 mg, 1.2 mmol), sodium tert-butoxide (5.76 g, 60 mmol), and toluene (100 mL) were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 110 °C for 3 h. After cooling to room temperature, the mixture was diluted with 100 mL of water, extracted with 2 × 100 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column filtered (MeOH / DCM = 8%) to give 6.1 g of product, m / z = 371 [M+1]. + .

[0552] Step B: 7-Chloro-2-fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazole[1,5-a]pyridine

[0553]

[0554] 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazole[1,5-a]pyridine (3.0 g, 8.1 mmol), NCS (1.2 g, 9.0 mmol), and DMF (80 mL) were added to a reaction flask. The reaction was carried out at room temperature for 2 h, quenched with 20 mL of saturated sodium bicarbonate, diluted with 200 mL of water, extracted with 3 × 150 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column filtered (MeOH / DCM = 6%) to give 3.6 g of product, m / z = 405 [M+1]. + .

[0555] Step C: 7-Chloro-2-fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde

[0556]

[0557] Add 30 mL of DMF to the reaction flask, add 2.28 g (15 mmol) of phosphorus oxychloride at 0-5 °C, and stir at room temperature for 0.5 h. Dissolve 2.0 g (5.0 mmol) of 7-chloro-2-fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazole[1,5-a]pyridine in 10 mL of dichloromethane, add to the reaction solution, and react at room temperature for 12 h until the reaction is complete. Add the reaction solution to 100 mL of ice water, adjust the pH to 8-9 with 10% sodium hydroxide solution, extract with 3 × 100 mL of ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, slurry with 50 mL of n-hexane, and filter to obtain 1.7 g of product, m / z = 433 [M+1]. + .

[0558] Step D: 4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0559]

[0560] 7-Chloro-2-fluoro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde (1.7 g, 3.9 mmol), hydrazine hydrate (85%) (2.3 g, 39 mmol), and DMSO (30 mL) were added to a reaction flask, and the reaction was carried out at 120 °C for 16 h. After cooling to room temperature, the mixture was diluted with 200 mL of water, extracted with 3 × 100 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 10%) to give 445 mg of product, m / z = 393 [M+1]. + .

[0561] Step E: 6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-phenol

[0562]

[0563] 4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (445 mg, 1.1 mmol), m-phenylenediamine (1.5 g, 11 mmol), dichloromethane (20 mL), and trifluoroacetic acid (5 mL) were added to a reaction flask. The reaction was carried out at room temperature for 2 h, and the product was concentrated to obtain 2.2 g of product, m / z = 273 [M+1]. + .

[0564] Step F: 6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yltrifluoromethanesulfonate

[0565]

[0566] 6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-phenol (2.2 g, crud), DIEA (1.4 g, 11 mmol), and DMF (10 mL) were added to a reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (589 mg, 1.7 mmol). The reaction was carried out at room temperature for 0.5 h until complete. The solution was diluted with 50 mL of water, extracted with 3 × 50 mL ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 8%) to give 260 mg of product 6, m / z = 405 [M+1]. + .

[0567] Step G: 1-(4-(5-(6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0568]

[0569] The following ingredients were added to the reaction flask: 6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (28 mg, 0.07 mmol), 6-(4-acryloylpiperazinyl)pyridine-3-boronic acid pinacol ester (48 mg, 0.14 mmol), cesium carbonate (46 mg, 0.14 mmol), Pd(dppf)Cl2 (5 mg, 0.007 mmol), 1,4-dioxane (2 mL), and water (0.2 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 3 h. The mixture was diluted with 20 mL of water, extracted with 2 × 20 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 10%) to obtain 5.1 mg of the product, m / z = 472 [M+1]. + .

[0570] 1HNMR (400MHz, DMSO-d6): δ12.57(brs,1H),8.62(s,1H),8.22(s,1H),8.07(d,J=8.8Hz,1H),7.54(s,1H),7.43(s,1H),7.08(d,J=8.8H z,1H),6.92-6.85(m,1H),6.19-6.15(m,1H),5.75-5.72(m,1H),3.73-3.69(m,8H),3.22-3.19(m,4H),2.25(s,3H),1.25-1.23(m,4H).

[0571] Example 40: Preparation of Compound 40

[0572] Step A: 5,6-Dibromo-1-methyl-1H-benzyl[d]imidazole

[0573]

[0574] 5-Bromo-1-methyl-1H-benzyl[d]imidazole (5 g, 23.7 mmol), AcOH (50 mL), and NBS (6.3 g, 35.5 mmol) were added to a reaction flask, and the reaction was carried out at 40 °C for 16 h. The reaction solution was poured into 500 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and column chromatography (PE:EA = 4:1) was performed to give 4.8 g of product, m / z = 291 [M+1]. + .

[0575] Step B: A mixture of 6-bromo-5-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazole and 5-bromo-6-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazole

[0576]

[0577] 5,6-Dibromo-1-methyl-1H-benzyl[d]imidazole (4.5 g, 15.5 mmol), tert-butyl(ethynyl)dimethylsilane (2.2 g, 15.5 mmol), TEA (6.3 g, 62.1 mmol), CuI (0.6 g, 3.1 mmol), Pd(PPh3)2Cl2 (1.1 g, 1.6 mmol), and DMF (50 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 50 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (PE:EA = 4:1) to obtain 1.1 g of product, m / z = 349,351 [M+1]. + .

[0578] Step C: 4-(5-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-6-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine and 4-(6-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-5-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0579]

[0580] A mixture of 6-bromo-5-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazole and 5-bromo-6-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazole (350 mg, 1.0 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (361 mg, 1.1 mmol), K2CO3 (276 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol), dioxane (10 mL), and water (2 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, and the organic phase was dried. The solvent was evaporated and purified by column chromatography (DCM:MeOH = 10:1) to obtain 40 mg of 4-(5-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-6-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine and 70 mg of 4-(6-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-5-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, m / z = 471 [M+1]. + .

[0581] Step D: 6-ethoxy-4-(5-ethynyl-1-methyl-1H-benzyl[d]imidazol-6-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0582]

[0583] 4-(5-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-6-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (40 mg, 0.08 mmol), THF (2 mL), and TBAF (0.2 mL, 1 min THF) were added to a reaction flask, and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was poured into 50 mL of water, extracted with DCM, the organic phase was dried, the solvent was evaporated, and column chromatography (methanol / dichloromethane = 8%) was performed to give 15.0 mg of product, m / z = 357 [M+1]. + .

[0584] 1 H-NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.60-8.61(m,1H),8.40(s,1H),8.02(s,1H),7.92(s, 1H),7.30-7.31(m,1H),7.20(s,1H),4.12-4.23(m,2H),3.86-3.90(m,4H),1.39-1.43(m,3H).

[0585] Example 41: Preparation of compound 41

[0586] Step A: 6-ethoxy-4-(6-ethynyl-1-methyl-1H-benzyl[d]imidazol-5-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0587]

[0588] 4-(6-((tert-butyldimethylsilyl)ethynyl)-1-methyl-1H-benzyl[d]imidazol-5-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (70 mg, 0.15 mmol), THF (4 mL), and TBAF (0.4 mL, 1 min THF) were added to a reaction flask, and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was poured into 50 mL of water, extracted with DCM, the organic phase was dried, the solvent was evaporated, and column chromatography (methanol / dichloromethane = 8%) was performed to give 25.0 mg of product, m / z = 357 [M+1]. + .

[0589] 1H-NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.58-8.59(m,1H),8.41(s,1H),8.04(s,1H),7.89(s, 1H),7.26-7.27(m,1H),7.06(s,1H),4.19-4.21(m,2H),3.94-3.97(m,4H),1.39-1.43(m,3H).

[0590] Example 42: Preparation of compound 42

[0591] Step A: N-(4-bromophenyl)acrylamide

[0592]

[0593] 4-Bromoaniline (3.44 g, 20 mmol), Et3N (4.1 g, 40 mmol), and DCM (20 mL) were added to the reaction flask. Acryloyl chloride (1.92 g, 21 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of water, filtered, and the filter cake was washed twice with water and dried to obtain 3.0 g of product, m / z = 226, 228 [M+1]. + .

[0594] Step B: N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide

[0595]

[0596] N-(4-bromophenyl)acrylamide (475 mg, 2.1 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)boronic acid (400 mg, 1.4 mmol), Pd(dppf)Cl2 (153 mg, 0.21 mmol), K2CO3 (290 mg, 2.1 mmol), KF (163 mg, 2.8 mmol), and 1,4-dioxane / water (5 mL / 1 mL) were added to a reaction flask. The reaction was carried out at 110 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (PE:EA = 1:1) to give 300 mg of product, m / z = 388 [M+1]. + .

[0597] Step C: N-(4-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide

[0598]

[0599] N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide (130 mg, 0.34 mmol), 4 M HCl (4 mL), and MeOH (4 mL) were added to the reaction flask. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The solvent was directly evaporated to dryness to give 80 mg of product, m / z = 304 [M+1]. + .

[0600] Step D: N-(4-(3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide

[0601]

[0602] N-(4-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide (50 mg, 0.165 mmol), NIS (37 mg, 0.165 mmol), and DMF (3 mL) were added to the reaction flask. The reaction was carried out at room temperature for 12 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (20 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (PE:EA = 1:1) to give 30 mg of product, m / z = 430 [M+1]. + .

[0603] Step E: N-(4-(3-(3-fluoro-4-((4-methylpyrimidin-2-yl)ether)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide

[0604]

[0605] N-(4-(3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-5-yl)phenyl)acrylamide (43 mg, 0.1 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)phenoxy)-4-methylpyrimidine (49 mg, 0.15 mmol), Pd(dppf)Cl2 (14 mg, 0.02 mmol), Cs2CO3 (48 mg, 0.15 mmol), KF (11 mg, 0.2 mmol), and 1,4-dioxane / water (2 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 110 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (10 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 3 mg of product, m / z = 506 [M+1]. + .

[0606] Example 43: Preparation of compound 43

[0607] Step A: (4-(4-(4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0608]

[0609] The following ingredients were added to the reaction flask: 6-bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (373 mg, 1.0 mmol), 4-(pyrrolidine-1-carbonyl)cyclohexyl-3-enyl-boronic acid pinacol ester (338 mg, 1.1 mmol), cesium carbonate (975 mg, 3.0 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol), 1,4-dioxane (12 mL), and water (1.2 mL). The mixture was purged with nitrogen three times and reacted at 115 °C for 18 h. The mixture was diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to obtain 300 mg of the product, m / z = 472 [M+1]. + .

[0610] Step B: (4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0611]

[0612] (4-(4-(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)carboxamide (300 mg, 0.63 mmol), m-phenylenediamine (879 mg, 6.3 mmol), and dichloromethane (15 mL) were added to the reaction flask. Then, trifluoroacetic acid (5 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 2 h, and the product was concentrated to obtain 1.5 g of product, m / z = 352 [M+1]. + .

[0613] Step C: 6-(4-(pyrrolidine-1-carbonyl)cyclohex-3-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate

[0614]

[0615] (4-(4-hydroxy-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)carboxamide (1.5 g, crude), DIEA (406 mg, 3.15 mmol), and DMF (10 mL) were added to the reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (270 mg, 0.75 mmol). The reaction was carried out at room temperature for 2 h. The mixture was diluted with 30 mL of water, extracted with 2 × 50 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 4%) to give 240 mg of the product, m / z = 484 [M+1]. + .

[0616] Step D: N-(4-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)methacrylamide

[0617]

[0618] The following were added to the reaction flask: 6-(4-(pyrrolidine-1-carbonyl)cyclohex-3-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (50 mg, 0.1 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)methacrylamide (44 mg, 0.15 mmol), and cesium carbonate (98 mg, 0.3 mmol). 0 mmol), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol), 1,4-dioxane (2 mL), water (0.2 mL), nitrogen purged three times, reacted at 80 °C for 3 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 5%) to give 10.1 mg of product, m / z = 495 [M+1]. + .

[0619] 1 HNMR(400MHz,DMSO-d6): δ12.69(brs,1H),10.04(s,1H),8.76(s,1H),7.97-7 .95(m,2H),7.89-7.86(m,2H),7.65(s,1H),6.51(s,1H),5.88(s,1H),5.58(s, 1H),3.55-3.52(m,2H),3.31-3.29(m,2H),2.78-2.64(m,3H),2.41-2.32(m,2H ),2.01-1.98(m,4H),1.93-1.89(m,2H),1.86-1.82(m,2H),1.72-1.68(m,1H).

[0620] Example 44: Preparation of compound 44

[0621] Step A: N-(3-methyl-4-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ylphenyl-4-yl)methacrylamide

[0622]

[0623] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (40 mg, 0.08 mmol), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)methacrylamide (37 mg, 0.12 mmol), and cesium carbonate (81 mg) to the reaction flask. The reaction mixture consisted of 0.25 mmol (g), Pd(dppf)Cl2 (6 mg, 0.008 mmol), 1,4-dioxane (2 mL), and water (0.2 mL). Nitrogen was purged three times, and the mixture was reacted at 90 °C for 1 h. The mixture was diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 6%) to obtain 3.1 mg, m / z = 509 [M+1]. + .

[0624] 1 HNMR (400MHz, DMSO-d6): δ12.63(brs,1H),9.92(s,1H),8.77(s,1H),7.79-7.72( m,2H),7.49-7.41(m,2H),7.39(s,1H),6.51(s,1H),5.87(s,1H),5.56(s,1H),3. 53-3.51(m,2H),3.31-3.29(m,2H),2.75-2.68(m,3H),2.51(s,3H),2.40-2.34(m ,2H),2.00-1.97(m,4H),1.92-1.89(m,2H),1.82-1.79(m,2H),1.69-1.64(m,1H).

[0625] Example 45: Preparation of compound 45

[0626] Step A: N-(5-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)methacrylamide

[0627]

[0628] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (50 mg, 0.10 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)methacrylamide (45 mg, 0.15 mmol), and cesium carbonate (100 mg) to the reaction flask. 0.30 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), 1,4-dioxane (2 mL), water (0.2 mL), nitrogen purged three times, reacted at 90 °C for 1 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 6%) to give 11.5 mg of product, m / z = 496 [M+1]. + .

[0629] 1 HNMR(400MHz,DMSO-d6): δ12.74(brs,1H),10.57(s,1H),8.88(s,1H),8.36 (s,1H),7.77(s,2H),7.63(s,1H),6.54(s,1H),6.02(s,1H),5.62(s,1H),3 .55-3.53(m,2H),3.31-3.29(m,2H),2.81-2.64(m,3H),2.41-2.32(m,2H), 2.01-1.98(m,4H),1.93-1.89(m,2H),1.86-1.82(m,2H),1.72-1.68(m,1H).

[0630] Example 46: Preparation of Compound 46

[0631] Step A: 6-(1-piperazinyl)pyridine-3-boronic acid pinacol ester trifluoroacetate

[0632]

[0633] 6-(4-Boc-1-piperazinyl)pyridine-3-boronic acid pinacol ester (1.0 g, 2.57 mmol), dichloromethane (10 mL), and trifluoroacetic acid (1 mL) were added to a reaction flask. The reaction was carried out at room temperature for 2 h, and the mixture was concentrated to give 6-(1-piperazinyl)pyridine-3-boronic acid pinacol ester trifluoroacetate (1.5 g, CRUD), m / z = 290 [M+1]. + .

[0634] Step B: 6-(4-methylpropionylpiperazin-1-yl)pyridine-3-boronic acid pinacol ester

[0635]

[0636] 6-(1-piperazinyl)pyridine-3-boronic acid pinacol ester trifluoroacetate (1.5 g, CRUD), DIEA (1.66 g, 12.9 mmol), and dichloromethane (30 mL) were added to the reaction flask. Then, methacryloyl chloride (267 mg, 2.57 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 1 h, quenched with 10 mL of saturated sodium bicarbonate, diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and concentrated by column chromatography (MeOH / DCM = 5%) to obtain 440 mg of product, m / z = 358 [M+1]. + .

[0637] Step C: 2-Methyl-1-(4-(5-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0638]

[0639] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (50 mg, 0.10 mmol), 6-(4-methylpropionylpiperazin-1-yl)pyridine-3-boronic acid pinacol ester (43 mg, 0.15 mmol), and cesium carbonate (98 mg, 0.3 mmol) to the reaction flask. Pd(dppf)Cl2 (7.3 mg, 0.01 mmol), 1,4-dioxane (2 mL), water (0.2 mL), nitrogen purged three times, reacted at 80 °C for 2 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 5%) to give 2.2 mg of product, m / z = 565 [M+1]. + .

[0640] 1HNMR (400MHz, DMSO-d6): δ12.69(brs,1H),8.73(s,1H),8.65(s,1H),8.38(s,1H),8.11(d,J=12.8Hz,1H),7.63(s,1H),7.10(d,J=12.8Hz,1 H),6.54(s,1H),5.26(s,1H),5.07(s,1H),3.64-3.53(m,10H),3.31- 3.29(m,2H),2.81-2.64(m,3H),2.41-2.32(m,2H),2.01-1.70(m,9H).

[0641] Example 47: Preparation of Compound 47

[0642] Step A: 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0643]

[0644] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (2.53 g, 10 mmol), Pd(OH)₂ / C (0.8 g), and MeOH / THF (20 mL / 5 mL) were added to the reaction flask. The reaction was carried out under hydrogen atmosphere and at 60 °C for 12 hours. The reaction was monitored by LCMS until complete. The reaction solution was filtered, the filter cake was washed twice with methanol, and dried to obtain 1.8 g of product, m / z = 175 [M+1]. + .

[0645] Step B: 4-((4-methoxybenzyl)ether)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0646]

[0647] 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (3.48 g, 20 mmol), K₂CO₃ (4.14 g, 3.0 mmol), and DMF (100 mL) were added to a reaction flask. At room temperature, p-methoxybenzyl chloride (2.51 g, 16 mmol) was added dropwise, and the reaction was allowed to proceed for 12 hours. The reaction was monitored by LCMS until complete. The reaction mixture was poured into water (100 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (PE:EA = 1:1) to give 5.1 g of the product, m / z = 295 [M+1]. + .

[0648] Step C: 3-Iodo-4-((4-methoxybenzyl)ether)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0649]

[0650] 4-((4-methoxybenzyl)ether)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (5.1 g, 17.3 mmol), NIS (4.3 g, 19.1 mmol), and DMF (50 mL) were added to the reaction flask. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (200 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (PE:EA = 1:1) to give 3.1 g of product, m / z = 421 [M+1]. + .

[0651] Step D: 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0652]

[0653] 3-Iodo-4-((4-methoxybenzyl)ether)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (840 mg, 2.0 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)phenoxy)-4-methylpyrimidine (990 mg, 3.0 mmol), Pd(dppf)Cl2 (300 mg, 0.4 mmol), Cs2CO3 (975 mg, 3.0 mmol), KF (116 mg, 2 mmol), and 1,4-dioxane / water (5 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 110 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 500 mg of product, m / z = 497 [M+1]. + .

[0654] 1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.48-8.52(m,2H),7.87-7.95(m,2H),7.39-7.41(m,2H), 7.09-7.21(m,3H),6.85-6.87(m,2H),6.52-6.57(m,1H),5.27(s,2H),3.72(s,3H),2.43(s,3H).

[0655] Example 48: Preparation of compound 48

[0656] Step A: 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0657]

[0658] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (0.2 g, 0.4 mmol), TFA (2 mL), DMOB (1 mL), and DCM (5 mL) were added to the reaction flask. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was directly evaporated to dryness to give 150 mg of product, m / z = 377 [M+1]. + .

[0659] Step B: 4-ethoxy-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0660]

[0661] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (50 mg, 0.133 mmol), Cs₂CO₃ (64 mg, 0.19 mmol), and DMF (3 mL) were added to a reaction flask. Iodoethane (22 mg, 0.145 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (10 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by reversed-phase column chromatography to obtain 20 mg of the product, m / z = 405 [M+1]. + .

[0662] 1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.48-8.51(m,2H),7.92-8.01(m,2H),7.39-7.51(m,1H),7.09- 7.21(m,2H),6.98-7.12(m,2H),4.25-4.30(m,2H),3.97-3.99(m,1H),2.44(s,3H),1.41-1.44(m,3H).

[0663] Example 49: Preparation of Compound 49

[0664] Step A: N-(3-fluoro-4-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)methacrylamide

[0665]

[0666] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (40 mg, 0.08 mmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)methacrylamide (37 mg, 0.12 mmol), and cesium carbonate (81 mg, 0.24 mmol), Pd(dppf)Cl2 (6 mg, 0.008 mmol), 1,4-dioxane (2 mL), water (0.4 mL), nitrogen purged three times, reacted at 90 °C for 1 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 6%) to give 11.8 mg of product, m / z = 513 [M+1]. + .

[0667] 1HNMR (400MHz, DMSO-d6): δ12.66(brs,1H),10.22(s,1H),8.81(s,1H),7.93(d,J=1 2.8Hz,1H),7.75-7.73(m,2H),7.64(s,1H),7.45(s,1H),6.48(s,1H),5.90(s,1H), 5.63(s,1H),3.55-3.52(m,2H),3.31-3.29(m,2H),2.78-2.64(m,3H),2.41-2.35( m,2H),2.00-1.97(m,4H),1.93-1.89(m,2H),1.85-1.80(m,2H),1.72-1.68(m,1H).

[0668] Example 50: Preparation of Compound 50

[0669] N-(4-(5-(4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1],5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)methacrylamide

[0670]

[0671] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate (75 mg, 0.15 mmol), N-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)piperazin-1-yl)methacrylamide (86 mg, 0.23 mmol), PdCl2(dppf) (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.3 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 9 mg of product, m / z = 605 [M+1]. + .

[0672] 1HNMR (400MHz, DMSO-d6): δ12.78(brs,1H),9.24(s,1H),8.74(s,1H),8.52(s,1H),8.19(d,J=8.8Hz,1H),8.05-7.90(m,3H),7 .73-7.65(m,2H),7.24(s,1H),7.00(d,J=8.8Hz,1H),5.25(s,1H),5.06(s,1H),3.70-3.60(m,8H),2.51(s,3H),1.90(s,3H).

[0673] Example 51: Preparation of compound 51

[0674] N-(4-(4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)acrylamide

[0675]

[0676] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate (75 mg, 0.15 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-ylphenyl)acrylamide (63 mg, 0.23 mmol), PdCl2(dppf) (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.3 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 8 h, and the reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3 mg of the product, m / z = 506 [M+1]. + . 1 HNMR (400MHz, DMSO-d6): δ12.80(brs,1H),10.33(s,1H),9.24(s,1H),8.53(s,1H),8.05-7.88(m,5H),7.88-7.8 3(m,2H),7.74-7.67(m,2H),7.24(s,1H),6.48-6.45(m,1H),6.33-6.28(m,1H),5.82-5.79(m,1H),2.52(s,3H).

[0677] Example 52: Preparation of compound 52

[0678] N-(4-(4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)methacrylamide

[0679]

[0680] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate (75 mg, 0.15 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)methacrylamide (66 mg, 0.23 mmol), PdCl2(dppf) (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.3 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 4 mg of product, m / z = 520 [M+1]. + .

[0681] 1 HNMR(400MHz,DMSO-d6): δ12.80(brs,1H),9.95(s,1H),9.24(s,1H),8.53(s,1H),8.05-7.82 (m,7H),7.75-7.65(m,2H),7.24(s,1H),5.86(s,1H),5.56(s,1H),2.47(s,3H),1.99(s,3H).

[0682] Example 53: Preparation of compound 53

[0683] Step A: 1-(4-(5-(4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0684]

[0685] Add 2.9 g (6.36 mmol) of 6-bromo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl))piperazin-1-yl)propyl-2-en-1-one to the reaction flask. (2.61 g, 7.63 mmol), Pd(dppf)Cl2 (464.9 mg, 0.64 mmol), cesium carbonate (6.26 g, 19.08 mmol), 1,4-dioxane (60 mL), water (6 mL), under nitrogen protection, heated to 90 °C, stirred for 24 hours, after which the reaction was completed, extracted with water and dichloromethane, and silica gel column chromatography gave 3.3 g of product, m / z = 594 [M+1]. + .

[0686] Step B: 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0687]

[0688] Add 1-(4-(5-(4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (3.3 g, 5.60 mmol), dichloromethane (30 mL), and m-phenylenediamine (153 mg, 1.1 mmol) to the reaction flask. Trifluoroacetic acid (6.3 g, 55.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated until no product was observed. DMF (20 mL) and DIEA (4.6 g, 33.34 mmol) were added. The mixture was cooled to 0–10 °C, and PhN(Tf)₂ was added in portions. The mixture was stirred at 0–10 °C for 2 hours. After the reaction was complete, water and dichloromethane were added for extraction. The product was obtained by silica gel column chromatography, yielding 600 mg of product, m / z = 522.1 [M+1]. + .

[0689] Step C: 1-(4-(5-(4-(3-fluoro-4-methoxyphenyl)-1Hpyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0690]

[0691] 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (36 mg, 0.07 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (17.6 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium (8.0 mg, 0.01 mmol), lithium carbonate (10.8 mg, 0.14 mmol), 1,4-dioxane (1 mL), and water (0.2 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 4 hours. After the reaction was completed, the product was obtained by silica gel column chromatography followed by lyophilization, yielding 1.2 mg of product, m / z = 498.1 [M+1]. + .

[0692] Example 54: Preparation of compound 54

[0693] Step A: 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0694]

[0695] 4-Bromo-6-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.34 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenoxy)-4-methylpyrimidine (575 mg, 1.74 mmol), PdCl2 (dppf) (73 mg, 0.1 mmol), Cs2CO3 (898 mg, 2.7 mmol), 1,4-dioxane (8 mL), and H2O (2 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 8 h, and the reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 200 mg of the product, m / z = 497 [M+1]. + .

[0696] Step B: 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol

[0697]

[0698] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (200 mg, 0.4 mmol), m-phenylenediamine (138 mg, 1.0 mmol), TFA (1 mL), and DCM (5 mL) were added to a reaction flask and reacted at 25 °C for 2 h. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added. The precipitated solid was filtered to give 200 mg of product, m / z = 377 [M+1]. +

[0699] Step C: 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate

[0700]

[0701] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol (150 mg, 0.4 mmol), DIEA (156 mg, 1.2 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (143 mg, 0.4 mmol), and DMF (3 mL) were added to a reaction flask and reacted at 0 °C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 150 mg of the product, m / z = 509 [M+1]. + .

[0702] Step D: 1-(4-(5-(4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)prop-1-one

[0703]

[0704] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate (75 mg, 0.15 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)piperazin-1-yl)propane-1-one (78 mg, 0.23 mmol), PdCl2(dppf) (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.3 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 7 mg of product, m / z = 578 [M+1]. + .

[0705] 1 HNMR (400MHz, DMSO-d6): δ12.79(brs,1H),9.24(s,1H),8.74(s,1H),8.52(s,1H),8.19(d,J=8.8Hz,1H),8.05-7.90(m, 3H),7.73-7.65(m,2H),7.24(s,1H),7.00(d,J=9.2Hz,1H),3.70-3.60(m,8H),2.40-2.32(m,5H),1.01(t,J=7.2Hz,3H).

[0706] Example 55: Preparation of compound 55

[0707] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0708]

[0709] 4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-trifluoromethanesulfonate (30 mg, 0.06 mmol), 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)piperazine (30 mg, 0.1 mmol), PdCl2(dppf) (7 mg, 0.01 mmol), Cs2CO3 (33 mg, 0.1 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 5 mg of product, m / z = 536 [M+1]. + .

[0710] 1 HNMR (400MHz, DMSO-d6): δ12.78(brs,1H),9.22(s,1H),8.71(s,1H),8.53(s,1H),8.15(d,J=8.8Hz,1H),8.03-7.99(m, 1H),7.95-7.92(m,2H),7.73-7.64(m,2H),7.24(s,1H),6.98(s,1H),3.68-3.58(m,4H),2.47(s,3H),2.29-2.12(m,4H).

[0711] Example 56: Preparation of Compound 56

[0712] Step A: (4-(4-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0713]

[0714] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (50 mg, 0.10 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenoxy)-4-methylpyrimidine (41 mg, 0.12 mmol), cesium carbonate (98 mg, 0.3 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) to the reaction flask. Purge with nitrogen three times, react at 90 °C for 2 h, dilute with 30 mL of water, and repeat the reaction at 2 × 50 mL. Extracted with dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to give 4.2 mg of product, m / z = 538 [M+1]. + .

[0715] 1 HNMR (400MHz, DMSO-d6): δ12.74(brs,1H),8.82(s,1H),8.52(s,1H),7.95(d,J=8.8Hz,1H),7.88-7.81(m,2H),7.71-7.65(m,2H),7.24(s,1H) ,6.58(s,1H),3.53-3.52(m,2H),3.31-3.29(m,2H),2.50(s,3H),2.02 -1.98(m,1H),1.96-1.89(m,2H),1.86-1.81(m,2H),1.72-1.64(m,1H).

[0716] Example 57: Preparation of Compound 57

[0717] Step A: 6-(1-piperazinyl)pyridine-3-boronic acid pinacol hydrochloride

[0718]

[0719] 6-(4-Boc-1-piperazinyl)pyridine-3-boronic acid pinacol ester (1.0 g, 2.57 mmol), methanol (10 mL), and 1,4-dioxane / hydrochloric acid solution (4N, 5 mL) were added to a reaction flask. The mixture was reacted at room temperature for 1 h, concentrated, and then slurried with 30 mL of methyl tert-butyl ether. The mixture was filtered to obtain 700 mg of the product, m / z = 290 [M+1]. + .

[0720] Step B: 6-(4-propionylpiperazin-1-yl)pyridine-3-boronic acid pinacol ester

[0721]

[0722] 6-(1-piperazinyl)pyridine-3-boronic acid pinacol ester hydrochloride (700 mg, CRUD), DIEA (1.66 g, 12.9 mmol), and dichloromethane (30 mL) were added to the reaction flask. Then, acryloyl chloride (262 mg, 2.83 mmol) was added to the reaction solution. The mixture was reacted at room temperature for 1 h, diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and concentrated by column chromatography (MeOH / DCM = 5%) to obtain 600 mg of product, m / z = 346 [M+1]. + .

[0723] Step C: 1-(4-(5-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-1-one

[0724]

[0725] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (50 mg, 0.10 mmol), 6-(4-propionylpiperazin-1-yl)pyridine-3-boronic acid pinacol ester (54 mg, 0.16 mmol), and cesium carbonate (98 mg, 0.3 mmol) to the reaction flask. Pd(dppf)Cl2 (7 mg, 0.01 mmol), 1,4-dioxane (2 mL), water (0.4 mL), nitrogen purged three times, reacted at 90 °C for 2 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 7%) to give 1.5 mg of product, m / z = 553 [M+1]. + .

[0726] Example 58: Preparation of Compound 58

[0727] Step A: N-(2-chloro-4-methylpyrimidin-5-yl)acrylamide

[0728]

[0729] 2-Chloro-4-methylpyrimidin-5-amine (1000 mg, 6.95 mmol), Et3N (1050 mg, 10.4 mmol), and DCM (20 mL) were added to a reaction flask. Acryloyl chloride (688 mg, 7.64 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with DCM, dried the organic phase, evaporated the solvent, and purified by normal-phase column chromatography to give 1200 mg of the product, m / z = 198 [M+1]. + .

[0730] Step B: N-(2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidin-5-yl)acrylamide

[0731]

[0732] N-(2-chloro-4-methylpyrimidin-5-yl)acrylamide (1.12 g, 6.0 mmol), 4-bromo-2-fluorophenol (1.14 g, 6.0 mmol), Cs₂CO₃ (2.9 g, 9.0 mmol), and DMF (10 mL) were added to a reaction flask. The reaction was carried out at 50 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by normal-phase column chromatography (PE / EA = 1:1) to obtain 500 mg of product, m / z = 352, 354 [M+1]. + .

[0733] Step C: N-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaboryl-2-yl)phenoxy)-4-methylpyrimidin-5-yl)acrylamide

[0734]

[0735] N-(2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidin-5-yl)acrylamide (352 mg, 1.0 mmol), Binp (508 mg, 2.0 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), KOAc (300 mg, 3.0 mmol), and 1,4-dioxane (5 mL) were added to a reaction flask. The reaction was carried out at 80 °C for 12 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by normal-phase column chromatography (PE / EA = 1:1) to obtain 100 mg of product, m / z = 400 [M+1]. + .

[0736] Step D: 6-Bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0737]

[0738] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (2.53 g, 10 mmol), K₂CO₃ (2.76 g, 20 mmol), and DMF (20 mL) were added to a reaction flask. Iodoethane (1.56 g, 10 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed for 12 hours. The reaction was monitored by LCMS until complete. The reaction mixture was poured into water (100 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by normal-phase column chromatography (PE / EA = 2:1) to obtain 2.5 g of product, m / z = 281, 283 [M+1]. + .

[0739] Step E: 4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0740]

[0741] 6-Bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (1.5 g, 5.33 mmol), Pd(OH)₂ / C (0.5 g), and MeOH / THF / Et₃N (20 mL / 5 mL / 5 mL) were added to the reaction flask. The reaction was carried out under hydrogen atmosphere and at 50 °C for 12 hours. The reaction was monitored by LCMS until complete. The reaction solution was filtered, the filter cake was washed twice with methanol, and dried to obtain 1.0 g of product, m / z = 203 [M+1]. + .

[0742] Step F: 4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0743]

[0744] 4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (1010 mg, 5.0 mmol), NIS (1350 mg, 6.0 mmol), and DMF (10 mL) were added to the reaction flask. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by normal phase column chromatography (PE / EA = 2:1) to give 500 mg of product, m / z = 329 [M+1]. + .

[0745] Step G: N-(2-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)-2-fluorophenoxy)-4-methylpyrimidin-5-yl)acrylamide

[0746]

[0747] 4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (66 mg, 0.2 mmol), N-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxanepentoboryl-2-yl)phenoxy)-4-methylpyrimidin-5-yl)acrylamide (96 mg, 0.24 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), Cs2CO3 (97 mg, 0.3 mmol), KF (5.8 mg, 0.1 mmol), and 1,4-dioxane / water (3 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 100 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (20 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 20 mg of product, m / z = 474 [M+1]. + .

[0748] 1 H NMR(400MHz,DMSO-d6)δ12.96(s,1H),9.91(s,1H),8.62(s,1H),8.50(s,1H),7.97-8.04(m,2H),7.45-7.49(m,1H),7.08-7.12(m,1 H),6.97-6.99(m,1H),6.49-6.56(m,1H),6.27-6.32(m,1H),5.81-5.84(m,1H),4.25-4.30(m,2H),2.37(s,3H),1.41-1.44(m,3H).

[0749] Example 59: Preparation of compound 59

[0750] Step A: 4-(5-bromopyridin-2-yl)-2-phenylpiperazine-1-tert-butyl carbonate

[0751]

[0752] 5-Bromo-2-fluoropyridine (1.2 g, 6.9 mmol), 2-phenylpiperazine-1-tert-butyl carbonate (2.0 g, 7.6 mmol), potassium carbonate (2.9 g, 21 mmol), and DMSO (30 mL) were added to a reaction flask, and the reaction was carried out at 110 °C for 4 h. The mixture was diluted with 150 mL of water, extracted with 3 × 80 mL ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column-secured (EA / PE = 10%) to give 4-(5-bromopyridin-2-yl)-2-phenylpiperazine-1-tert-butyl carbonate (440 mg), m / z = 418 [M+1]. + .

[0753] Step B: 1-(5-bromopyridin-2-yl)-3-phenylpiperazine hydrochloride

[0754]

[0755] 4-(5-bromopyridin-2-yl)-2-phenylpiperazine-1-tert-butyl carbonate (540 mg, 1.29 mmol), methanol (10 mL), and 1,4-dioxane / hydrochloric acid solution (4N, 5 mL) were added to a reaction flask. The mixture was reacted at room temperature for 2 h, and then concentrated to give 1-(5-bromopyridin-2-yl)-3-phenylpiperazine hydrochloride (520 mg, CRUD), m / z = 318 [M+1]. + .

[0756] Step C: 1-(4-(5-bromopyridin-2-yl)-2-phenylpiperazin-1-yl)prop-2-en-1-one

[0757]

[0758] 1-(5-bromopyridin-2-yl)-3-phenylpiperazine hydrochloride (200 mg, 0.51 mmol), DIEA (330 mg, 2.55 mmol), and dichloromethane (8 mL) were added to the reaction flask. Then, acryloyl chloride (51 mg, 0.56 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 2 h, quenched with 10 mL of saturated sodium bicarbonate, diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and concentrated by column chromatography (EA / PE = 35%) to obtain 140 mg of product, 73%, m / z = 372 [M+1]. + .

[0759] Step D: 1-(2-phenyl-4-((5-boranoylpinacol ester)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0760]

[0761] 1-(4-(5-bromopyridin-2-yl)-2-phenylpiperazin-1-yl)prop-2-en-1-one (140 mg, 0.38 mmol), pinacol diboronate (286 mg, 1.13 mmol), potassium acetate (110 mg, 1.13 mmol), Pd(dppf)Cl2 (27 mg, 0.04 mmol), and 1,4-dioxane (3 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 80 °C for 12 h. After filtration, the mixture was washed with 20 mL of ethyl acetate, the filtrate was concentrated, and the solution was slurried with 20 mL of n-hexane. After filtration, 160 mg of the product was obtained, m / z = 420 [M+1]. + .

[0762] Step E: 1-(2-phenyl-4-(5-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0763]

[0764] Add 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (60 mg, 0.12 mmol), 1-(2-phenyl-4-((5-boranoylpinacol)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (78 mg, CRUD), and cesium carbonate (101 mg, 0.3 mmol) to the reaction flask. 1 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol), 1,4-dioxane (2.5 mL), water (0.5 mL), nitrogen purged three times, reacted at 100 °C for 2 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 5%) to give 1.8 mg of product, m / z = 627 [M+1]. + .

[0765] 1HNMR (400MHz, DMSO-d6): δ12.69(brs,1H),8.72(s,1H),8.63(s,1H),8.09(d,J=8 .8Hz,1H),7.65-7.60(m,2H),7.40-7.25(m,5H),7.04(s,1H),6.51(s,1H),6.25-6 .21(m,1H),5.78-5.72(m,1H),4.04-4.01(m,1H),3.53-3.52(m,2H),3.38-3.35(m ,4H),3.31-3.29(m,2H),2.72-2.68(m,3H),2.36-2.30(m,4H),2.01-1.78(m,6H).

[0766] Example 60: Preparation of Compound 60

[0767] Step A: N-(5-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0768]

[0769] The following substances were added to the reaction flask: 6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (50 mg, 0.1 mmol), 2-acrylamidopyridine-5-boronic acid pinacol ester (41 mg, 0.15 mmol), cesium carbonate (98 mg, 0.3 mmol), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 3 h. The mixture was diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 7%) to obtain 2.7 mg of the product, m / z = 482 [M+1]. + .

[0770] 1HNMR (400MHz, DMSO-d6): δ12.74(brs,1H),11.04(s,1H),8.87(s,1H),8.81(s,1H),8.45(s,2H),8.39(s,1H),7.78(s,1H),7.64(s,1H),6.67-6. 65(m,1H),6.40-6.36(m,1H),5.86-5.83(m,1H),3.55-3.52(m,2H),2.5 2-2.50(m,3H),2.41-2.33(m,2H),2.00-1.65(m,6H),1.26-1.24(m,2H).

[0771] Example 61: Preparation of compound 61

[0772] 1-(4-(5-(4-(4-(((4-methylpyrimidin-2-yl)oxy)phenyl))-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0773]

[0774] 6-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (100 mg, 0.19 mmol), 4-methyl-2-(4-(4,4,5,5-methyl-1,3,2-dioxaborane-2-yl)phenoxy)pyrimidine (71.9 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (22.2 mg, 0.02 mmol), lithium carbonate (28.4 mg, 0.38 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 16 hours. After the reaction was completed, the product was obtained by silica gel column chromatography followed by lyophilization, yielding 6 mg of product, m / z = 558.1 [M+1]. + .

[0775] 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),9.20(d,1H,J=1.2),8.73-8.72(d,1H,J=2.4),8.53-8.51(d, 1H,J=5.2),8.19-8.18(d,1H,J=2.4),8.06-8.04(d,2H,J=8.8),7.89-7.88(d,1H,J=1.2),7.72(s, 1H),7.48-7.46(d,2H,J=4.2),7.21-7.20(d,1H,J=2.4),7.03-7.01(d,1H,J=4.4),6.92-6.85(dd, 1H, J=5.2), 6.19-6.14 (dd, 1H, J=2.4), 5.75-5.72 (dd, 1H, J=2.4), 3.72-3.64 (m, 8H), 1.25 (s, 3H).

[0776] Example 62: Preparation of compound 62

[0777] Step A: 6-Bromo-4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0778]

[0779] 6-Bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (562 mg, 2.0 mmol), NIS (675 mg, 3.0 mmol), and DMF (5 mL) were added to the reaction flask. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (50 mL), extracted with EA, dried the organic phase, evaporated the solvent, and purified by normal phase column chromatography (PE / EA = 1:1) to give 300 mg of product, m / z = 363, 365 [M+1]. + .

[0780] Step B: 6-Bromo-4-ethoxy-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0781]

[0782] 6-Bromo-4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.37 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)phenoxy)-4-methylpyrimidine (182 mg, 0.55 mmol), Pd(dppf)Cl2 (54 mg, 0.074 mmol), Cs2CO3 (180 mg, 0.55 mmol), KF (58 mg, 1.0 mmol), and 1,4-dioxane / water (5 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 100 °C for 8 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (50 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by normal-phase column chromatography (PE / EA = 1:1) to obtain 100 mg of product, m / z = 483 [M+1]. + .

[0783] Step C: 1-(4-(5-(4-ethoxy-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)acrylamide

[0784]

[0785] 6-Bromo-4-ethoxy-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.2 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (100 mg, 0.3 mmol), Pd(dppf)Cl2 (30 mg, 0.03 mmol), Cs2CO3 (100 mg, 0.3 mmol), KF (58 mg, 1 mmol), and 1,4-dioxane / water (5 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 100 °C for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 10 mg of product, m / z = 620 [M+1]. + . 1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.80-8.90(s,1H),8.50-8.80(m,7H),7.46-7.60(m,2H),6.15- 6.19(m,1H),5.72-5.75(m,2H),4.25-4.30(m,2H),3.70-3.92(m,8H),2.44(s,3H),1.24-1.30(m,3H).

[0786] Example 63: Preparation of compound 63

[0787] Step A: 1-(4-(5-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0788]

[0789] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (237 mg, 1.0 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (377 mg, 1.1 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), Cs2CO3 (488 mg, 1.5 mmol), KF (58 mg, 1 mmol), and 1,4-dioxane / water (5 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (100 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 110 mg of product, m / z = 374 [M+1]. + .

[0790] Step B: 1-(4-(5-(3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0791]

[0792] 1-(4-(5-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperidin-1-yl)propyl-2-en-1-one (1000 mg, 2.69 mmol), NIS (603 mg, 2.69 mmol), and DMF (10 mL) were added to the reaction flask. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (50 mL) and filtered to obtain 500 mg of crude product, m / z = 500 [M+1]. + .

[0793] Step C: 1-(4-(5-(3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyll)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperazin-1-yl)acrylamide

[0794]

[0795] 1-(4-(5-(3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)pyridin-2-yl)piperidin-1-yl)propyl-2-en-1-one (50 mg, 0.1 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)phenoxy)-4-methylpyrimidine (50 mg, 0.15 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), Cs2CO3 (19 mg, 0.15 mmol), KF (5.8 mg, 0.1 mmol), and 1,4-dioxane / water (3 mL / 0.5 mL) were added to the reaction flask. The reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into water (10 mL), extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by reversed-phase column chromatography to obtain 0.6 mg of product, m / z = 576 [M+1]. + .

[0796] Example 64: Preparation of Compound 64

[0797] Step A: N-(4-methyl-5-(6-(4-pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yll)pyridin-2-yl)acrylamide

[0798]

[0799] The following were added to the reaction flask: pyrrolidine-1-yl(4-(4-boronic acid pinacol ester-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)carboxamide (90 mg, CRUD), N-(5-bromo-4-methylpyridin-2-yl)acrylamide (40 mg, 0.16 mmol), cesium carbonate (90 mg, 0.26 mmol), and Pd(d ppf)Cl2 (7.3 mg, 0.01 mmol), 1,4-dioxane (2 mL), water (0.4 mL), nitrogen purged three times, reacted at 100 °C for 1 h, diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 6%) to give 2.3 mg of product, m / z = 496 [M+1]. + .

[0800] 1 HNMR(400MHz,DMSO-d6): δ12.69(brs,1H),10.90(s,1H),8.82(s,1H),8.38 (s,1H),8.33(s,1H),7.61(s,1H),7.23(s,1H),6.70-6.64(m,1H),6.50(s, 1H),6.39-6.34(m,1H),5.85-5.82(m,1H),3.55-3.52(m,2H),3.31-3.29(m ,2H),2.78-2.64(m,3H),2.39-2.33(m,2H),2.23(s,3H),2.00-1.65(m,6H).

[0801] Example 65: Preparation of Compound 65

[0802] Step A: (4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)(pyrrolidine-1-yl)formamide

[0803]

[0804] The following ingredients were added to the reaction flask: 6-bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (454 mg, 1.2 mmol), 4-(pyrrolidine-1-carbonyl)phenylboronic acid pinacol ester (550 mg, 1.8 mmol), cesium carbonate (1.17 g, 3.6 mmol), Pd(dppf)Cl2 (87 mg, 0.12 mmol), 1,4-dioxane (12 mL), and water (2 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 16 h. After cooling, the mixture was diluted with 50 mL of water and extracted with 2 × 50 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to obtain 240 mg of the product, m / z = 468 [M+1]. + .

[0805] Step B: (4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)(pyrrolidine-1-yl)formamide

[0806]

[0807] (4-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)(pyrrolidine-1-yl)carboxamide (240 mg, 0.51 mmol), m-phenylenediamine (208 mg, 1.5 mmol), and methanol (10 mL) were added to the reaction flask. Then, 1,4-dioxane / hydrochloric acid solution (4 mL) was added to the reaction system. The reaction was carried out at room temperature for 2 h, and the product was concentrated to obtain 1.1 g of product, CRUD, m / z = 348 [M+1]. + .

[0808] Step C: 6-(4-pyrrolidine-1-carbonyl)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-yl-trifluoromethanesulfonate

[0809]

[0810] (4-(4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)phenyl)(pyrrolidine-1-yl)carboxamide (1.1 g, crud), DIEA (322 mg, 2.5 mmol), and DMF (15 mL) were added to the reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (214 mg, 0.6 mmol). The reaction was carried out at room temperature for 2 h until complete. The solution was diluted with 50 mL of water, extracted with 2 × 100 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA / DCM = 40%) to give 48 mg of the product, m / z = 480 [M+1]. + .

[0811] Step D: N-(5-(6-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0812]

[0813] The following ingredients were added to the reaction flask: 6-(4-pyrrolidine-1-carbonyl)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (48 mg, 0.1 mmol), (6-acrylamido-3-yl)pyridineboronic acid (72 mg, 0.21 mmol), cesium carbonate (81 mg, 0.25 mmol), Pd(dppf)Cl2 (4 mg, 0.005 mmol), 1,4-dioxane (2.5 mL), and water (0.4 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 1 h. The mixture was diluted with 30 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to obtain 3.5 mg of the product, m / z = 478 [M+1]. + .

[0814] 1 HNMR (400MHz, DMSO-d6): δ12.83(brs,1H),11.06(s,1H),9.32(s,1H),8.96(s,1H),8.48-8.46(m,2H),8.04-8.00(m, 3H),7.71-7.66(m,3H),73-6.68(m,1H),6.42-6.38(m,1H),5.87-5.85(m,1H),3.51-3.47(m,4H),1.94-1.86(m,4H).

[0815] Example 66: Preparation of Compound 66

[0816] Step A: 1-(4-(4-(6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0817]

[0818] The following were added to the reaction flask: 6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (20 mg, 0.04 mmol), (2-(4-acryloylpiperazin-1-yl)pyridin-4-yl)boronic acid (16 mg, 0.06 mmol), cesium carbonate (33 mg, 0.1 mmol), and Pd. (dppf)Cl2 (2.9 mg, 0.004 mmol), 1,4-dioxane (2 mL), water (0.2 mL), nitrogen purged three times, reacted at 90 °C for 3 h, diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 5%) to give 1.1 mg of product, m / z = 551 [M+1]. + .

[0819] Example 67: Preparation of Compound 67

[0820] Step A: Pyrrolidine-1-yl(4-(4-boronic acid pinacol ester-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)formamide

[0821]

[0822] 6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (65 mg, 0.13 mmol), pinacol diboronate (41 mg, 0.17 mmol), potassium acetate (40 mg, 0.4 mmol), Pd(dppf)Cl2 (10 mg, 0.013 mmol), and 1,4-dioxane (3 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 12 h. After filtration, concentration, and hexane slurrying, the mixture was filtered again to obtain 110 mg of product, m / z = 462 [M+1]. + .

[0823] Step B: (4-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0824]

[0825] The following were added to the reaction flask: pyrrolidine-1-yl(4-(4-boronic acid pinacol ester-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)carboxamide (110 mg, CRUD), N-(5-bromo-4-fluoropyridin-2-yl)acrylamide (30 mg, 0.12 mmol), cesium carbonate (136 mg, 0.42 mmol), and Pd(d 10 mg (0.01 mmol) Cl2, 2.5 mL 1,4-dioxane, and 0.5 mL water were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 12 h. The mixture was diluted with 20 mL of water, extracted with 2 × 30 mL dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 6%) to give 2.5 mg of the product, m / z = 336 [M+1]. + .

[0826] 1 HNMR (400MHz, DMSO-d6): δ12.57(brs,1H),8.62(s,1H),7.93(s,1H),7.90(s,1H),7.60(d,J=9.2Hz,1H),6 .40(s,1H),3.55-3.52(m,2H),3.31-3.29(m,2H),2.73-2.54(m,3H),2.37-2.33(m,2H),1.99-1.60(m,6H).

[0827] Example 68: Preparation of Compound 68

[0828] Step A: 6-Bromo-3-iodo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0829]

[0830] 6-Bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (375 mg, 1.0 mmol), NIS (336 mg, 1.5 mmol), and DMF (5 mL) were added to a reaction flask and reacted at room temperature for 2 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and stirred, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 500 mg of product, m / z = 499 [M+1]. + .

[0831] Step B: 6-Bromo-3-iodo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0832]

[0833] 6-Bromo-3-iodo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (300 mg, 0.6 mmol), p-toluenesulfonic acid (11 mg, 0.06 mmol), DHP (100 mg, 1.2 mmol), and THF (5 mL) were added to a reaction flask and reacted at 40 °C for 2 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 230 mg of the product, m / z = 583 [M+1]. +

[0834] Step C: 3-(benzyloxy)-6-bromo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0835]

[0836] 6-Bromo-3-iodo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.26 mmol), CsCO3 (168 mg, 0.52 mmol), benzyl alcohol (556 mg, 5.2 mmol), CuI (24 mg, 0.13 mmol), 1,10-phenanthroline (23 mg, 0.13 mmol), and NMP (3 mL) were added to a reaction flask and reacted at 110 °C for 12 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 60 mg of the product, m / z = 563 [M+1]. + .

[0837] Step D: (4-(3-(benzyloxy)-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole)[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)(pyrrolidine-1-yl)methyl ketone

[0838]

[0839] 3-(benzyloxy)-6-bromo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (60 mg, 0.1 mmol), pyrrolidine-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclohexyl-3-en-1-yl) methyl ketone (46 mg, 0.15 mmol), PdCl2(dppf) (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.3 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 20 mg of product, m / z = 662 [M+1]. + .

[0840] Step E: (4-(3-(benzyloxy)-4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)(pyrrolidine-1-yl)methyl ketone

[0841]

[0842] (66 mg, 0.1 mmol) of (4-(3-(benzyloxy)-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole)[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)(pyrrolidine-1-yl) methyl ketone, 138 mg, 1.0 mmol, TFA (1 mL), and DCM (5 mL) were added to a reaction flask and reacted at 25 °C for 2 h. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure, and 10 mL of methyl tert-butyl ether was added. The precipitated solid was filtered to give 20 mg of product, m / z = 458 [M+1]. +

[0843] Step F: 3-(benzyloxy)-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yltrifluoromethanesulfonate

[0844]

[0845] (4-(3-(benzyloxy)-4-hydroxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)(pyrrolidine-1-yl) methyl ketone (20 mg, 0.04 mmol), DIEA (16 mg, 0.12 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14 mg, 0.04 mmol), and DMF (2 mL) were added to a reaction flask and reacted at 0 °C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and stirred, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 10 mg of the product, m / z = 590 [M+1]. + .

[0846] Step G: 1-(4-(5-(3-(benzyloxy)-6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3),4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0847]

[0848] 3-(benzyloxy)-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (10 mg, 0.02 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (9 mg, 0.03 mmol), PdCl2(dppf) (7 mg, 0.01 mmol), Cs2CO3 (33 mg, 0.1 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.4 mg of product, m / z = 657 [M+1]. + .

[0849] 1HNMR (400MHz, DMSO-d6): δ11.50(brs,1H),8.68(s,1H),8.49(s,1H),7.96(d,J =8.8Hz,1H),7.53(s,1H),7.40-7.32(m,5H),6.92-6.88(m,1H),6.57(s,1H),6 .48(s,1H),6.24-6.22(m,1H),5.78-5.75(m,1H),5.22(s,2H),3.75-3.62(m,4 H),3.58-3.41(m,8H),2.75-2.60(m,2H),2.40-2.26(m,2H),2.01-1.62(m,7H).

[0850] Example 69: Preparation of Compound 69

[0851] Step A: 4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0852]

[0853] 6-Bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.8 mmol), KOAc (700 mg, 7.2 mmol), PdCl2 (dppf) (140 mg, 0.2 mmol), pinacol diboronate (1370 mg, 5.4 mmol), and dioxane (10 mL) were added to a reaction flask. The mixture was reacted under N2 protection at 100 °C for 5 h, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 600 mg of the product, m / z = 329 [M+1]. + .

[0854] Step B: 6-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-amine

[0855]

[0856] 4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.45 mmol), 6-iodo-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-amine (150 mg, 0.30 mmol), PdCl2(dppf) (22 mg, 0.03 mmol), Cs2CO3 (196 mg, 0.60 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 30 mg of product, m / z = 533 [M+1]. + .

[0857] 1 HNMR (400MHz, DMSO-d6): δ12.71(brs,1H),8.55(s,1H),8.42(s,1H),8.24(s,1H),7.87(s,1H),7.40-7.36(m,2H),7 .21-7.18(m,2H),7.12(s,1H),6.87(s,1H),4.17(q,J=7.2Hz,2H),3.70(s,3H),2.38(s,3H),1.37(t,J=7.2Hz,3H).

[0858] Example 70: Preparation of Compound 70

[0859] Step A: 4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0860]

[0861] 6-Bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (1.13 g, 3.0 mmol), KOAc (1.20 g, 12.0 mmol), PdCl2 (dppf) (220 mg, 0.3 mmol), pinacol diboronate (2.29 g, 9.0 mmol), and dioxane (20 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 5 h under N2 protection, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1.0 g of the product, m / z = 421 [M+1].+ .

[0862] Step B: 6-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-amine

[0863]

[0864] 4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (315 mg, 0.75 mmol), 6-iodo-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-amine (230 mg, 0.50 mmol), PdCl2(dppf) (37 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.0 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.8 mg of product, m / z = 625 [M+1]. + .

[0865] 1 HNMR (400MHz, DMSO-d6): δ12.72(brs,1H),8.50(s,1H),8.37(s,1H),8.24(s,1H),7.85(s,1H),7.41(d,J=8.8Hz,2H),7.37-7. 35(m,2H),7.21-7.17(m,2H),7.12(s,1H),7.04(s,1H),6.98-6.95(m,1H),5.26(s,2H),3.75(s,3H),3.65(s,3H),2.36(s,3H).

[0866] Example 71: Preparation of Compound 71

[0867] Step A: 4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-tert-butyl carbonate

[0868]

[0869] Add 4-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.52 mmol), 4-(4-bromo-5-methyl-1H-pyrazole-1-yl)piperidine-1-tert-butyl carbonate (350 mg, 1.02 mmol), tetrakis(triphenylphosphine)palladium (118 mg, 0.10 mmol), potassium carbonate (280 mg, 2.03 mmol), 1,4-dioxane (5 mL), and water (1 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 6 hours. After the reaction is complete, extract with water and dichloromethane, and obtain the product 340 mg, m / z = 466 [M+1] by silica gel column chromatography. + .

[0870] Step B: 4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine

[0871]

[0872] Add 340 mg (0.73 mmol) of 4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-tert-butyloxycarbonyl, 1.5 mL of trifluoroacetic acid, and 4 mL of dichloromethane to a reaction flask. Stir at room temperature for 2 hours. After the reaction is complete, concentrate until no product is obtained, extract with water and dichloromethane, collect the aqueous phase, adjust the pH of the aqueous phase to 9-10 with a strong sodium oxidizing solution, and extract with DCM / iPrOH = 1:4. Dry the organic phase with anhydrous sodium sulfate and concentrate until no product is obtained to give 140 mg of a pale yellow solid, m / z = 366 [M+1]. + .

[0873] Step C: (3-(4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-carbonyl)cyclobutyl)amino tert-butyl carbonate

[0874]

[0875] Add the following to the reaction flask: 4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine (140 mg, 0.33 mmol), dichloromethane (2 mL), and DIEA (84.8 mg, 0.66 mmol). After cooling to 0–10 °C, add EDCI (75.4 mg, 0.39 mmol), HOBt (53.3 mg, 0.39 mmol), and 3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (84.8 mg, 0.39 mmol). Stir at 0–10 °C for 0.5 hours. After the reaction is complete, extract with water and dichloromethane. Silica gel column chromatography yields 90 mg of product, m / z = 563.3 [M+1]. + .

[0876] Step D: N-(3-(4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-carbonyl)cyclobutyl)acrylamide

[0877]

[0878] Add (90 mg, 0.16 mmol) of (3-(4-(4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-carbonyl)cyclobutyl)amino tert-butyl carbonate, 2 mL of methanol, and 0.5 mL of 1,4-dioxane hydrogen chloride solution (4 mol / L) to the reaction flask, and stir at room temperature for 1 hour. After the reaction was completed, the solution was concentrated until no product was observed. DMF (1 mL) and DIEA (124 mg, 0.96 mmol) were added sequentially. The mixture was cooled to 0–10 °C, and acryloyl chloride (14 mg, 0.16 mmol) was added dropwise. The mixture was stirred at 0–10 °C for 0.5 hours. After the reaction was complete, water and dichloromethane were added for extraction. The organic phase was collected and concentrated until no product was observed. The product was purified by reverse-phase column chromatography and lyophilized to obtain 34.6 mg of product, m / z = 517.2 [M+1]. +. 1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.40(s,2H),7.85(s,1H),7.81(s,1H),6.94(s,1H ),6.16-6.09(m,2H),5.60-5.57(d,1H,J=2.4),4.55-4.49(m,2H),4.39-4.33(q,2H,J=6 .8),4.30-4.24(m,1H),3.94-3.91(m,1H),3.23-3.12(m,2H),2.82-2.76(m,1H),2.50(s ,3H),2.48-2.41(m,2H),2.20-2.18(m,2H),1.90-1.83(m,4H),1.51-1.48(t,3H,J=6.8).

[0879] Example 72: Preparation of compound 72

[0880] 6-(4-amino-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0881]

[0882] 6-(4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-7-methyl-5-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-amine (5 mg, 0.08 mmol), m-phenylenediamine (138 mg, 1.0 mmol), TFA (1 mL), and DCM (5 mL) were added to a reaction flask and reacted at 25 °C for 2 h. The reaction was monitored by LCMS until complete. The solution was concentrated under reduced pressure and separated by column chromatography to obtain 0.67 mg of the product, m / z = 505 [M+1]. + .

[0883] Example 73: Preparation of Compound 73

[0884] Step A: (4-(4-(1H-indol-5-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0885]

[0886] 6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (40 mg, 0.08 mmol), 5-indoleboronic acid pinacol ester (30 mg, 0.12 mmol), cesium carbonate (78 mg, 0.24 mmol), Pd(dppf)Cl2 (6 mg, 0.008 mmol), 1,4-dioxane (2 mL), and water (0.2 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 85 °C for 3 h. The mixture was diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 10%) to obtain 2.8 mg of the product, m / z = 451 [M+1]. + .

[0887] 1 HNMR (400MHz, DMSO-d6): δ12.65(brs,1H),11.35(s,1H),8.73(s,1H),8.07(s,1H),7.66-7.61(m,4H),7.47(s,1H),6. 59(s,1H),6.51(s,1H),3.55-3.52(m,2H),3.31-3.29(m,2H),2.78-2.56(m,3H),2.39-2.32(m,2H),2.03-1.64(m,6H).

[0888] Example 74: Preparation of Compound 74

[0889] 1-(4-(5-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)acetone

[0890]

[0891] Add 4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.3 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)acetone (101 mg, 0.3 mmol), Cs2CO3 (199 mg, 0.6 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), dioxane (5 mL), and water (1 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 10:1) to obtain 22.9 mg of product, m / z = 406 [M+1]. + . 1 H-NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.85-8.86(m,1H),8.44-8.46(m,1H),8.18-8.21(m,1H),7.04 -7.06(m,1H),6.93-6.95(m,2H),4.21-4.26(m,2H),3.57-3.63(m,8H),2.06(s,3H),1.42-1.46(m,3H).

[0892] Example 75: Preparation of Compound 75

[0893] Step A: 1-(4-(5-(6-bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)acetone

[0894]

[0895] Add 6-bromo-4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (200 mg, 0.49 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)piperazin-1-yl)acetone (163 mg, 0.49 mmol), Cs2CO3 (320 mg, 0.98 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), dioxane (10 mL), and water (2 mL) to the reaction flask, purge with nitrogen three times, and react at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phase was dried, the solvent was evaporated, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 100 mg of product, m / z = 484, 486 [M+1].+ .

[0896] Step B: 1-(4-(5-(6-(2,3-dimethylphenyl)-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)acetone

[0897]

[0898] Add 1-(4-(5-(6-bromo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)acetone (100 mg, 0.2 mmol), (2,3-dimethylphenyl)boronic acid (31 mg, 0.2 mmol), Cs₂CO₃ (130 mg, 0.4 mmol), Pd(dppf)Cl₂ (15 mg, 0.02 mmol), dioxane (5 mL), and water (1 mL) to a reaction flask. Purge with nitrogen three times and react at 90 °C for 1 hour. Monitor the reaction for completeness using LC-MS. Pour the reaction solution into 50 mL of water, extract with EA, dry the organic phase, evaporate the solvent, and purify by column chromatography (DCM:MeOH = 10:1) to obtain 36.6 mg of product, m / z = 510 [M+1]. + .

[0899] 1 H-NMR(400MHz,DMSO-d6)δ12.73(s,1H),8.91(s,1H),8.38(s,1H),8.23-8.26(m,1H),7.19-7.27(m,3H),6.95-6.97( m,1H),6.88(s,1H),4.27-4.32(m,2H),3.57-3.64(m,8H),2.33(s,3H),2.21(s,3H),2.07(s,3H),1.44-1.47(m,3H).

[0900] Example 76: Preparation of Compound 76

[0901] Step A: 7-chloro-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-phenol

[0902]

[0903] 7-Chloro-4-((4-methoxybenzyl)oxy)-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (400 mg, 0.94 mmol), m-phenylenediamine (388 mg, 2.81 mmol), and dichloromethane (10 mL) were added to the reaction flask. Then, trifluoroacetic acid (4 mL) was added dropwise to the reaction system. The reaction was carried out at room temperature for 1 h, and the product was concentrated to obtain 1.1 g of product, m / z = 307 [M+1]. + .

[0904] Step B: 7-Chloro-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate

[0905]

[0906] 7-Chloro-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-phenol (1.1 g, crud), DIEA (1.1 g, 9.0 mmol), and DMF (15 mL) were added to a reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (386 mg, 1.1 mmol). The reaction was carried out at room temperature for 1 h until complete. The solution was diluted with 50 mL of water, extracted with 2 × 100 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 7%) to give 230 mg of product, m / z = 439 [M+1]. + .

[0907] Step C: 1-(4-(5-(7-chloro-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0908]

[0909] The following ingredients were added to the reaction flask: 7-chloro-6-(4-methylpiperazin-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (80 mg, 0.18 mmol), 6-(4-acryloylpiperazinyl)pyridine-3-boronic acid pinacol ester (93 mg, 0.27 mmol), cesium carbonate (176 mg, 0.54 mmol), Pd(dppf)Cl2 (13 mg, 0.02 mmol), 1,4-dioxane (4 mL), and water (0.5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 5 h. The mixture was diluted with 20 mL of water, extracted with 2 × 30 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 9%) to give 3.1 mg of the product, m / z = 506 [M+1]. + .

[0910] 1 HNMR (400MHz, DMSO-d6): δ12.87(brs,1H),8.64(s,1H),8.09(d,J=8.8Hz,1H),7.65(s,1H),7.52(s,1H),7.42(s,1H),7.11(d,J=8.8H z,1H),6.92-6.88(m,1H),6.20-6.15(m,1H),5.76-5.73(m,1H),3.80-3.64(m,8H),3.16-3.12(m,4H),2.66-2.58(m,4H),2.29(s,3H).

[0911] Example 77: Preparation of Compound 77

[0912] Step A: N-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)cyclohexyl-1-en-1-yl)-1H-indazol-6-yl)phenylacrylamide

[0913]

[0914] N-(4-(7-chloro-1H-indazol-6-yl)-3-fluorophenyl)acrylamide (100 mg, 0.317 mmol), 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)cyclohexane-3-en-1-yl)oxy)pyrimidine (150 mg, 0.476 mmol), potassium phosphate (134 mg, 0.634 mmol), cesium fluoride (48 mg, 0.317 mmol), Xphos Pd G3 (54 mg, 0.0634 mmol), dioxane (5 mL), and water (0.5 mL) were added to a reaction flask. The reaction was carried out at 100 °C for 4 hours. The reaction was monitored by LCMS until complete. Ethyl acetate (5 mL) was added to the reaction mixture, the organic phase was separated, evaporated to dryness, and purified by reverse-phase column chromatography to give 11.5 mg of product, m / z = 470 [M+1]. + .

[0915] 1 H NMR(400MHz,DMSO-d6)δ13.0(s,1H),10.5(s,1H),8.42(d,1H),8.13(s,1H),7.71(dd,1H),7.69(dd,1H),7.33-6.97(m,2H),6.98-6.97 (m,2H),6.33(dd,1H),6.32(dd,1H),5.83(dd,1H),5.62(dd,1H),5.20-5.19(m,1H),2.51-2.50(m,1H),2.41(s,3H),2.38-1.99(m,5H).

[0916] Example 78: Preparation of Compound 78

[0917] Step A: 3-(benzyloxy)-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0918]

[0919] 6-Bromo-3-iodo-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (583 mg, 1.0 mmol), CsCO3 (650 mg, 2.0 mmol), benzyl alcohol (2160 mg, 20.0 mmol), CuI (95 mg, 0.5 mmol), 1,10-phenanthroline (90 mg, 0.5 mmol), and NMP (5 mL) were added to a reaction flask and reacted at 120 °C for 16 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 150 mg of the product, m / z = 485 [M+1]. + .

[0920] Step B: 3-(benzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0921]

[0922] 3-(benzyloxy)-4-((4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (150 mg, 0.3 mmol), m-phenylenediamine (138 mg, 1.0 mmol), TFA (1 mL), and DCM (5 mL) were added to a reaction flask and reacted at 25 °C for 2 h. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added. The precipitated solid was filtered to give 50 mg of the product, m / z = 281 [M+1]. +

[0923] Step C: 3-(benzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-yltrifluoromethanesulfonate

[0924]

[0925] 3-(benzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (50 mg, 0.18 mmol), DIEA (70 mg, 0.54 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (65 mg, 0.18 mmol), and DMF (2 mL) were added to a reaction flask and reacted at 0 °C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 40 mg of the product, m / z = 413 [M+1]. + .

[0926] Step D: 1-(4-(5-(3-(benzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0927]

[0928] 3-(benzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (40 mg, 0.1 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (51 mg, 0.15 mmol), PdCl2(dppf) (7 mg, 0.01 mmol), Cs2CO3 (65 mg, 0.2 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 10 mg of product, m / z = 480 [M+1]. + . 1 HNMR (400MHz, DMSO-d6): δ11.52(brs,1H),8.77(s,1H),8.44(s,1H),7.91(d,J=8.8Hz,1H),7.40-7.19(m,6H),7.15(t,J=7.2Hz,1H),6. 92-6.86(m,1H),6.57(d,J=8.8Hz,1H),6.17(d,J=12.4Hz,1H),5.74(d,J=8.8Hz,1H),5.22(s,2H),3.66-3.63(m,4H),3.46-3.42(m,4H).

[0929] Example 79: Preparation of Compound 79

[0930] Step A: 6-Bromo-4-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0931]

[0932] 6-Bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (500 mg, 1.34 mmol), cesium carbonate (1.1 g, 3.37 mmol), and DMF (10 mL) were added to a reaction flask. The temperature was lowered to 0-5 °C, and iodomethane (284 mg, 2.0 mmol) was added. The mixture was allowed to rise naturally to room temperature for 2 h until the reaction was complete. The solution was diluted with 50 mL of water, extracted with 2 × 80 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column-sected (EA / DCM = 10%) to give 6-bromo-4-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (300 mg), m / z = 387 [M+1]. + .

[0933] Step B: (4-(4-(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0934]

[0935] The following ingredients were added to the reaction flask: 6-bromo-4-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (300 mg, 0.78 mmol), 4-(pyrrolidine-1-carbonyl)cyclohexyl-3-enyl-boronic acid pinacol ester (1.13 g, 2.9 mmol), cesium carbonate (762 mg, 2.34 mmol), Pd(dppf)Cl2 (57 mg, 0.08 mmol), 1,4-dioxane (10 mL), and water (1 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 20 h. The mixture was diluted with 50 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to obtain 280 mg of the product, m / z = 486 [M+1]. + .

[0936] Step C: (4-(4-hydroxy-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide

[0937]

[0938] (4-(4-(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)carboxamide (280 mg, 0.57 mmol), m-phenylenediamine (529 mg, 3.8 mmol), and dichloromethane (10 mL) were added to the reaction flask. Then, trifluoroacetic acid (4 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1.5 h, and the product was concentrated to obtain 800 mg of product, m / z = 366 [M+1]. + .

[0939] Step D: 1-Methyl-6-(4-(pyrrolidine-1-carbonyl)cyclohex-3-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate

[0940]

[0941] (4-(4-hydroxy-1-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)carboxamide (800 mg, crud), DIEA (361 mg, 2.8 mmol), and DMF (5 mL) were added to the reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (295 mg, 0.82 mmol). The reaction was carried out at room temperature for 2 h until complete. The solution was diluted with 50 mL of water, extracted with 2 × 100 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA / DCM = 40%) to give 180 mg of the product, m / z = 498 [M+1]. + .

[0942] Step E: 1-(4-(5-(1-methyl-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0943]

[0944] The following substances were added to the reaction flask: 1-methyl-6-(4-(pyrrolidine-1-carbonyl)cyclohex-3-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (80 mg, 0.16 mmol), 6-(4-acryloylpiperazinyl)pyridine-3-boronic acid pinacol ester (72 mg, 0.21 mmol), cesium carbonate (156 mg, 0.48 mmol), Pd(dppf)Cl2 (12 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.3 mL). The mixture was purged with nitrogen three times, reacted at 90℃ for 3 h, diluted with 30 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH / DCM = 5%) to give 1-(4-(5-(1-methyl-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one (31.5 mg), m / z = 565 [M+1]. + .

[0945] 1 HNMR (400MHz, DMSO-d6): δ8.75(s,1H),8.64(s,1H),8.09(d,J=8.8Hz,1H),7.66 (s,1H),7.59(s,1H),7.09(d,J=8.8Hz,1H),6.92-6.85(m,1H),6.51(s,1H),6.20 -6.15(m,1H),5.76-5.73(m,1H),3.92(s,3H),3.79-3.64(m,8H),3.53-3.59(m, 2H),3.31-3.29(m,2H),2.74-2.66(m,1H),2.32-2.27(m,2H),2.01-1.62(m,6H).

[0946] Example 80: Preparation of Compound 80

[0947] 3-(2,3-dimethylbenzene)-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0948]

[0949] Add 4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (25 mg, 0.08 mmol), (2,3-dimethylbenzene)boric acid (13.7 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.008 mmol), potassium carbonate (84.1 mg, 0.18 mmol), 1,4-dioxane (1 mL), and water (0.2 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 8 hours. After the reaction is complete, purify by silica gel column chromatography followed by reverse-phase column chromatography, and lyophilize to obtain 10 mg of product, m / z = 307 [M+1]. + .

[0950] 1H NMR (400MHz, DMSO-d6) δ12.61 (s, 1H), 8.44-8.42 (d, 1H, J = 6.8), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 1H), 7.03-7.00 (t, 1H, J=7.6), 6.82-6.80 (d, 1H, J=7.6), 4.01-3.96 (q, 2H, J=7.2), 2.32 (s, 3H), 2.13 (s, 3H), 0.94-0.91 (t, 3H, J=7.2).

[0951] Example 81: Preparation of Compound 81

[0952] 3-(2,3-Dimethylphenyl)-4-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0953]

[0954] Add 4-ethoxy-3-iodo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (50 mg, 0.15 mmol), 3,4-dihydro-2H-pyran (19.2 mg, 0.23 mmol), p-toluenesulfonic acid (2.6 g, 0.015 mmol), and tetrahydrofuran (2 mL) to the reaction flask. Heat to 80 °C and stir for 3 hours. After the reaction is complete, extract with water and dichloromethane, concentrate until no residue appears, and use directly for the next step.

[0955] After concentrating 1,4-dioxane (2 mL) in the residue from the previous step, (2,3-dimethylbenzene)boric acid (34.3 mg, 0.23 mmol), tetraphenylphosphine palladium (17.6 mg, 0.015 mmol), potassium carbonate (42.1 mg, 0.31 mmol), and water (0.2 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 4 hours. After the reaction was completed, the product was purified by silica gel column chromatography, followed by reverse-phase column chromatography and lyophilized to obtain 15 mg of product, m / z = 391.1 [M+1]. + .

[0956] 1H NMR(400MHz, DMSO-d6)δ8.50-8.48(d,1H,J=6.8),7.25-7.23(d,2H,J=7.6),7.17 -7.13(t,1H,J=7.6),7.07-7.04(t,1H,J=6.8),6.86-6.84(d,1H,J=7.6),5.59-5. 56(m,1H),4.00-3.93(m,3H),3.68-3.65(m,1H),2.62-2.59(m,1H),2.32(s,3H),2 .13(s,3H),2.10-2.03(m,2H),1.79-1.72(m,1H),1.57(m,2H),0.91-0.87(t,3H).

[0957] Example 82: Preparation of Compound 82

[0958] Step A: 4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0959]

[0960] 6-Bromo-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (373 mg, 1 mmol), Pd / C (10%, 40 mg), and THF (10 mL) were added to a reaction flask, H2 was displaced, and the reaction was carried out at room temperature for 8 h. The reaction was monitored by LCMS until completion. The solution was concentrated under reduced pressure to give 200 mg of product, m / z = 295 [M+1]. + .

[0961] Step B: 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol

[0962]

[0963] 4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (200 mg, 0.7 mmol), m-phenylenediamine (414 mg, 2.1 mmol), TFA (1 mL), and DCM (5 mL) were added to a reaction flask and reacted at 25 °C for 2 h. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added. The precipitated solid was filtered to give 100 mg of product, m / z = 175 [M+1]. +

[0964] Step C: 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-yltrifluoromethanesulfonate

[0965]

[0966] 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (100 mg, 0.57 mmol), DIEA (147 mg, 1.14 mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (200 mg, 0.57 mmol), and DMF (2 mL) were added to a reaction flask and reacted at 0 °C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 100 mg of the product, m / z = 307 [M+1]. + .

[0967] Step D: 1-(4-(5-(1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one

[0968]

[0969] 1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (100 mg, 0.30 mmol), 1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)pyridin-2-yl)piperazin-1-yl)propyl-2-en-1-one (154 mg, 0.45 mmol), PdCl2(dppf) (22 mg, 0.03 mmol), Cs2CO3 (196 mg, 0.60 mmol), 1,4-dioxane (2 mL), and H2O (0.5 mL) were added to the reaction flask. Under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction was monitored by LCMS until it was complete. The solution was quenched by stirring with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 22 mg of product, m / z = 374 [M+1]. +. 1 HNMR (400MHz, DMSO-d6): δ12.71(brs,1H),8.82(s,1H),8.60(s,1H),8.07(d,J=8.8Hz,1H),7.66(s,1H),7.49(d,J=6.8 Hz,1H),7.20(t,J=6.8Hz,1H),7.12(s,1H),6.95-6.85(m,1H),6.20-6.15(m,1H),5.76-5.71(m,1H),3.82-3.54(m,8H).

[0970] Example 83: Preparation of Compound 83

[0971] Step A: 6-(benzyloxy)-4-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0972]

[0973] 6-(benzyloxy)-4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (2.15 g, 5.0 mmol), NCS (739 mg, 5.5 mmol), and DMF (25 mL) were added to a reaction flask. The reaction was carried out at 60 °C for 1.5 h. The mixture was diluted with 100 mL of water, extracted with 2 × 100 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column filtered (EA / DCM = 5%) to obtain 890 mg of the product, m / z = 461 [M+1]. + .

[0974] Step B: 4-(5-(6-(benzyloxy)-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate

[0975]

[0976] The following were added to the reaction flask: 6-(benzyloxy)-4-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (890 mg, 1.9 mmol), 6-(4-Boc-1-piperazinyl)pyridine-3-boronic acid pinacol ester (1.13 g, 2.9 mmol), cesium carbonate (1.88 g, 5.7 mmol), and Pd. (dppf)Cl2 (139 mg, 0.19 mmol), 1,4-dioxane (15 mL), water (2 mL), nitrogen purged three times, reacted at 95 °C for 15 h, diluted with 50 mL of water, extracted with 2 × 100 mL of dichloromethane, combined with organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (EA / PE = 50%) to give 680 mg of product, m / z = 644 [M+1]. + .

[0977] Step C: 4-(5-(7-chloro-6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate

[0978]

[0979] Add 300 mg (0.47 mmol) of 4-(5-(6-(benzyloxy)-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate, ethyl acetate (15 mL), and methanol (5 mL) to the reaction flask, purge with nitrogen, and add 10% palladium on carbon. 100 mg), purged three times with hydrogen, and reacted at room temperature under hydrogen atmosphere for 2 hours until complete. The mixture was filtered and concentrated to obtain 260 mg of 4-(5-(7-chloro-6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate, m / z = 554 [M+1]. + .

[0980] Step D: 4-(5-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethanesulfonyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate

[0981]

[0982] 4-(5-(7-chloro-6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carbonate tert-butyl ester (260 mg, 0.47 mmol), DIEA (182 mg, 1.4 mmol), and DMF (8 mL) were added to a reaction flask, followed by N-phenylbis(trifluoromethanesulfonyl)imide (201 mg, 0.56 mmol). The reaction was carried out at room temperature for 2 h until complete. The solution was diluted with 50 mL of water, extracted with 2 × 100 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA / PE = 35%) to give 310 mg of product 4, m / z = 686 [M+1]. + .

[0983] Step E: 4-(5-(7-chloro-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate

[0984]

[0985] Add 4-(5-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethanesulfonyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate (310 mg, 0.47 mmol), 4-(pyrrolidine-1-carbonyl)cyclohex-3-en-yl-boronic acid pinacol ester (207 mg, 0.68 mmol), and cesium carbonate (4 40 mg (1.35 mmol), Pd(dppf)Cl2 (33 mg, 0.05 mmol), 1,4-dioxane (8 mL), water (1 mL), nitrogen purged three times, reacted at 90 °C for 2 h, diluted with 30 mL of water, extracted with 2 × 50 mL dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography (MeOH / DCM = 5%) to give 190 mg of product, m / z = 715 [M+1]. + .

[0986] Step F: (4-(7-chloro-4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide hydrochloride

[0987]

[0988] 4-(5-(7-chloro-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate (190 mg, 0.26 mmol), 1,4-dioxane / HCl (4N, 5 mL), and methanol (5 mL) were added to the reaction flask and reacted at room temperature for 2 h until the reaction was complete. Concentration yielded 220 mg of crude (4-(7-chloro-4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)formamide hydrochloride, m / z = 531 [M+1] + .

[0989] Step G: 1-(4-(5-(7-chloro-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0990]

[0991] (4-(7-chloro-4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-yl)(pyrrolidine-1-yl)carboxamide hydrochloride (220 mg, 0.26 mmol), DIEA (336 mg, 2.6 mmol), and DCM (10 mL) were added to the reaction flask, followed by acryloyl chloride (23.5 mg, 0.26 mmol). The reaction was carried out at 0-5 °C for 0.5 h until it was complete. Quenched in 10 mL of saturated sodium bicarbonate, diluted with 20 mL of water, extracted with 50 mL of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase column chromatography (MeOH / NH4HCO3: 0-62%) to give 42 mg of 1-(4-(5-(7-chloro-6-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one, m / z = 585 [M+1]. + .

[0992] 1HNMR (400MHz, DMSO-d6): δ12.90(brs,1H),8.65(s,1H),8.08(d,J=8.8Hz,1H) ,7.65(s,1H),7.43(s,1H),7.10(d,J=9.2Hz,1H),6.92-6.88(m,1H),6.20-6.1 5(m,1H),5.96(s,1H),5.76-5.73(m,1H),3.80-3.64(m,8H),3.59-3.53(m,2H ),3.33-3.31(m,2H),2.81-2.72(m,2H),2.42-2.28(m,3H),1.98-1.62(m,6H).

[0993] Example 84: Preparation of Compound 84

[0994] Step A: tert-butyl 4-(5-(6-(4-(ethoxycarbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carbonate

[0995]

[0996] 4-(5-(6-bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-tert-butyl carbonate (750 mg, 1.5 mmol), ethyl 4-boronate-3-cyclohexenecarboxylate (843 mg, 3.0 mmol), cesium carbonate (1.47 g, 4.5 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), 1,4-dioxane (12 mL), and water (2 mL) were added to the reaction flask. Under nitrogen protection, the reaction was carried out at 120 °C for 24 h. The mixture was diluted with 30 mL of water, extracted with 2 × 50 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column filtered (MeOH / DCM = 4%) to obtain 630 mg of product, m / z = 572 [M+1]. + .

[0997] Step B: 4-(4-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-ene-1-carboxylic acid

[0998]

[0999] Add tert-butyl 4-(5-(6-(4-(ethoxycarbonyl)cyclohex-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-1-carbonate (630 mg, 1.1 mmol), lithium hydroxide (120 mg, 5.0 mmol), tetrahydrofuran (20 mL), methanol (4 mL), and water (2 mL) to a reaction flask. React at 60 °C for 2 h until complete. Cool to 0-10 °C and dissolve in 2N methanol hydrochloric acid. Adjust the pH of the solution to 5-6, stir for 10 minutes, add 90 mL of dichloromethane and 10 mL of methanol for dilution, dry with anhydrous sodium sulfate, filter and concentrate, then add 30 mL of methyl tert-butyl ether, slurry for 30 minutes, filter, and dry under reduced pressure to obtain 4-(4-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1-hydro-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-carboxylic acid (460 mg), m / z = 544 [M+1]. + .

[1000] Step C: 4-(5-(6-(4-((2-(4-methylpiperazin-1-yl)ethyl)formamide)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-tert-butyl carbonate

[1001]

[1002] The following ingredients were added to the reaction flask: (4-(4-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-carboxylic acid (100 mg, 0.37 mmol), 2-(4-methylpiperazin-1-yl)ethyl-1-amine (105 mg, 0.74 mmol), DIEA (236 mg, 1.83 mmol), HATU (167 mg, 0.44 mmol), and DMF (5 mL). The reaction was carried out at room temperature for 2 h until complete. The mixture was diluted with 30 mL of water, extracted with 3 × 30 mL of ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (MeOH / DCM = 15%) to obtain 160 mg of the product, m / z = 669 [M+1]. + .

[1003] Step D: N-(2-(4-methylpiperazin-1-yl)ethyl)-4-(4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-ene-1-carboxamide hydrochloride

[1004]

[1005] Add 160 mg (0.24 mmol) of 4-(5-(6-(4-(((2-(4-methylpiperazin-1-yl)ethyl)formamide)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-tert-butyl carbonate and 5 mL of dioxane hydrochloride solution (4N) to the reaction flask. Methanol (5 mL), reacted at room temperature for 3 h, and concentrated to give N-(2-(4-methylpiperazin-1-yl)ethyl)-4-(4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-ene-1-carboxamide hydrochloride (120 mg, crude product), m / z = 569 [M+1] + .

[1006] Step E: 4-(4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-yl-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)cyclohex-3-ene-1-carboxamide

[1007]

[1008] N-(2-(4-methylpiperazin-1-yl)ethyl)-4-(4-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-ene-1-carboxamide hydrochloride (120 mg, 0.17 mmol), DIEA (220 mg, 1.7 mmol), DMF (3 mL), and acryloyl chloride (14 mg, 0.15 mmol) were added to the reaction flask. The reaction was carried out at a warm temperature for 0.5 h, quenched with 0.5 mL of saturated ammonium bicarbonate, concentrated, and separated by reverse-phase column chromatography (MeOH / NH4HCO3: 0-65%) to give 4-(4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-yl-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)cyclohexyl-3-en-1-carboxamide (4.5 mg), m / z = 623 [M+1]. + .

[1009] 1HNMR (400MHz, DMSO-d6): δ12.69(brs,1H),8.74(s,1H),8.65(s,1H),8.10(d,J=8.8Hz ,1H),7.80(s,1H),7.66-7.62(m,2H),7.12-7.08(m,1H),6.92-6.88(m,1H),6.50(s,1 H),6.20-6.15(m,1H),5.76-5.73(m,1H),3.80-3.64(m,8H),3.3.25-3.16(m,2H),2.6 9-2.50(m,3H),2.48-2.26(m,12H),2.13(s,3H),2.01-1.98(m,1H),1.76-1.68(m,1H).

[1010] Example 85: Preparation of Compound 85

[1011] Step A: 4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine

[1012]

[1013] Add 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (700 mg, 2.23 mmol), 4-(4-bromo-5-methyl-1H-pyrazole-1-yl)piperidine-1-tert-butyl carbonate (920 mg, 2.67 mmol), tetrakis(triphenylphosphine)palladium (255 mg, 0.22 mmol), potassium carbonate (615.3 mg, 4.46 mmol), 1,4-dioxane (7 mL), and water (1 mL) to the reaction flask. Under nitrogen protection, heat to 90 °C and stir for 8 hours. After the reaction is complete, extract with water and dichloromethane, concentrate until no residue appears, and use directly for the next step.

[1014] Dichloromethane (4 mL) and trifluoroacetic acid (1.5 mL) were added to the concentrated residue, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the residue was concentrated until no further reaction occurred. The residue was then extracted with water and dichloromethane. The aqueous phase was collected, and the pH was adjusted to 9–10 with sodium hydroxide aqueous solution. Extraction was performed using DCM / iPrOH = 1:4. The organic phase was dried over anhydrous sodium sulfate and concentrated until no further reaction occurred to obtain 130 mg of a pale yellow solid, m / z = 352 [M+1]. + .

[1015] Step B: ((1S,3S)-3-amino-1-methylcyclobutyl)(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidin-1-yl)methyl ketone

[1016]

[1017] Add 4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine (40 mg, 0.11 mmol), dichloromethane (2 mL), and DIEA (29.4 mg, 0.22 mmol) to the reaction flask. After cooling to 0–10 °C, add EDCI (26.1 mg, 0.14 mmol), HOBt (18.4 mg, 0.14 mmol), and (1S,3S)-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutane-1-carboxylic acid (31.3 mg, 0.14 mmol) sequentially. Stir at 0–10 °C for 0.5 hours. After the reaction is complete, add water and dichloromethane for extraction. Concentrate until no residue appears and use directly for the next step.

[1018] Methanol (4 mL) and 1,4-dioxane hydrogen chloride solution (4 mol / L, 1 mL) were added to the concentrated residue. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the residue was concentrated until no product was observed. The residue was then extracted with water and dichloromethane. The aqueous phase was collected and its pH was adjusted to 9–10 with sodium hydroxide aqueous solution. The mixture was then extracted with DCM / iPrOH = 1:4. The organic phase was dried over anhydrous sodium sulfate and concentrated until no product was observed to obtain 20 mg of product, m / z = 463.2 [M+1]. +

[1019] Step D: N-((1S,3S)-3-(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-carbonyl)-3-methylcyclobutyl)acrylamide

[1020]

[1021] Add ((1S,3S)-3-amino-1-methylcyclobutyl)(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidin-1-yl) methyl ketone (20 mg, 0.043 mmol), DMF (1 mL), and DIEA (11.1 mg, 0.086 mmol) to a reaction flask. Cool to 0–10 °C, add acryloyl chloride (3.9 mg, 0.043 mmol) dropwise, and stir at 0–10 °C for 0.5 hours. After the reaction is complete, extract with water and dichloromethane, collect the organic phase, concentrate until no product is found, purify by reverse-phase column chromatography, and lyophilize to obtain 6 mg of product, m / z = 517.1 [M+1]. + .

[1022] 1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.44(s,1H),8.34(s,1H),7.87(s,1H) ,7.80(s,1H),6.96(s,1H),6.11-6.09(m,2H),5.60-5.57(dd,1H),4.62-4.5 2(m,2H),4.36-4.2-30(m,1H),4.07(s,3H),3.71-3.69(m,1H),3.25-3.21(m ,1H),2.79-2.76(m,1H),2.33-2.30(m,4H),1.94-1.83(m,5H),1.24(s,3H).

[1023] Example 86: Preparation of Compound 86

[1024] Step A: ((1R,3R)-3-amino-1-methylcyclobutyl)(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidin-1-yl)methyl ketone

[1025]

[1026] Add 4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine (40 mg, 0.11 mmol), dichloromethane (2 mL), and DIEA (29.4 mg, 0.22 mmol) to the reaction flask. After cooling to 0–10 °C, add EDCI (26.1 mg, 0.14 mmol), HOBt (18.4 mg, 0.14 mmol), and (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-methylcyclobutane-1-carboxylic acid (31.3 mg, 0.14 mmol) sequentially. Stir at 0–10 °C for 0.5 hours. After the reaction is complete, add water and dichloromethane for extraction. Concentrate until no residue appears and use directly for the next step.

[1027] Methanol (4 mL) and 1,4-dioxane hydrogen chloride solution (4 mol / L, 1 mL) were added to the concentrated residue. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the residue was concentrated until no product was observed. The residue was then extracted with water and dichloromethane. The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 9–10 with sodium hydroxide aqueous solution. The mixture was then extracted with DCM / iPrOH = 1:4. The organic phase was dried over anhydrous sodium sulfate and concentrated until no product was observed to obtain 22 mg of product, m / z = 463.2 [M+1]. +

[1028] Step B: N-((1R,3R)-3-(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidine-1-carbonyl)-3-methylcyclobutyl)acrylamide

[1029]

[1030] Add ((1R,3R)-3-amino-1-methylcyclobutyl)(4-(4-(4-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazole-1-yl)piperidin-1-yl) methyl ketone (22 mg, 0.048 mmol), DMF (1 mL), and DIEA (11.1 mg, 0.096 mmol) to a reaction flask. Cool to 0–10 °C, add acryloyl chloride (3.9 mg, 0.048 mmol) dropwise, and stir at 0–10 °C for 0.5 hours. After the reaction is complete, extract with water and dichloromethane, collect the organic phase, concentrate until no product is found, purify by reverse-phase column chromatography, and lyophilize to obtain 8.5 mg of product, m / z = 517.1 [M+1]. + .

[1031] 1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.44(s,1H),8.42(s,1H),7.87(s,1H),7.8 0(s,1H),6.96(s,1H),6.24-6.17(q,1H),6.10-6.05(dd,1H,J=2.0),5.61-5.58( dd,1H,J=2.0),4.56-4.55(s,2H),4.08(s,3H),4.01-3.97(m,1H),3.71(s,1H),3 .25-3.20(m,3H),2.90-2.85(m,3H),1.94-1.89(m,6H),1.42(s,3H),1.24(s,1H).

[1032] Example 87: Preparation of Compound 87

[1033] Step A: 4-(5-(6-(4-((R)-2-cyanopyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[1034]

[1035] Add 4-(4-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-carboxylic acid (200 mg, 0.37 mmol), (R)-pyrrolidine-2-onitrile trifluoroacetate (155 mg, 0.74 mmol), DIEA (236 mg, 1.83 mmol), HATU (167 mg, 0.44 mmol), and DMF (8 mL) to the reaction flask. The reaction was carried out at room temperature for 2 h, diluted with 30 mL of water, extracted with 2 × 30 mL of dichloromethane, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column filtered (MeOH / DCM = 8%) to give tert-butyl 4-(5-(6-(4-((R)-2-cyanopyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1-hydro-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-1-carboxylic acid (200 mg, 70% purity), m / z = 622 [M+1]. + .

[1036] Step B: (2R)-1-(4-(4-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a)]pyridin-6-yl)cyclohex-3-en-1-carbonyl)pyrrolidine-2-carboxamide hydrochloride

[1037]

[1038] 4-(5-(6-(4-((R)-2-cyanopyrrolidine-1-carbonyl)cyclohexyl-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.3 mmol), dioxane hydrochloride solution (2N, 4 mL), and methanol (4 mL) were added to a reaction flask. The reaction was carried out at room temperature for 1 h, and the solution was concentrated to obtain (2R)-1-(4-(4-(6-(piperidine-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-carbonyl)pyrrolidine-2-carboxamide hydrochloride (220 mg, crude product), m / z = 540 [M+1]. + .

[1039] Step C: (2R)-1-(4-(4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-ene-1-carbonyl)pyrrolidine-2-carboxamide

[1040]

[1041] (2R)-1-(4-(4-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-carbonyl)pyrrolidine-2-carboxamide hydrochloride (220 mg, 0.3 mmol), DIEA (387 mg, 3.0 mmol), and DCM (6 mL) were added to the reaction flask, followed by acryloyl chloride (27 mg, 0.3 mmol). The reaction was carried out at room temperature for 0.5 h until it was complete. Quenching with 10 mL saturated sodium bicarbonate, diluting with 20 mL water, extracting with 50 mL dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (MeOH / DCM = 5%) to obtain the crude product. Further purification by reverse-phase column chromatography (MeOH / NH4HCO3: 0-70%) yielded (2R)-1-(4-(4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-1-hydropyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohex-3-en-1-carbonyl)pyrrolidine-2-carboxamide (16.8 mg), m / z = 594 [M+1]. + .

[1042] 1 HNMR (400MHz, DMSO-d6): δ12.69(brs,1H),8.73(s,1H),8.65(s,1H),8.10(d,J=8 .8Hz,1H),7.68-7.52(m,2H),7.30-7.08(m,2H),6.90-6.85(m,2H),6.52-6.48(m, 1H),6.15(d,J=16.8Hz,1H),5.76-5.73(m,1H),4.42-4.10(m,1H),3.80-3.48(m, 10H),2.80-2.67(m,2H),2.49-2.30(m,3H),2.10-1.79(m,5H),1.76-1.56(m,1H).

[1043] Example 88: Preparation of Compound 88

[1044] Step A: 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-3-(4-methylpyrimidin-2-yl)urea

[1045]

[1046] 2-Fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)aniline (200 mg, 0.8 mmol), DCM (5 mL), and p-nitrophenyl chloroformate (202 mg, 1.0 mmol) were added sequentially to a reaction flask. The mixture was reacted at 25 °C for 2 h. The solvent was directly evaporated to dryness. The crude product was dissolved in pyridine (5 mL), and 4-methylpyrimidin-2-amine (109 mg, 1.0 mmol) was added. The mixture was reacted at 100 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 160 mg of the product, m / z = 373 [M+1]. + .

[1047] Step B:

[1048] N-(4-methylpyrimidin-2-yl)-N'-(2-fluoro-4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)phenyl)urea

[1049]

[1050] 3-Iodo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (140 mg, 0.43 mmol), 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]-3-(4-methylpyrimidin-2-yl)urea (160 mg, 0.43 mmol), K₂CO₃ (118 mg, 0.85 mmol), Pd(dppf)Cl₂ (31 mg, 0.04 mmol), dioxane (3 mL), and water (0.5 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 7.1 mg of the product, m / z = 447 [M+1]. + .

[1051] 1 H-NMR(400MHz,DMSO-d6)δ12.85(s,1H),12.20-12.21(m,1H),10.34(s,1H),8.48-8.56(m,2H),8.37-8.41( m,1H),7.99-8.03(m,2H),7.55-7.65(m,1H),6.99-7.09(m,3H),4.30-4.32(m,2H),1.48-1.50(m,3H),1.24

[1052] Example 89: Preparation of Compound 89

[1053] Step A: 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-3-(3-methylphenyl)urea

[1054]

[1055] 2-Fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)aniline (200 mg, 0.8 mmol) and DCM (5 mL) were added sequentially to a reaction flask. TEA (172 mg, 1.7 mmol) and triphosgene (105 mg, 0.3 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 0.5 h. Then, 3-methylaniline (86 mg, 0.8 mmol) was added, and the reaction was carried out at 25 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 76 mg of the product. m / z = 371 [M+1] + .

[1056] Step B: N-(3-methylphenyl)-N'-(2-fluoro-4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)phenyl)urea

[1057]

[1058] 3-Iodo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (67 mg, 0.2 mmol), 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]-3-(3-methylphenyl)urea (76 mg, 0.2 mmol), K₂CO₃ (55 mg, 0.4 mmol), Pd(dppf)Cl₂ (14 mg, 0.02 mmol), dioxane (3 mL), and water (0.5 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 10 mg of the product, m / z = 445 [M+1]. + .

[1059] 1H-NMR(400MHz,DMSO-d6)δ12.83(s,1H),9.04(s,1H),8.66-8.67(m,1H),8 .48-8.50(m,1H),8.26-8.30(m,1H),7.93-7.97(m,2H),7.33(s,1H),7.25 -7.27(m,1H),7.17-7.21(m,1H),7.08-7.11(m,1H),6.98-7.00(m,1H),6. 82-6.84(m,1H),4.28-4.34(m,3H),2.31-2.31(m,3H),1.47-1.51(m,2H).

[1060] Example 90: Preparation of Compound 90

[1061] Step A: 3-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-1-(pyrimidin-2-yl)urea

[1062]

[1063] 2-Fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)aniline (200 mg, 0.8 mmol), DCM (5 mL), and p-nitrophenyl chloroformate (202 mg, 1.0 mmol) were added sequentially to a reaction flask. The mixture was reacted at 25 °C for 2 h. The solvent was evaporated to dryness, and the crude product was dissolved in pyridine (5 mL). Then, pyrimidine-2-amine (95 mg, 1.0 mmol) was added, and the mixture was reacted at 100 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 140 mg of product, m / z = 359 [M+1]. + .

[1064] Step B: N-(pyrimidin-2-yl)-N'-(2-fluoro-4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)phenyl)urea

[1065]

[1066] 3-Iodo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (130 mg, 0.39 mmol), 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-3-(pyrimidin-2-yl)urea (140 mg, 0.39 mmol), K₂CO₃ (101 mg, 0.78 mmol), Pd(dppf)Cl₂ (28 mg, 0.04 mmol), dioxane (3 mL), and water (0.5 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 2.1 mg of the product, m / z = 433 [M+1]. + .

[1067] Example 91: Preparation of Compound 91

[1068] Step A: 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-3-(propane-2-yl)urea

[1069]

[1070] 2-Fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)aniline (250 mg, 1.1 mmol) and DCM (5 mL) were added to a reaction flask. TEA (213 mg, 2.1 mmol) and triphosgene (110 mg, 0.4 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 0.5 h. Propyl-2-amine (62 mg, 1.1 mmol) was then added, and the reaction was carried out at 25 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 100 mg of product, m / z = 323 [M+1]. + .

[1071] Step B: N-(propane-2-yl)-N'-(2-fluoro-4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)phenyl)urea

[1072]

[1073] 3-Iodo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (100 mg, 0.3 mmol), 1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]-3-(propane-2-yl)urea (100 mg, 0.3 mmol), K₂CO₃ (83 mg, 0.6 mmol), Pd(dppf)Cl₂ (22 mg, 0.03 mmol), dioxane (3 mL), and water (0.5 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 16.3 mg of the product, m / z = 397 [M+1]. + .

[1074] 1 H-NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.47-8.49(m,1H),8.23-8.27(m,2H),7.87-7.90(m,2H),7.07-7.10(m,1H) ,6.97-6.99(m,1H),6.57-6.59(m,1H),4.29-4.30(m,2H),3.78-3.79(m,1H),1.45-1.48(m,3H),0.86-0.88(m,6H).

[1075] Example 92: Preparation of compound 92

[1076] Step A: 3-(2-fluoro-4-aminophenyl)-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[1077]

[1078] 3-Iodo-4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (1 g, 3 mmol), 2-fluoro-4-(tetramethyl-1,3,2-dioxaborane-2-yl)aniline (0.7 g, 0.3 mmol), K₂CO₃ (830 mg, 6 mmol), Pd(dppf)Cl₂ (0.2 g, 0.3 mmol), dioxane (10 mL), and water (2 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into 50 mL of water, extracted with EA, dried the organic phase, evaporated the solvent, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 150 mg of product, m / z = 312 [M+1]. + .

[1079] Step B: N-(2-fluoro-4-(4-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-3-yl)phenyl)-2-pyrimidinamide

[1080]

[1081] 4-{12-ethoxy-4,5,7,8-tetraazatricyclo[6.4.0.0^{2,6}]dodecyl-1,3,6,9,11-pentan-3-yl}-2-fluoroaniline (50 mg, 0.2 mmol), methyl pyrimidine-2-carboxylate (2 mg, 0.2 mmol), and toluene (3 mL) were added to a reaction flask. Trimethylaluminum (1 M, 0.2 mL, 0.2 mmol) was added at 0 °C. After naturally warming to room temperature, the mixture was heated to 105 °C for 16 h. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 21.3 mg of product, m / z = 418 [M+1]. +1 .

[1082] H-NMR(400MHz,DMSO-d6)δ12.95(s,1H),10.55(s,1H),9.09-9.10(m,2H),8.50-8.54(m,1H),8.18-8.22(m,1H),8 .05-8.07(m,2H),7.79-7.82(m,1H),7.10-7.13(m,1H),7.00-7.02(m,1H),4.29-4.35(m,2H),1.48-1.51(m,3H).

[1083] Example 93: Preparation of Compound 93

[1084] Step A: 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethane sulfonate

[1085]

[1086] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (400 mg, 4.7 mmol), p-toluenesulfonic acid monohydrate (13.8 mg, 0.07 mmol), and tetrahydrofuran (15 mL) were added to a reaction flask. The reaction was carried out at 60 °C for 2 h. TLC showed that the reaction was complete. The reaction solution was directly concentrated and column chromatography (PE / EA = 10%) to give 1.4 g of product, m / z = 469, 471 [M+1]. + .

[1087] Step B: N-(4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide

[1088]

[1089] 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethane sulfonate (600 mg, 1.28 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acrylamide (385 mg, 1.4 mmol), Pd(dppf)Cl2 (93.5 mg, 0.128 mmol), cesium carbonate (1.25 g, 3.84 mmol), dioxane (6 mL) / H2O (1.2 mL) were added to the reaction flask. The mixture was purged with nitrogen three times and reacted at 80 °C for 1 h. The reaction solution was directly concentrated and subjected to column chromatography (PE / EA = 20%) to obtain 310 mg of product, m / z = 466 [M+1]. + .

[1090] Step C: N-(4-(6-(3-acrylamido-4-(tetrahydropyrrole-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide

[1091]

[1092] N-(4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide (100 mg, 0.214 mmol) and N-(2-(tetrahydropyrrole-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acrylamide (87.6 mg, 0.214 mmol) were added to the reaction flask. 118 mmol), Pd(dppf)Cl2 (15.7 mg, 0.0214 mmol), cesium carbonate (210 mg, 0.321 mmol), dioxane (0.5 mL), H2O (0.1 mL), nitrogen purged three times, reacted at 100 °C for 1 h, TLC showed complete reaction, the reaction solution was directly concentrated, and column chromatography (PE / EA = 1) gave 100 mg of product, m / z = 630 [M+1] + .

[1093] Step D: N-(4-(6-(3-acrylamido-4-(pyrrolidine-1-carbonyl)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide

[1094]

[1095] N-(4-(6-(3-acrylamido-4-(tetrahydropyrrole-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide (100 mg, 0.159 mmol), TFA (44 mg, 0.15 mmol), and DCM (0.2 mL) were added to the reaction flask. The reaction was carried out at room temperature for 1 h. The reaction solution was directly concentrated, diluted with water (50 mL), and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. Column chromatography (PE / EA = 1) was performed to obtain 20 mg of product, m / z = 546 [M+1]. + .

[1096] 1 H NMR(400MHz,DMSO-d6)δ12.79(brs,1H),10.16(s,1H),10.08(s,1H),8.21(s,1H),7.99-7.87(m,4H),7.84-7.66(m,2H),7.52(d,2H), 6.58-6.44(m,1H),6.28(d,2H),6.78(d,1H),3.54-3.42(m,2H),2.48-2.32(m,2H),1.95-1.74(m,4H),1.23(s,1H),1.18-1.11(m,3H).

[1097] Example 94: Preparation of Compound 94

[1098] Step A: 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-yltrifluoromethanesulfonate

[1099]

[1100] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (20 g, 0.08 mol), 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (34.3 g, 0.096 mol), and DMF (250 mL) were added to the reaction flask. The reaction solution was cooled to 0 °C, and DIEA (31 g, 0.24 mol) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed overnight at 0 °C. The reaction solution was poured into water, filtered, and the filter cake was washed three times with water. The crude product was purified by column chromatography (PE / EA = 4:1) to obtain 5 g of product, m / z = 384 [M+1]. +

[1101] Step B: 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[1102]

[1103] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yltrifluoromethanesulfonate (5 g, 0.013 mol) and THF (50 mL) were added to a reaction flask, followed by p-toluenesulfonic acid monohydrate (49.4 mg, 0.4 mmol). The reaction mixture was reacted overnight at 60 °C. The reaction solution was evaporated to dryness and concentrated by column chromatography (PE / EA = 4:1) to give 5 g of product, m / z = 469 [M+1]. +

[1104] Step C: (4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate

[1105]

[1106] 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (5 g, 10.7 mmol), N-[4-(tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]carbamate tert-butyl ester (3.4 g, 10.7 mmol), cesium carbonate (10.4 g, 32.1 mmol), and Pd(dppf)Cl2 (780 mg, 1.07 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL) in a reaction flask. The reaction was carried out at room temperature under nitrogen for 1 hour, and TLC showed that the reaction was complete. The reaction solution was evaporated to dryness, and the product was separated and concentrated by column chromatography (PE / EA = 4:1) to give 4.2 g of product, m / z = 512 [M+1]. +

[1107] Step D: 4-(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-3-nitrobenzoate

[1108]

[1109] (4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate (2 g, 4 mmol), [4-(methoxycarbonyl)-2-nitrophenyl]boronic acid (896 mg, 4 mmol), cesium fluoride (1.824 g, 12 mmol), and Pd(dppf)Cl2 (292 mg, 0.4 mmol) were added to a reaction flask, dissolved in 1,4-dioxane (20 mL) and water (2 mL). The reaction was carried out at 90 °C under nitrogen for 7 hours, and TLC showed that the reaction was complete. The reaction solution was directly evaporated to dryness, and the product was separated and concentrated by column chromatography (PE / EA = 4:1) to obtain 1.45 g of product, m / z = 613 [M+1]. +

[1110] Step E: 4-(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)-3-nitrobenzoic acid

[1111]

[1112] 1.4 g (2.3 mmol) of methyl 4-(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-3-nitrobenzoate was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (20 mL, 5 / 3 / 1), followed by the addition of lithium hydroxide hydrate (192 mg, 4.6 mmol). The reaction was carried out at room temperature for 1 hour. The pH was adjusted to less than 7 with 1% citric acid aqueous solution, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give 1.4 g of the product, m / z = 599 [M+1]. +

[1113] Step F: (4-(6-(2-nitro-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate

[1114]

[1115] 4-(4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)-3-nitrobenzoic acid (1.4 g, 2.3 mmol), pyrrolidine (500 mg, 6.9 mmol), and triethylamine (697 mg, 6.9 mmol) dissolved in dichloromethane (10 mL) were added to the reaction flask. PyBOP (1.83 g, 3.45 mmol) was then added, and the reaction was allowed to proceed overnight at room temperature. TLC showed that the reaction was complete. The reaction solution was evaporated to dryness, and the product was separated and concentrated by column chromatography (PE / EA = 4:1) to obtain 1.7 g of product, m / z = 652 [M+1]. +

[1116] Step G: (4-(6-(2-amino-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate

[1117]

[1118] (4-(6-(2-nitro-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate (1.7 g, 2.6 mmol) and ammonium chloride (167 mg, 3.1 mmol) were added to a reaction flask, dissolved in ethanol (20 mL) and water (2 mL). Iron powder (116 mg, 2.08 mmol) was then added, and the reaction was carried out at 50 °C for 2 hours. The reaction solution was filtered, and the residue was washed three times with dichloromethane. The organic phase was concentrated, and the product was separated and concentrated by column chromatography (DCM / MeOH = 10:1) to obtain 1.04 g of product, m / z = 622 [M+1]. +

[1119] Step H: 4-(6-(2-acrylamido-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate

[1120]

[1121] (4-(6-(2-amino-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate (500 mg, 0.8 mmol) and DIEA (309.6 mg, 2.4 mmol) dissolved in dichloromethane (5 mL) were added to the reaction flask and cooled to 0 °C. Acryloyl chloride (72.8 mg, 0.8 mmol) dissolved in 2 mL of dichloromethane was added dropwise to the reaction solution. After the addition was complete, the reaction was carried out at 0 °C for 1 hour. A small amount of methanol was added to the reaction solution, followed by water. The mixture was extracted with dichloromethane / methanol (20 mL, 3 / 1), and the organic phase was concentrated to obtain 500 mg of product, m / z = 676 [M+1]. +

[1122] Step I: N-(2-(4-(4-aminophenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-(pyrrolidine-1-carbonyl)phenyl)acrylamide

[1123]

[1124] 4-(6-(2-acrylamido-4-(pyrrolidine-1-carbonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)tert-butyl carbamate (500 mg, 0.74 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (3 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and the pH was adjusted to greater than 7 with 0.5 N NaOH solution. Extraction was performed using dichloromethane / methanol (20 mL, 3 / 1). The organic phase was evaporated to dryness and subjected to column chromatography (DCM / MeOH = 10:1) to obtain 70 mg of the product, m / z = 492 [M+1]. +

[1125] Step J: N-(4-(6-(2-acrylamido-4-(pyrrolidine-1-carbonyl)phenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)acrylamide

[1126]

[1127] N-(2-(4-(4-aminophenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-(pyrrolidine-1-carbonyl)phenyl)acrylamide (10 mg, 0.02 mmol) and DIEA (8 mg, 0.06 mmol) were added to a reaction flask in a mixed solvent of dichloromethane (3 mL) and DMF (1 mL). The mixture was cooled to 0 °C, and acryloyl chloride (2 mg, 0.02 mmol, dissolved in 1 mL dichloromethane) was added dropwise. The reaction was continued at 0 °C until the starting material disappeared. The reaction was quenched with methanol in an ice bath, concentrated under reduced pressure, purified by reverse column chromatography (TFA / MeCN), and lyophilized to give 4 mg of the product, m / z = 546 [M+1]. +

[1128] 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.85(s,1H),8.89(s,1H),7.95-7.93(m,2H ),7.90(s,1H),7.88-7.85(m,1H),7.84-7.82(m,1H),7.75(s,1H),7.67(d,1H),7. 54-7.45(m,2H),6.56-6.48(m,1H),6.47-6.37(m,1H),6.35-6.17(m,2H),5.86-5 .78(m,1H),5.77-5.67(m,1H),1.89-1.82(m,4H),1.52(s,1H),1.30-1.18(m,4H).

[1129] Example 95: Preparation of Compound 95

[1130] Step A: N-(4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)propionamide

[1131]

[1132] 6-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl-trifluoromethanesulfonate (0.3 g, 0.64 mmol), N-[4-(tetramethyl-1,3,2-dioxaborane-2-ester)phenyl]propionamide (176 mg, 0.64 mmol), cesium carbonate (624 mg, 1.92 mmol), dioxane (3 mL), and water (0.6 mL) were added to the reaction flask. The mixture was purged with nitrogen three times, and Pd(dppf)Cl2 (46.8 mg, 0.064 mmol) was added. The reaction was carried out at 80 °C for 1 h. TLC showed that the reaction was complete. The reaction solution was directly filtered and concentrated, and column chromatography (PE / EA = 10%) yielded 200 mg of product, m / z = 466, 468 [M+1]. + .

[1133] Step B: N-(5-(4-(4-phenylpropionamide)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)-2-(pyrrolidine-1-carbonyl)phenyl)acrylamide

[1134]

[1135] Add N-(4-(6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)phenyl)propionamide (0.15 g, 0.32 mmol) and N-(2-(tetrahydropyrrole-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acrylamide (0.12 g) to the reaction flask. The following solutions were added: 0.32 mmol of cesium carbonate (312 mg, 0.963 mmol), 1.5 mL of dioxane, and 0.3 mL of H₂O. The mixture was purged with nitrogen three times, and then Pd(dppf)Cl₂ (23.4 mg, 0.032 mmol) was added. The mixture was reacted at 80 °C for 1 h. The reaction solution was directly filtered and concentrated, and column chromatography (PE / EA = 1) was performed to obtain 150 mg of the product, m / z = 630 [M+1]. + .

[1136] Step C: N-(5-(4-(4-phenylpropionamide)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-2-(pyrrolidine-1-carbonyl)phenyl)acrylamide

[1137]

[1138] N-(5-(4-(4-phenylpropionamide)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,4]pyrazol[1,5-a]pyridin-6-yl)-2-(pyrrolidine-1-carbonyl)phenyl)acrylamide (150 mg, 0.238 mmol), TFA (0.7 mL), and DCM (1.5 mL) were added to the reaction flask. The reaction was carried out at room temperature for 1 h. The reaction solution was directly concentrated and subjected to column chromatography (PE / EA = 1) to give 45.3 mg of product, m / z = 548 [M+1]. + .

[1139] 1 H NMR(400MHz,DMSO-d6)δ12.79(brs,1H),10.44(s,1H),10.08(s,1H),9.19(s,1H),8.21(s,1H),7.97(s,1H),7.86-7.6 8(m,3H),7.54(d,1H),6.66-6.44(m,2H),6.42-6.18(m,2H),3.56-3.44(m,2H),1.94-1.76(m,4H),1.26-1.22(m,1H).

[1140] Example 96: Preparation of Compound 96

[1141] Step A: N-(2-(4-(4-propamidophenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-(pyrrolidine-1-carbonyl)phenyl)acrylamide

[1142]

[1143] N-(2-(4-(4-aminophenyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)-5-(pyrrolidine-1-carbonyl)phenyl)acrylamide (35 mg, 0.07 mmol) and DIEA (27 mg, 0.21 mmol) were added to a reaction flask in a mixed solvent of dichloromethane (3 mL) and DMF (1 mL). The mixture was cooled to 0 °C, and propionyl chloride (6.5 mg, 0.07 mmol, dissolved in 1 mL of dichloromethane) was added dropwise. The reaction was continued at 0 °C until the starting material disappeared. The reaction was quenched with methanol in an ice bath, concentrated under reduced pressure, purified by reverse column chromatography (TFA / MeCN), and lyophilized to give 7.5 mg of the product, m / z = 548 [M+1]. +

[1144] 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),10.14(s,1H),9.83(s,1H),8.88(s,1H),7.93-7.76(m,4H),7.75-7.61(m,2H),7.53-7.42(m,1H),6. 46-6.35(m,1H),6.27-6.16(m,1H),5.73(s,1H),3.56-3.46(m,4H),2 .43-2.29(m,2H),1.96-1.79(m,4H),1.52(d,2H),1.16-1.06(t,3H).

[1145] Example 97: Preparation of Compound 97

[1146] Step A: (4-(3-iodo-4-(4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone

[1147]

[1148] (4-(3-iodo-4-(4-methoxybenzyl)oxy)-1H-pyrazol[3,4:3,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone (350 mg, 0.59 mmol), TsOH (102 mg, 0.59 mmol), DHP (74 mg, 0.88 mmol), and THF (4 mL) were added sequentially to the reaction flask, and the mixture was heated to 50°C and reacted for 3 hours. The reaction was monitored by LCMS until complete, and the product was purified by column chromatography (dichloromethane / methanol = 30 / 1) after concentration to obtain 560 mg of product. m / z = 682 [M+H] + .

[1149] Step B: 4-(4-methoxybenzyloxy)-3-(2-phenylcyclopropyl)-1-(tetrahydropyran-2-yl)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone

[1150]

[1151] The following ingredients were added sequentially to the reaction flask: (4-(3-iodo-4-(4-methoxybenzyl)oxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol[3',4':3,,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone (500 mg, 0.74 mmol), 4,4,5,5-tetramethyl-2-(2-phenylcyclopropyl)-1,3,2-dioxaborane (270 mg, 1.1 mmol), PdCl2(dppf) (66 mg, 0.08 mmol), Ag2O (19 mg, 0.08 mmol), Cs2CO3 (724 mg, 2.22 mmol), 1,4-dioxane (11 mL), and water (4 mL). The reaction was carried out at 110 °C for 1.5 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the organic phase was separated, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 100 mg of product.

[1152] m / z = 672[M+H] + .

[1153] Step C: 3-(2-phenylcyclopropyl)-6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-enyl)-1-(trifluoromethanesulfonyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yltrifluoromethanesulfonate

[1154]

[1155] 4-(4-methoxybenzyloxy)-3-(2-phenylcyclopropyl)-1-tetrahydropyran-2-yl-1H-pyrazol[3,4:3,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone (100 mg, 0.15 mmol), DCM (7 mL), and DMOB (104 mg, 0.75 mmol) were added sequentially to the reaction flask. After cooling in an ice bath, TFA (3 mL) was added, and the reaction solution was reacted at room temperature for 1 hour. The reaction was monitored by TLC until complete, and the solution was concentrated to dryness to obtain the crude intermediate. After dissolving in DMF (4 mL), DIEA (155 mg, 1.2 mmol) was added, and PhN(Tf)2 (215 mg, 0.6 mmol) was added under ice bath cooling. After stirring at room temperature for 48 hours, the reaction solution was reacted at 50 degrees Celsius for 2 hours. The reaction was monitored by LCMS until complete. Water (4 mL) was added, and the mixture was extracted with ethyl acetate (10 mL), concentrated to dryness, and purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain 62 mg of product.

[1156] m / z = 732[M+H] + .

[1157] Step D: 1-(4-(5-(3-(2-phenylcyclopropyl)-6-(4-(pyrrolidine-1-carbonyl)cyclohexen-1-en-1-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1158]

[1159] 3-(2-phenylcyclopropyl)-6-(4-(pyrrolidine-1-carbonyl)cyclohexyl-1-enyl)-1-(trifluoromethanesulfonyl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yltrifluoromethanesulfonate (44 mg, 0.126 mmol), PdCl2 (dppf), DCM (8 mg, 0.009 mmol), CsF (41 mg, 0.252 mmol), and 1,4-dioxane (3 mL) were added sequentially to the reaction flask. The mixture was heated to 60°C for 2.5 h under nitrogen protection. The reaction was monitored for completeness by LCMS. After cooling, saturated brine (3 mL) was added, and the mixture was extracted with ethyl acetate (8 mL). The organic phase was concentrated to obtain the crude intermediate. Methanol (6 mL) and an aqueous solution of potassium carbonate (2 mL, 0.42 mmol) were added, and the mixture was reacted at 60°C for 1.5 h. The reaction was monitored by LCMS until complete. After cooling, DCM (10 mL) and sodium hydroxide aqueous solution (0.1 N, 3 mL) were added. The organic phase was separated and washed successively with saturated ammonium chloride and saturated brine. The organic phase was concentrated and purified by reverse preparative purification (acetonitrile-0.5% TFA aqueous solution) to obtain 1.1 mg of product. m / z = 667 [M+H] + .

[1160] 1 H-NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.72(s,1H),8.45-8.46(m,1H), 7.82-7.85(m,1H),7.43(s,1H),7.15-7.24(m,3H),6.86-6.93(m,3H),6. 77-6.79(m,1H),6.45(s,1H),6.17-6.21(m,1H),5.74-5.77(m,1H),3.33 -3.80(m,15H),2.18-2.21(m,1H),1.75-2.05(m,9H),1.48-1.70(m,3H).

[1161] Example 98: Preparation of Compound 98

[1162] Step A: (4-(4-methoxybenzyl)oxy)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone

[1163]

[1164] 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridine (372 mg, 1.0 mmol), pyrrolidone-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclohexane-3-en-1-yl) methyl ketone (305 mg, 1.0 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), K2CO3 (414 mg, 3.0 mmol), 1,4-dioxane (6 mL), and water (3 mL) were added sequentially to the reaction flask. The reaction was carried out at 90°C for 16 hours under nitrogen protection. After cooling, the organic phase was separated, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 103 mg of product.

[1165] m / z = 472[M+H] + .

[1166] Step B: (4-(3-iodo-4-(4-methoxybenzyl)oxy)-1H-pyrazole[3,4:3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone

[1167]

[1168] (4-(4-methoxybenzyl)oxy)-1H-pyrazol[3,4:3,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone (763 mg, 1.62 mmol), DMF (15 mL), and NIS (437 mg, 1.94 mmol) were added sequentially to the reaction flask. The reaction solution was reacted at room temperature for 4 hours. The reaction was monitored by LCMS until complete. Water (70 mL) was added to the reaction solution with stirring. The mixture was filtered, and the filter cake was collected and purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain 566 mg of product.

[1169] m / z = 598[M+H] + .

[1170] Step C: (Z)-(4-(4-methoxybenzyl)oxy)-3-styryl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)(pyrrolidine-1-yl)methyl ketone

[1171]

[1172] The following ingredients were added sequentially to the reaction flask: (4-(3-iodo-4-(4-methoxybenzyl)oxy)-1H-pyrazol[3,4:3,4]pyrazol[1,5-a]pyridin-6-yl)cyclohexyl-3-en-1-yl)pyrrolidine-1-methyl ketone (200 mg, 0.33 mmol), 4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborane (115 mg, 0.50 mmol), PdCl2(dppf) (24 mg, 0.033 mmol), K2CO3 (138 mg, 1.0 mmol), 1,4-dioxane (2 mL), and water (1 mL). The reaction was carried out at 100 °C for 3 hours under nitrogen protection. The reaction was monitored by LCMS until complete. After cooling, the organic phase was separated, concentra...

Claims

1. The compound represented by formula (I), its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs: in, A is selected from 5-14 heteroaryl groups; B is selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3); E does not exist or is selected from C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3); Each R a They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl, -OR1, -N(R2)(R3); each R a1 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a2 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl, -OR1, -N(R2)(R3); each R a2 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a3 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, -OR1, -N(R2)(R3), -C(O)NH2; each R a3 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), -C(O)NH2, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl, C 1-10 Alkyl-3-14-membered heterocyclic groups, -OR1, -N(R2)(R3); Each R b They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. b1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkyne group, -OR1, -N(R2)(R3); each R b1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, -OR1, -N(R2)(R3); Each R e They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. e1 The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 6-14 Aryl, -S(O)2-C 1-10 Alkyl, -OR1, -N(R2)(R3); each R e1 They may be the same or different, and are independently selected from halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, 5-14 membered heteroaryl, -OR1, -N(R2)(R3); L1 is absent or selected from no substitution or is optionally replaced by one, two or more Rs. L1 The following groups are substituted: C 2-10 alkenyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic; each R L1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl groups, -OR1, -N(R2)(R3); L2 is absent or selected from O, NH, C(O), -NHC(O)-, -NHC(O)NH-, N(C 1-6 alkyl); Each R1, R2, and R3 may be the same or different, and is independently selected from H, without substitution, or arbitrarily determined by one, two, or more Rs. r The following groups are substituted: C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl; Each R r They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, 3-14 membered heterocyclic, 5-14 membered heteroaryl; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2, 3, 4 or 5.

2. The compound, its tautomers, stereoisomers, isotope-labeled derivatives, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Cycle A is selected from 9-12 heteroaryl groups; Preferably, ring A is selected from Preferably, Selected from Preferably, each R a They may be the same or different, and are independently selected from H, halogens, unsubstituted, or optionally composed of one, two, or more R atoms. a1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, OH; each R a1 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a2 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -OR1, -N(R2)(R3); each R a2 They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. a3 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, -OR1, -N(R2)(R3), -C(O)NH2; each R a3 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), -C(O)NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 1-6 Alkyl-3-8-membered heterocyclic groups, -OR1, -N(R2)(R3); Preferably, each R a They may be the same or different, and are independently selected from H, halogens, unsubstituted, or optionally composed of one, two, or more R atoms. a1 The following groups are substituted: OH, methyl, methoxy, ethoxy, vinyl, propynyl, cyclopropyl, cyclohexyl, benzyloxy, phenyl, monofluoroethoxy, difluoroethoxy, piperazine, pyrazolyl, pyranyl, tetrahydropyranyl, pyridyl, cyclohexenyl, aziridine, and aziridine. Preferably, each R a They may be the same or different, and are independently selected from H, Cl, OH, methoxy, ethoxy, cyclopropyl, benzyloxy, phenyl, pyridyl, monofluoroethoxy, difluoroethoxy, 3. The compound, its tautomers, stereoisomers, isotope-labeled derivatives, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs according to claim 1 or 2, characterized in that, B is selected from C. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 5-10 heterocyclic, 5-10 heteroaryl; Preferably, B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, piperidinyl, cyclohexenyl, benzimidazolyl, indolyl, tetrahydropyranyl, etc. Preferably, B is selected from Preferably, each R b They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. b1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -OR1, -N(R2)(R3); each R b1 They may be the same or different, and are independently selected from H, halogens, OH, CN, NH2, oxo (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, -OR1, -N(R2)(R3); Preferably, each R b They are either the same or different, and are independently selected from H, F, Cl, OH, NH2, methyl, methoxy, trifluoromethyl, ethynyl, -C(O)NH2; Preferably, when R b If it is not H, Selected from 4. The compound, its tautomer, stereoisomer, isotope label, hydrate, solvate, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-3, characterized in that, E does not exist or is selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-8 membered heteroaryl, -OR1, -N(R2)(R3); Preferably, E is absent or selected from ethyl, propyl, propenyl, 2-butenyl, pyrimidinyl, cyclobutyl, monoheterocyclobutyl, phenyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyridinyl, morpholinyl, Preferably, each R e They may be the same or different, and are independently selected from H, halogen, OH, CN, NH2, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R. e1 The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, -S(O)2-C 1-6 Alkyl, -OR1, -N(R2)(R3); each R e1 They may be the same or different, and are independently selected from halogens, OH, CN, NH2, oxo (=O), and C. 1-6 Alkyl, -OR1, -N(R2)(R3), pyrimidinyl; Preferably, It does not exist or is selected from CN, methyl, isopropyl, tetrahydropyrrolyl, morpholinyl, 5. The compound, its tautomer, stereoisomer, isotope label, hydrate, solvate, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-4, characterized in that, L1 is absent or selected from no substitution or is optionally replaced by one, two or more Rs. L1 The following groups are substituted: C 2-6 alkenyl, C 1-6 Alkyl, 5-10 heteroaryl; each R L1 They may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy; Preferably, L1 is absent or selected from unsubstituted or optionally substituted by one, two or more R L1 The following groups are substituted: vinyl, ethoxy, pyrazolyl; each R L1 They may be the same or different, and are independently selected from H, F, and methoxy groups; Preferably, L1 is absent or selected from Preferably, L2 is absent or selected from O, NH, C(O), -NHC(O)-, -NHC(O)NH-, and N(CH3).

6. The compound, its tautomer, stereoisomer, isotope label, hydrate, solvate, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-5, characterized in that, The compound shown in formula (I) has the following structure: Among them, rings B, E, and R a R b R e L1, L2, m, n, and p have the definitions described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the following structure: Among them, rings E and R a R b R e L2, n, p have the definition of any one of claims 1-5, X1, X2, X3, X4 are the same or different, are independently selected from N or CH, and at most two are selected from N.

7. The compound, its tautomer, stereoisomer, isotope label, hydrate, solvate, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-6, characterized in that, The compound shown in formula (I) is selected from the following compounds:

8. A method for preparing the compound of any one of claims 1-7, its tautomers, stereoisomers, isotope-labeled derivatives, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, said preparation method comprising the following steps: The following compound 1 was reacted with compound 2 to obtain the compound shown in formula (I); Among them, rings A, B, E, and R a R b R e L1, L2, m, n, p have the definitions described in any one of claims 1-7; X is selected from leaving groups, such as halogens.

9. A pharmaceutical composition comprising the compound of any one of claims 1-7, its tautomer, stereoisomer, isotope label, hydrate, solvate, pharmaceutically acceptable salt, or prodrug.

10. The use of the compound of any one of claims 1-7, its tautomers, stereoisomers, isotope-labeled compounds, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a medicament; Preferably, the pharmaceutical composition or the drug is used to treat tumors, such as cancer; Preferably, the drug is an FGFR inhibitor; Preferably, the tumor includes, but is not limited to, at least one of the following: sarcoma, myeloma, lymphoma, melanoma, brain tumor, spinal cord tumor, and germ cell tumor; Preferably, the cancer includes, but is not limited to, at least one of the following: urothelial carcinoma, breast cancer, endometrial cancer, squamous cell carcinoma of the lung, ovarian cancer, bile duct cancer, lymphoma, blood cancer (such as leukemia), stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, lung cancer, central nervous system cancer, cervical cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer.

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