Cycloalkyl or heterocyclyl substituted heteroaryl compounds and compositions and uses thereof

Abstract

The present invention relates to compounds of formula (I) or their tautomers, stereoisomers, prodrugs, crystalline forms, pharma- ceutically acceptable salts, hydrates, or solvates, pharmaceutical compositions thereof, and uses of said compounds, their tautomers, stereoisomers, prodrugs, crystalline forms, pharma- ceutically acceptable salts, hydrates, or solvates, and said pharmaceutical compositions in the treatment and / or prevention of wild-type and / or mutant BTK kinase mediated diseases. TIFF2025508964000279.tif8460(I)

Description

[Technical field]

[0001] The present disclosure belongs to the technical field of medicine. The present disclosure relates to highly selective substituted cycloalkyl or heterocyclyl substituted heteroaryl compounds, especially those having inhibitory effect against Bruton's tyrosine kinase (BTK) and its C481 mutation, pharmaceutical compositions containing the same, and preparation methods and uses thereof. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) belongs to the Tec family of cytoplasmic tyrosine kinases, which is the second largest non-receptor kinase family in humans. It is expressed in all cell lineages of the hematopoietic system (except T cells) and is present in bone marrow, spleen, and lymph nodes. Inactivating mutations in the gene encoding Btk cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (XID) in mice. These two diseases are characterized by severe defects in B cell development and function, suggesting that Btk plays a crucial role for B cell development and function. Furthermore, constitutive activation of Btk in B cells leads to the accumulation of autoreactive plasma cells. Preclinical studies have shown that Btk-deficient mice are resistant to the development of collagen-induced arthritis. Furthermore, clinical studies of Rituxan, a CD20 antibody that exhausts mature B cells, have revealed the important role of B cells in many inflammatory diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Furthermore, aberrant activation of Btk plays an important role in the pathogenesis of B cell lymphoma, suggesting that Btk inhibition may be used to treat hematological malignancies.

[0003] Ibrutinib, a covalent Btk inhibitor, has been approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM) and chronic graft-versus-host disease (cGVHD). Despite its excellent efficacy and universal tolerability, adverse events associated with Btk insufficiency that are not commonly observed in patients (e.g., bleeding, nausea and diarrhea) have been reported.

[0004] These ibrutinib-related side effects are believed to be primarily related to off-target effects of ibrutinib, which has been shown to inhibit EGFR and Tec. Targeting EGFR can cause significant skin toxicity and gastrointestinal side effects, as the EGFR signaling cascade contributes to the biology of the skin and gastrointestinal system. Both Btk and Tec belong to the Tec family of kinases. Platelets express Btk and Tec, which play a role downstream of glycoprotein VI (GPVI) signaling. Tec compensates for the lack of Btk in signaling downstream of GPVI in rat platelets. Inhibition of Tec kinase by ibrutinib may prevent platelet aggregation and contribute to the observed bleeding. Therefore, Btk inhibitors with high BTK inhibition and low EGFR and Tec inhibition are needed to reduce or avoid bleeding, eczema, and diarrhea.

[0005] Ibrutinib also binds irreversibly to interleukin-2-inducible tyrosine kinase (ITK). ITK plays a key role in the natural killer function of FcR-stimulated NK cells, which is necessary for antibody-dependent NK cell-dependent cytotoxicity (ADCC). Today, ADCC is the standard treatment for B-cell malignancies when anti-CD20 antibodies, e.g., rituximab, are combined with chemotherapy, so it would be desirable to have a Btk inhibitor with higher Btk selectivity than ITK.

[0006] Irreversible and covalent reversible BTK inhibitors specifically target the cysteine ​​residue C481 of Btk. Primary and secondary drug resistance has emerged following treatment with ibrutinib. Mutations in BTK, such as C481S, C481Y, C481Y, C481R, and C481F, have been shown to clearly prevent drug binding. The observed incidence of drug resistance is expected to increase with clinical use rather than clinical trials.

[0007] Therefore, it is an object of the present disclosure to provide BTK inhibitors with different binding modes, particularly reversible inhibitors. It is a further object of the present disclosure to provide Btk inhibitors with high selectivity for Btk inhibition compared to EGFR, Tec and ITK inhibition. Summary of the Invention

[0008] The present disclosure provides novel cycloalkyl- or heterocyclyl-substituted heteroaryl compounds, compositions comprising the same and uses thereof, wherein the compounds have better inhibitory activity and selectivity against Btk and C481 mutant BTK kinases, and have good pharmacodynamic and / or pharmacokinetic properties, and may treat BTK kinase-mediated diseases or disorders.

[0009] In this regard, the present disclosure adopts the following technical solutions:

[0010] In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, Ring A has the structure: [ka] and; The ring in which X1 to X5 are arranged is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X3 is a N atom or a C atom; X4 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O, S, NH or C(R Y1 )2, where R Y1 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y3 is N, CD or CH; Z1 is C(O)NH2; Z2 is NH2; Alternatively, Z1 and Z2 together with the atoms to which they are attached form the structure: [ka] Forming; Wherein X6 is N, CD, CH or C-OH; X7 is N, CD or CH; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D, OH or NH2; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, halogen, C 1~6 Alkyl, C1~6 Haloalkyl, C 3~6 cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- or -C(R1)(R1')-C(R2)(R2')- together form -CH=CH-; Alternatively, R1 and R2 may be joined to form C 1~4 Forming an alkylene; R4 is H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R4' is H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; R s H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R t H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 3- to 7-membered heterocyclyl and C 1~4 One or more H in the alkylene may be replaced with D until fully deuterized; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0011] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, and a pharma- ceutically acceptable excipient, and optionally other therapeutic agents.

[0012] In another aspect, the disclosure relates to the use of a compound of the disclosure, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the disclosure, in the manufacture of a medicament for treating and / or preventing a wild-type and / or mutant BTK kinase-mediated disease; wherein the mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G, and BTK C481W, and optionally is BTK C481S.

[0013] In another aspect, the disclosure relates to a method for treating and / or preventing a disease mediated by wild-type and / or mutant BTK kinase in a subject, said method comprising administering to said subject a compound of the disclosure or a pharma- ceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of the disclosure; wherein said mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G, and BTK C481W, and optionally is BTK C481S.

[0014] In another aspect, the disclosure relates to a compound of the disclosure, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the disclosure, for use in the treatment and / or prevention of a disease mediated by wild-type and / or mutant BTK kinase; wherein the mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G, and BTK C481W, and optionally is BTK C481S.

[0015] Moreover, in certain aspects, the BTK-mediated disease of the present disclosure is selected from an allergic disease, an autoimmune disease, an inflammatory disease, and cancer.

[0016] In yet certain aspects, the BTK-mediated disease of the present disclosure is a B cell proliferative disease selected from chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with trilineage myelodysplastic disorder, mixed plasma leukemia, myelodysplastic syndrome, myeloproliferative disorder, marginal zone lymphoma, and Waldenstrom's macroglobulinemia.

[0017] Moreover, in certain aspects, the BTK-mediated disease of the present disclosure is multiple myeloma.

[0018] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] (definition) (chemical definition) Definitions of specific functional groups and chemical terms are further detailed below.

[0020] When a range of values ​​is listed, it is intended to include each value and each subrange within that range. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 It is intended to include alkyl.

[0021] "C 1~6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, C 1~4 Alkyl is selected. Examples of alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-pentyl (C5) and n-hexyl (C6). Whether or not the alkyl group is modified with the term "substituted", each alkyl group can be independently optionally substituted, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent. Suitable substituents are defined as follows:

[0022] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In some embodiments, the halo group is F, Cl or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0023] Therefore, "C 1~6 "Haloalkyl" refers to any of the above "C" substituted with one or more halo groups. 1~6 In some embodiments, C 1~4 Haloalkyl is selected, and C 1~2 Haloalkyl is selected. Examples of haloalkyl include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0024] "C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and no heteroatoms. 3~7 Cycloalkyl is selected, C 3~6 Cycloalkyl is selected, and C 5~6 Cycloalkyl is selected. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, in which case the carbon number still indicates the carbon number of the cycloalkyl system. Examples of cycloalkyl include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), cyclohex ... 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. Whether or not the cycloalkyl group is modified with the term "substituted," each cycloalkyl group independently can be optionally substituted, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent. Suitable substituents are defined as follows:

[0025] "3-10 membered heterocyclyl" refers to a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be carbon or nitrogen, where valence permits. In some embodiments, 3-7 membered heterocyclyl is selected, which is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms. In some embodiments, 3-6 membered heterocyclyl is selected, which is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms. Also, 5-6 membered heterocyclyl is selected, which is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms. "Heterocyclyl" also includes ring systems in which a heterocyclyl, as defined above, is fused to one or more cycloalkyl, aryl, or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, in which case the number of ring atoms still indicates the number of ring atoms in the heterocyclyl ring system. Whether or not the heterocyclyl group is modified with the term "substituted", each heterocyclyl group independently can be optionally substituted, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent. Suitable substituents are defined as follows:

[0026] Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 8-membered heterocyclyl groups having one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of 5-membered heterocyclyl groups (also referred to herein as 5,6-bicycloheterocyclyl) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Examples of 6-membered heterocyclyl groups (also referred to herein as 6,6-bicycloheterocyclyl) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0027] Examples of substituents attached to carbon atoms include, but are not limited to, halo, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -COH, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(Raa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Or the two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2Raa , =NR bb OR =NOR cc is substituted with a group; R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or two R aa The groups taken together form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R bb are each independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc 2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups taken together form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R ddis substituted with a group; R cc are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or two R cc The groups taken together form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R dd are each independently halo, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff)2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee 2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd The substituents may be taken together to form =O or =S; R ee are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R ff are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or two R ffThe groups taken together form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R gg are each independently halo, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - , -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 Aryl, C3-C7 heterocyclyl, or C5-C 10 heteroaryl; or two geminal R gg The substituents together may form =O or =S, where X - is the counter ion.

[0028] Examples of substituents attached to a nitrogen atom include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc ) 2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bonded to the nitrogen atom. cc The groups taken together form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc and R dd is as defined above.

[0029] "Deuterated," "deuterated" or "D-substituted" means that one or more hydrogens in a group or compound have been replaced with deuterium; the deuteration can be mono-, di-, poly- or full-substitution. The terms "substituted with one or more deuteriums" and "deuterated one or more times" are used interchangeably.

[0030] "Non-deuterated compound" refers to a compound in which the amount of deuterium atoms is not greater than the naturally occurring amount of deuterium isotope (0.015%).

[0031] The amount of deuterium isotopes at the deuteration sites is at least greater than the amount of natural deuterium isotopes (0.015%), alternatively greater than 30%, alternatively greater than 50%, alternatively greater than 75%, alternatively greater than 95%, alternatively greater than 99%.

[0032] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic responses, etc., within the scope of reasonable medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using conventional methods in the art, such as ion exchange, are also included. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, glycerol ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-terminated salts, such as tetrahydrofuran, ... + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0033] A "subject" to which dosing is planned includes, but is not limited to, humans (i.e., male or female of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or old adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0034] "Disease," "disorder," and "condition" are used interchangeably herein.

[0035] As used herein, unless otherwise indicated, the terms "treat," "therapeutic intervention," and "treatment" contemplate actions taken when a subject is afflicted with a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or prevent or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions taken before a subject acquires a particular disease, disorder, or condition ("prophylactic treatment").

[0036] "Combination," "in combination," and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present disclosure. For example, the compounds disclosed herein may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or may be administered in a single unit dosage form together with other therapeutic agents.

[0037] Detailed Description of the Invention (compound) As used herein, "a compound of the disclosure" refers to a compound of Formula (I) below (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0038] In one embodiment, the present disclosure provides a compound of formula (I): [ka] (I) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, Ring A has the structure: [ka] and; The ring in which X1 to X5 are arranged is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X3 is a N atom or a C atom; X4 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O, S, NH or C(R Y1 )2, where R Y1 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(RY2 )2, where R Y2 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y3 is N, CD or CH; Z1 is C(O)NH2; Z2 is NH2; Alternatively, Z1 and Z2, together with the atoms to which they are attached, form the structure: [ka] Forming; Wherein X6 is N, CD, CH or C-OH; X7 is N, CD or CH; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D, OH or NH2; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- or -C(R1)(R1')-C(R2)(R2')- together form -CH=CH-; Alternatively, R1 and R2 may be joined to form C 1~4 Forming an alkylene; R4 is H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R4' is H, D, halogen, C 1~6Alkyl or C 1~6 is haloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; R s H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R t H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; In the above group, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 3- to 7-membered heterocyclyl and C 1~4 One or more H in the alkylene may be replaced with D until fully deuterized; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0039] (Regarding Ring A and X1 to X5) In one embodiment, ring A has the structure: [ka] in other embodiments, ring A has the structure: [ka] It is.

[0040] In certain embodiments, X1 is N; in other certain embodiments, X1 is CD or CH. In certain embodiments, X2 is an N atom; in other certain embodiments, X2 is a C atom. In certain embodiments, X3 is an N atom; in other certain embodiments, X3 is a C atom. In certain embodiments, X4 is an N atom; in other certain embodiments, X4 is a C atom. In certain embodiments, X5 is an N atom; in other certain embodiments, X5 is a C atom.

[0041] In certain embodiments, ring A has the structure: [ka] or the structure: [ka] It is.

[0042] In further certain embodiments, ring A has the structure: [ka] or the structure: [ka] It is.

[0043] (About Y1) In one embodiment, Y1 is O; in another embodiment, Y1 is S; in another embodiment, Y1 is NH; in another embodiment, Y1 is C(R Y1 )2.

[0044] In certain embodiments, Y is C(R Y1 )2, where R Y1 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 haloalkyl; in other particular embodiments, Y is C(R Y1 )2, where R Y1are independently H, D or halogen, or Y1 is CH2.

[0045] (About Y2) In one embodiment, Y2 is a bond; in another embodiment, Y2 is C(R Y2 )2; in other embodiments, Y2 is C(R Y2 )2C(R Y2 )2.

[0046] In certain embodiments, Y2 is C(R Y2 )2, where R Y2 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 haloalkyl; in other particular embodiments, Y2 is C(R Y2 )2, where R Y2 is independently H, D or halogen, or Y2 is CH2.

[0047] In certain embodiments, Y2 is C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 haloalkyl; in other particular embodiments, Y2 is C(R Y2 )2C(R Y2 )2, where R Y2 is independently H, D or halogen, or Y2 is CH2CH2.

[0048] (About Y3) In one embodiment, Y3 is N; in another embodiment, Y3 is CD; in another embodiment, Y3 is CH.

[0049] (Regarding Z1 and Z2) In one embodiment, Z1 is C(O)NH2 and Z2 is NH2; in another embodiment, Z1 and Z2, together with the atom to which they are attached, form the structure: [ka] Form.

[0050] In certain embodiments, Z1 and Z2, together with the atom to which they are attached, form the structure: [ka] and X6 is N; in other particular embodiments, Z1 and Z2 together with the atom to which they are attached form the structure: [ka] and X6 is CD or CH; in other particular embodiments, Z1 and Z2 together with the atom to which they are attached form the structure: [ka] and X6 is C-OH; in other particular embodiments, Z1 and Z2 together with the atom to which they are attached form the structure: [ka] and X7 is N; in other particular embodiments, Z1 and Z2 together with the atom to which they are attached form the structure: [ka] and X7 is CD or CH.

[0051] (Regarding R1 and R1') In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen; in another embodiment, R1 is OH.

[0052] In one embodiment, R1' is H; in another embodiment, R1' is D; in another embodiment, R1' is halogen.

[0053] (Regarding R2 and R2') In one embodiment, R2 is H; in another embodiment, R2 is D; in another embodiment, R2 is OH; in another embodiment, R2 is NH2.

[0054] In one embodiment, R2' is H; in another embodiment, R2' is D; in another embodiment, R2' is C. 1~6 alkyl; in other embodiments, R is C 1~6 It is haloalkyl.

[0055] (Regarding R3 and R3') In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is OH; in another embodiment, R3 is CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 in other embodiments, R3 is CH2OH.

[0056] In one embodiment, R3' is H; in another embodiment, R3' is D; in another embodiment, R3' is halogen; in another embodiment, R3' is C. 1~6 alkyl; in other embodiments, R is C 1~6 haloalkyl; in other embodiments, R3' is C 3~6 in other embodiments, R3' is a 3- to 7-membered heterocyclyl.

[0057] In certain embodiments, R2 is OH and R3 is H; in other certain embodiments, R2 is H and R3 is OH; in other certain embodiments, R2 is H and R3 is CH2OH.

[0058] In another particular embodiment, -C(R)(R')-C(R Y1 )2- taken together form -CH=CH-; in other particular embodiments, -C(R1)(R1')-C(R2)(R2')- taken together form -CH=CH-.

[0059] In another particular embodiment, R1 and R2 are joined to form C 1~4 Forms an alkylene or methylene.

[0060] (Regarding R4 and R4') In one embodiment, R4 is H; in another embodiment, R4 is D; in another embodiment, R4 is halogen; in another embodiment, R4 is C. 1~6 alkyl; in other embodiments, R4 is C 1~6 It is haloalkyl.

[0061] In one embodiment, R4' is H; in another embodiment, R4' is D; in another embodiment, R4' is halogen; in another embodiment, R4' is C. 1~6 alkyl; in other embodiments, R is C 1~6 It is haloalkyl.

[0062] (Regarding R and R') In one embodiment, R is halogen or F.

[0063] In one embodiment, R' is C 1~6 alkyl; in other embodiments, R' is C 1~6 in other embodiments, R' is methyl.

[0064] Any technical solution or any combination thereof in any one of the above embodiments may be combined with any technical solution or any combination thereof in any one of the other embodiments. For example, any technical solution or any combination thereof of ring A, Y1 to Y3, Z1 to Z2, R1 and R1', R2 and R2', R3 and R3', R and R' may be combined. The present disclosure includes any combination of such technical solutions, although not exhaustively listed for the sake of brevity.

[0065] Specifically, the present disclosure relates to the following embodiments: 1. Formula (I): [ka] (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, Ring A has the structure: [ka] and; The ring in which X1 to X5 are arranged is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X3 is a N atom or a C atom; X4 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O, S, NH or C(R Y1 )2, where R Y1 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D, halogen, and C 1~6 Alkyl or C 1~6 is haloalkyl; Y3 is N, CD or CH; Z1 is C(O)NH2; Z2 is NH2; Alternatively, Z1 and Z2, together with the atoms to which they are attached, form the structure: [ka] Forming; Wherein X6 is N, CD, CH or C-OH; X7 is N, CD or CH; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D, OH or NH2; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- or -C(R1)(R1')-C(R2)(R2')- together form -CH=CH-; Alternatively, R1 and R2 may be joined to form C 1~4 Forming an alkylene; R4 is H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R4' is H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; R s H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R t H, D, halogen, C 1~6 Alkyl or C 1~6 is haloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; In the above group, C 1~6Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 3- to 7-membered heterocyclyl and C 1~4 One or more H in the alkylene may be replaced by D until fully deuterized; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0066] 2. Ring A has the structure: [ka] or the structure: [ka] or further comprising: [ka] or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0067] 3. Ring A has the structure: [ka] or the structure: [ka] or further comprising: [ka] or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0068] 4. A compound according to any one of embodiments 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein Y1 is O.

[0069] 5. Y1 is C(R Y1 4. The compound of any one of embodiments 1-3, wherein R is CH2, or CH3, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0070] 6. A compound according to any one of embodiments 1-5, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein Y2 is a bond.

[0071] 7. Y2 is C(R Y2 )2 or C(R Y2 )2C(R Y2 6. The compound of any one of embodiments 1 to 5, wherein R is CH or CHCH, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0072] 8. A compound according to any one of embodiments 1-7, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein Y3 is CH.

[0073] 9. A compound according to any one of embodiments 1 to 8, wherein R2 is OH and R3 is H, or R2 is H and R3 is OH, or R2 is H and R3 is CH2OH, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0074] 10. A compound according to any one of embodiments 1-9, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein R is F.

[0075] 11. The compound according to any one of embodiments 1-10, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein R' is methyl.

[0076] 12. A compound of the general formula: [ka] [ka] [ka] [ka] wherein each group is as defined in any one of embodiments 1 to 11. or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0077] 13.Formula (II): [ka] (II) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0078] 14.Formula (II-1): [ka] (II-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; provided that at least one of R2 and R3 is OH or CH2OH.

[0079] 15. X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is F; R' is methyl; With the proviso that at least one of R2 and R3 is OH or CH2OH; A compound according to embodiment 14, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0080] 16.Formula (III): [ka] (III) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X2 is N, CD or CH; X5 is N, CD or CH; X6 is N, CD, CH or C-OH; X7 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y 1 is independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0081] 17.Formula (III-1): [ka] (III-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X2 is N, CD or CH; X5 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0082] 18.Formula (III-2): [ka] (III-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X2 is N, CD or CH; X5 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; provided that at least one of R2 and R3 is OH or CH2OH.

[0083] 19.X2 is N; X5 is N; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is F; R' is methyl; With the proviso that at least one of R2 and R3 is OH or CH2OH; A compound according to embodiment 18, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0084] 20.Formula (IV): [ka] (IV) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, The ring in which X1 to X5 are arranged is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X3 is a N atom or a C atom; X4 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where Ra is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0085] 21.Formula (IV-1): [ka] (IV-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, the ring in which X1, X2 and X5 are located is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0086] 22.Formula (IV-2): [ka] (IV-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, the ring in which X1, X2 and X5 are located is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O or C(R Y1 )2, where R Y1are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; provided that at least one of R2 and R3 is OH or CH2OH.

[0087] 23. The ring in which X1, X2 and X5 are located is an aromatic ring; X1 is N, CD or CH; X2 is a N atom or a C atom; X5 is a N atom or a C atom; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is F; R' is methyl; With the proviso that at least one of R2 and R3 is OH or CH2OH; 23. A compound according to embodiment 22, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0088] 24.Formula (V): [ka] (V) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0089] 25. Formula (VI): [ka] (VI) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0090] 26. Formula (VI-1): [ka] (VI-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; provided that at least one of R2 and R3 is OH or CH2OH.

[0091] 27. X1 is N, CD or CH; X6 is N, CD or CH; Y1 is O or C(R Y1)2, where R Y1 are independently H, D or halogen; Y2 is a bond or C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R3 is H, D, OH or CH2OH; R is F; R' is methyl; With the proviso that at least one of R2 and R3 is OH or CH2OH; 27. A compound according to embodiment 26, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0092] 28.Formula (VII): [ka] (VII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; Y1 is O; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; or -C(R1)(R1')-C(R2)(R2') together form -CH=CH-; or R1 and R2 combine to form -CH2-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 One or more H in the cycloalkyl and -CH2- may be replaced with D up to full deuteration; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0093] 29.Formula (VII-1): [ka] (VII-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OH; R3' is H or D; or R1 and R2 combine to form -CH2-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 One or more H in haloalkyl and -CH2- may be replaced with D up to full deuteration; provided that at least one of R2 and R3 is OH or CH2OH.

[0094] 30. X1 is N; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H or D; R3 is H, D, OH or CH2OH; R3' is H or D; or R1 and R2 combine to form -CH2-; R is F; R' is methyl; With the proviso that at least one of R2 and R3 is OH or CH2OH; A compound according to embodiment 29, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0095] 31.Formula (VII): [ka] (VII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; Y1 is C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2)2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- together form -CH=CH-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0096] 32.Formula (VII-2): [ka] (VII-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; Y1 is C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H or D; Alternatively, -C(R3)(R3')-C(R Y1 )2- together form -CH=CH-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0097] 33. X1 is N; Y1 is C(R Y1 )2, where R Y1 is independently H or D; Y2 is bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H or D; Alternatively, -C(R3)(R3')-C(R Y1 )2- come together to form -CH=CH-; R is F; R' is methyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a That is, A compound according to embodiment 32, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0098] 34.Formula (VIII): [ka] (VIII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; Y1 is O or C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is a bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where RY2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- or -C(R1)(R1')-C(R2)(R2')- together form -CH=CH-; Alternatively, R1 and R2 may be joined to form C 1~4 Forming an alkylene; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 3- to 7-membered heterocyclyl and C 1~4 One or more H in the alkylene may be replaced with D until fully deuterized; However, at least one of R2 and R3 is OH or CH2OR a [is].

[0099] 35. X1 is N, CD or CH; Y1 is O; Y2 is bond, C(R Y2 )2 or C(R Y2 )2C(RY2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; or -C(R1)(R1')-C(R2)(R2') together form -CH=CH-; or R1 and R2 combine to form -CH2-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a That is, A compound according to embodiment 34, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0100] 36. X1 is N, CD or CH; Y1 is C(R Y1 )2, where R Y1 are independently H, D or halogen; Y2 is bond, C(R Y2 )2 or C(R Y2 )2C(R Y2 )2, where R Y2 are independently H, D or halogen; R1 is H, D, halogen or OH; R1' is H, D or halogen; R2 is H, D or OH; R2' is H, D, C 1~6 Alkyl or C 1~6 is haloalkyl; R3 is H, D, OH or CH2OR a where R a is H, C 1~6 Alkyl or C 1~6 is haloalkyl; R3' is H, D, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~6 is cycloalkyl; Alternatively, -C(R3)(R3')-C(R Y1 )2- come together to form -CH=CH-; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, at least one of R2 and R3 is OH or CH2OR a That is, A compound according to embodiment 34, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0101] 37.Formula (VIII-1): [ka] (VIII-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X1 is N, CD or CH; Y1 is O, CHD, CD2 or CH2; R2 is H, D or OH; R3 is H, D or CH2OH; R is a halogen; R' is C 1~6 Alkyl or C 1~6 is haloalkyl; Here, C in the above group 1~6 Alkyl and C 1~6 One or more H in the haloalkyl may be replaced with D up to full deuteration; provided that neither R2 nor R3 is H.

[0102] 38. X1 is N; Y1 is O, CHD, CD2 or CH2; R2 is H, D or OH; R3 is H, D or CH2OH; R is F; R' is methyl; However, neither R2 nor R3 is H. A compound according to embodiment 37, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0103] 39. The structure: [ka] [ka] [ka] [ka]

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[0104] 40. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, and a pharma- ceutically acceptable excipient, optionally including other therapeutic agents.

[0105] 41. Use of a compound according to any one of embodiments 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to embodiment 40, in the manufacture of a medicament for treating and / or preventing a wild-type and / or mutant BTK kinase mediated disease, wherein the mutant BTK kinase is optionally selected from C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G and BTK C481W, and optionally is BTK C481S.

[0106] 42. A method for treating and / or preventing a wild-type and / or mutant BTK kinase mediated disease in a subject, comprising administering to the subject a compound according to any one of embodiments 1 to 39, or a pharma- ceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition according to embodiment 40, wherein the mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G, and BTK C481W, and optionally is BTK C481S.

[0107] 43. A compound according to any one of embodiments 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to embodiment 40, for use in the treatment and / or prevention of a wild-type and / or mutant BTK kinase-mediated disease, wherein the mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G and BTK C481W, and optionally is BTK C481S.

[0108] 44. The use according to embodiment 41, or the method according to embodiment 42, or the compound or composition for use according to embodiment 43, wherein the BTK-mediated disease is selected from an allergic disease, an autoimmune disease, an inflammatory disease, and cancer.

[0109] 45. The use according to embodiment 41, or the method according to embodiment 42, or the compound or composition for use according to embodiment 43, wherein the BTK-mediated disease is a B-cell proliferative disease selected from chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with myelodysplastic disorders in three lineages, mixed lineage leukemia, myelodysplastic syndromes, myeloproliferative diseases, marginal zone lymphoma, and Waldenström's macroglobulinemia.

[0110] 46. ​​The use according to embodiment 41, or the method according to embodiment 42, or the compound or composition for use according to embodiment 43, wherein the BTK-mediated disease is multiple myeloma.

[0111] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist as various stereoisomers, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods well known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, other isomers can be prepared by asymmetric synthesis.

[0112] "Tautomer" refers to an isomer in which one functional group in a compound undergoes a structural transformation into another functional group, where the compound and the isomer can rapidly transform into each other and thus be in dynamic equilibrium. The two isomers are called tautomers.

[0113] It will be understood by those skilled in the art that organic compounds may form complexes with solvents that react with them or that precipitate or crystallize them. These complexes are known as "solvates." When the solvent is water, the complexes are known as "hydrates." The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0114] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by solvolysis. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, further including both solvates of stoichiometric composition and solvates of non-stoichiometric composition. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, and methanolates.

[0115] The term "hydrate" refers to a compound associated with water. In general, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A compound may form more than one hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0116] The compounds of the present disclosure may be in amorphous or crystalline form (crystal form or polymorph). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) that is a particular crystal packing arrangement. All polymorphs have the same elemental composition. In general, different crystalline forms have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound may be prepared by crystallization under various conditions.

[0117] The present disclosure also includes isotopically labeled compounds, which are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms whose atomic masses or mass numbers are different from those of the atoms common in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as: 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compound of the present disclosure, its prodrugs, and pharma- ceutically acceptable salts of said compounds or said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms, are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, e.g., compounds containing radioactive isotopes (e.g., 3 H and 14 C) incorporation can be used to measure the distribution of drugs and / or substrates in tissues. Tritium ( 3 H) and carbon-14 ( 14C isotope) is selected. Additionally, heavier isotopes such as deuterium ( 2 H) may be selected in some cases because its high metabolic stability can result in therapeutic effects, such as an increased half-life in vivo or a reduced required dose. The isotopically labeled compounds of formula (I) and their prodrugs in the present disclosure can generally be prepared by using a readily available isotopically labeled reagent instead of a nonisotopically labeled reagent in the following schemes and / or procedures disclosed in the Examples and Preparations.

[0118] In addition, prodrugs are also included in the context of this disclosure. The term "prodrug" as used herein refers to a compound that is converted in vivo into an active form that has a therapeutic effect, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, Ed. Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) pp. 115-130, each of which is incorporated herein by reference.

[0119] A prodrug is any covalently bonded compound disclosed herein that releases the parent compound in vivo when administered to a patient. Prodrugs are typically prepared by modifying functional groups such that the modification can be cleaved by routine manipulation or degradation in vivo to generate the parent compound. Prodrugs include, for example, compounds disclosed herein bonded to any functional group where the hydroxy, amino, or sulfhydryl group is cleaved to form the hydroxy, amino, or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include (but are not limited to) acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives at the hydroxy, amino, or sulfhydryl functional groups of the compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters and ethyl esters can be used. Esters may be active themselves and / or may be hydrolyzed under in vivo conditions in humans. Suitable pharma- ceutically acceptable in vivo hydrolysable ester groups include those groups which break down readily in the human body to leave the parent acid or its salt.

[0120] Pharmaceutical Compositions, Formulations, and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0121] The pharma- ceutically acceptable excipient for use in the present disclosure refers to a non-toxic carrier, auxiliary, or vehicle that does not impair the pharmacological activity of the compound with which it is formulated.The pharma-ceutically acceptable carrier, auxiliary, or vehicle that may be used in the compositions of the present disclosure includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substrates (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0122] The disclosure also includes kits (e.g., pharmaceutical packs). The kits provided may include a compound disclosed herein, another therapeutic agent, and a first or second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a disposable package or other material) that includes the compound disclosed herein or another therapeutic agent. In some embodiments, the kits provided may also optionally include a third container that includes a pharma- ceutically acceptable excipient for diluting or suspending the compound disclosed herein and / or another therapeutic agent. In some embodiments, the compound disclosed herein, provided in the first container, and the other therapeutic agent, provided in the second container, are combined to form a unit dosage form.

[0123] The pharmaceutical compositions provided in the present disclosure may be administered by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral mucosal, vaginal, implant, or other means of administration. For example, as used herein, parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraventricular, intralesional, and intracranial injection or infusion techniques.

[0124] The compounds provided herein are generally administered in effective amounts. The amount of compound actually administered is typically determined by a physician, taking into account the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0125] When used to prevent the disorders disclosed herein, the compounds provided herein are typically administered to subjects at risk of developing the condition in the dosages described above, under the supervision of a physician, based on the advice of a physician.Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as susceptible to developing the condition.

[0126] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or may continue indefinitely, such as for the remaining lifespan of a subject. In certain embodiments, chronic administration aims to maintain a certain level of the compound in the blood, such as within the therapeutic window, for an extended period of time.

[0127] The pharmaceutical composition of the present disclosure may also be delivered using various dosing methods. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, for example, to quickly raise the concentration of the compound in the blood to an effective level. The bolus administration is arranged according to the desired systemic level of the active ingredient, for example, an intramuscular or subcutaneous bolus administration allows for a sustained release of the active ingredient, while a bolus delivered directly into a vein (e.g., by intravenous drip) allows for a more rapid delivery and quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered by continuous infusion, for example, intravenous drip, to maintain a steady state concentration of the active ingredient in the subject's body. In yet other embodiments, the pharmaceutical composition may be administered by an initial bolus administration, followed by continuous infusion.

[0128] Compositions for oral administration may be in the form of bulk solutions or suspensions, or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, pretreated ampoules or syringes containing liquid compositions, or pills, tablets, capsules, and the like, in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or about 1 to about 40% by weight), with the remainder including various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0129] For oral administration, 1 to 5 times daily, particularly 2 to 4 times daily, typically 3 times daily, is a typical regimen. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of a compound provided herein, and each separate dose provides from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0130] Transdermal administration is generally selected to result in blood concentrations similar to or lower than those achieved using injection administration, generally in amounts ranging from about 0.01 to about 20% by weight, or from about 0.1 to about 20% by weight, or from about 0.1 to about 10% by weight, or from about 0.5 to about 15% by weight.

[0131] Injection dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for about 1 to about 120 hours, particularly over a 24 to 96 hour period. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve adequate steady state levels. Maximum total doses are not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0132] Liquid dosage forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid dosage forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0133] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0134] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as ointments, active ingredients are typically combined with a paraffinic or water-miscible ointment base. Alternatively, active ingredients may be formulated into creams, for example with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients to improve the stability of the active ingredient or the formulation for skin penetration. All such transdermal formulations and ingredients are included within the scope provided herein.

[0135] The compounds provided herein can also be administered by a transdermal device, that is, transdermal administration can be accomplished using a patch, either of the reservoir or porous membrane type, or of a solid matrix variety.

[0136] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other ingredients and processing techniques are set out in Chapter 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0137] The compounds disclosed herein can also be administered in sustained release dosage forms or via sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0138] The present disclosure also relates to pharma- ceutically acceptable formulations of the compounds disclosed herein. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrin, which consist of 6, 7, and 8 α-1,4 linked glucose units, respectively, which may optionally contain one or more substituents (including but not limited to methyl, hydroxyalkyl, acryl, and sulfoalkyl ether substitutions) on the attached sugar moiety. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol (see, e.g., U.S. Patent No. 5,376,645). In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0139] (Indications) In another aspect, there is provided the use of a compound of formula (I) as disclosed herein (including all individual embodiments and generic subsets disclosed herein), or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, as a medicament.

[0140] The compounds of the present disclosure exhibit potent and selective inhibition of BTK. For example, the compounds of the present disclosure exhibit nanomolar potency against wild-type BTK and BTK kinases encoded by the BTK gene that contain BTK kinase inhibitor-resistant mutations, such as C481S, C481F, C481Y, C481R, C481T, C481G, or C481W, or the mutation is C481S. In some embodiments, inhibition of C481S is similar to that observed in wild-type BTK.

[0141] In some embodiments, the compounds of the present disclosure selectively target the BTK kinase. For example, the compounds of the present disclosure may selectively target the BTK kinase over other kinases or non-kinase targets. In some embodiments, the compounds of the present disclosure may selectively target the BTK kinase over one or more of the following kinases: BRK, CSK, ERBB4, FYN, MEK1, MEK2, TEC, TXK, YES1, BMX, BLK, EGFR, ITK, SRC, JAK1, JAK2, and JAK3.

[0142] In some embodiments, the compounds of the disclosure exhibit at least 30-fold selectivity for BTK kinase over other kinases. For example, the compounds of the disclosure exhibit at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity, at least 100-fold selectivity, at least 200-fold selectivity, at least 300-fold selectivity, at least 400-fold selectivity, at least 500-fold selectivity, at least 600-fold selectivity, at least 700-fold selectivity, at least 800-fold selectivity, at least 900-fold selectivity, or at least 1000-fold selectivity over other kinases. In some embodiments, the compounds of the disclosure exhibit at least 100-fold selectivity for BTK kinase over other kinases. In some embodiments, the selectivity for BTK kinase over other kinases is measured in a cellular assay (e.g., the cellular assays provided herein).

[0143] The compounds of the present disclosure are useful for treating diseases and conditions that are treated with BTK kinase inhibitors, such as BTK-associated diseases and conditions, such as proliferative diseases, such as cancers, including hematological cancers and solid tumors, and inflammatory conditions, immune disorders, or fibrotic diseases.

[0144] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a BTK-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a BTK-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a BTK-associated cancer) is a B-cell malignancy. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a BTK-associated cancer) is a Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., splenic marginal zone lymphoma, extramuscular marginal zone B-cell lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), central nervous system primary lymphocytic lymphoma, small lymphocytic lymphoma, chronic lymphocytic lymphoma, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, precursor B-cell acute lymphocytic leukemia, hairy cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, plasma cell myeloma, plasma cell neoplasm, bone cancer, bone metastasis, breast cancer, gastroesophageal junction cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer, head and neck cancer or glioma.

[0145] In some embodiments, the hematological cancer is a leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, or myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic lymphoma (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AML), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), acute myeloid leukemia with trilineage myelodysplastic disorder (AML ... / TMDS), mixed plasma leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., splenic marginal zone lymphoma, extramuscular marginal zone B-cell lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), primary central nervous system malignant lymphoma, small lymphocytic lymphoma, precursor B-cell acute lymphoblastic leukemia, Hairy cell leukemia, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma. Other examples of hematological cancers include myelodysplastic disorders (MPD), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer is mantle cell lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, or marginal zone lymphoma.

[0146] In some embodiments, the solid tumor is selected from bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, and head and neck cancer.

[0147] In some embodiments, the immune-mediated disease is selected from the group consisting of arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's disease, Ord's thyroiditis, and the like. thyroiditis), Graves' disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma and vulvodynia, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, Colitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, enterocolitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, hepatitis, inflammatory bowel disease, suppurative inflammation, pharyngitis, mastitis, meningitis, osteomyelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis , pleuritis, phlebitis, pneumonia, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tenosynovitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, graft versus host disease, transplantation, blood transfusion, anaphylaxis, allergic reactions, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

[0148] In some embodiments, the inflammatory disease is selected from the group consisting of arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, medial epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, hepatitis, and suppurative sweat glands. adenitis, laryngitis, mastitis, meningitis, osteomyelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pulmonary disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tenosynovitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

[0149] In some embodiments, the autoimmune disease is selected from the group consisting of lupus and Sjogren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's disease, Ord's thyroiditis, and the like. thyroiditis), Graves' disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma and vulvodynia.

[0150] In some embodiments, the xenoimmune disease is selected from the group consisting of graft versus host disease, transplantation, blood transfusion, anaphylaxis, allergic reactions, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic rhinitis.

[0151] In some embodiments, the fibrosis is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, idiopathic interstitial pneumonia (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver disease, fatty liver (e.g., nonalcoholic steatohepatitis (NASH)), cholesterol-induced liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, cholestasis, and bile duct disease.

[0152] In the therapeutic methods of the present disclosure, an "effective amount" refers to an amount or dosage sufficient to provide the desired therapeutic effect to an individual in need of treatment. An effective amount or dosage of a compound of the present disclosure can be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials) and conventional factors (e.g., the method or route of drug delivery, the pharmacokinetics of the drug, the severity and route of infection, the health and weight of the individual, and the judgment of the treating physician). Exemplary dosages include ranges of about 0.1 mg to 1 g / day, or about 1 mg to 50 mg / day, or about 50 mg to 250 mg / day, or about 250 mg to 1 g / day. The total dosage can be in single or divided dosage units (e.g., BID, TID, QID).

[0153] After the patient's disease is improved, the dosage may be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, may be reduced to an amount that maintains the desired therapeutic or preventive effect, depending on the symptoms. Of course, when the symptoms are alleviated to an appropriate degree, treatment may then be discontinued. However, the patient may require long-term intermittent treatment upon any recurrence of symptoms. The patient may require long-term slow treatment.

[0154] (Drug Combinations) The compounds of the present disclosure described herein may be used in combination with one or more other active ingredients in a pharmaceutical composition or method of treating diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or agents that alleviate the side effects of therapeutic agents against the targeted disease. Combinations may be used to increase efficacy, improve other disease symptoms, reduce one or more adverse effects, or reduce the required dosage of the compounds of the present disclosure. The additional active ingredients may be formulated as a pharmaceutical composition separate from the compounds of the present disclosure, or may be included in a single pharmaceutical composition together with the compounds of the present disclosure. The additional active ingredients may be administered simultaneously with, before, or after the administration of the compounds of the present disclosure.

[0155] The combination of drugs includes additional active ingredients known or observed to be effective in treating the diseases and conditions described herein, including those that are effective against other targets related to the disease. For example, the compositions and formulations and treatment methods of the present disclosure may further include other drugs or pharmaceuticals, such as other active agents useful in treating or ameliorating the target disease or associated symptoms or conditions. Such other drugs for cancer indications include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum agents, mitotic inhibitors, antibodies, hormone therapy, or corticosteroids. Suitable combination drugs for pain indications include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the present disclosure may additionally include one or more such active agents, and the methods of treatment may additionally include administering an effective amount of one or more such active agents. EXAMPLES

[0156] The present disclosure will be further described in detail with specific examples. It should be understood that these examples are used to illustrate the present disclosure, and are not used to limit the scope of the present disclosure. In the following examples, the experimental methods that do not describe specific environments are usually based on conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, parts and percentages are parts by weight and percentages by weight.

[0157] Generally, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (for example, 0° C. to 100° C., or 0° C. to 80° C.) The reaction time is usually 0.1 to 60 hours, or 0.5 to 24 hours.

[0158] The abbreviations used herein have the following meanings: TBDMSCl: tert-butyldimethylsilyl chloride TBDPSCl: tert-butyldiphenylchlorosilane Dess-Martin oxidant: 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide CAN:Ce(NH4)2(NO3)6 DIAD: Diisopropyl azodicarboxylate PPTS or PyTs: Pyridinium p-toluenesulfonate Pd(OAc)2: Palladium acetate Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Pd(OAc)2: Palladium acetate Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) DMAP: 4-dimethylaminopyridine DIPEA: N,N-diisopropylethylamine OTf2: Trifluoromethanesulfonic anhydride NaBH3CN: Sodium cyanoborohydride MsCl: methylsulfonyl chloride NIS: N-iodosuccinimide T3P: n-propylphosphonic acid cyclic anhydride MTBE: Methyl tert-butyl ether TPP: Triphenylphosphine

[0159] Preparation of intermediate compound A-1 2-((4-bromophenyl)(methoxy)methylene)malononitrile [ka] A-1

[0160] The following synthetic route was chosen: [ka]

[0161] Step 1: Synthesis of 2-((4-bromophenyl)(hydroxy)methylene)malononitrile compound Toluene (100 mL), THF (20 mL) and malononitrile (compound 2, 6.3 mL, 100.3 mmol) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to -10°C and 4-bromobenzoyl chloride (20 g, 91.1 mmol) was added. The mixture was stirred for 10 min and DIPEA (31.8 mL, 182.3 mmol) was added dropwise slowly. The whole process took 30 min and the internal temperature was controlled not to exceed -10°C. After the addition was complete, the mixture was allowed to warm slowly to room temperature and stirred for 2 h. Ethyl acetate (200 mL) and 1 M aqueous hydrochloric acid (200 mL) were added and the mixture was stirred for 10 min. The organic layer was separated and washed successively with 1 M hydrochloric acid (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was added to petroleum ether / ethyl acetate (100 mL, 20 / 1), stirred for 20 min, filtered, washed with petroleum ether and blown dry to give 20 g of a grey solid in 88.1% yield. LC-MS (APCI): m / z=249.0 (M+1). + .

[0162] Step 2: Synthesis of intermediate compound A-1 Sodium hydride (2.48 g, 61.84 mmol, 60% by weight dispersion in silicon oil) was added to a 250 mL three-neck flask equipped with a magnetic stirrer and a condenser. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous THF (40 mL) was added under ice-water bath cooling. The mixture was stirred and dispersed. A solution of 2-((4-bromophenyl)(hydroxy)methylene)malononitrile (14 g, 56.2 mmol) in anhydrous THF (40 mL) was added dropwise. The mixture was stirred and reacted under ice-water bath for 30 minutes. Dimethyl sulfate (16.0 mL, 168.6 mmol) was added dropwise. After the addition was complete, the temperature was raised to 80° C. and the mixture was stirred and reacted overnight. The mixture was cooled to room temperature. Saturated saline (80 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 7.3 g of a white solid in 49.4% yield. LC-MS (APCI): m / z=231.0 (M+1). + .

[0163] Preparation of intermediate compound A-2 5-amino-3-(4-bromophenyl)-1-(3-hydroxycyclohexane)-1H-pyrazole-4-carbonitrile [ka] A-2

[0164] The following synthetic route was chosen: [ka]

[0165] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol compound Cyclohexane-1,3-diol (3 g, 25.86 mmol), imidazole (2.64 g, 1.5 eq, 38.79 mmol) and DMF (50 mL) were added in sequence to a 250 mL two-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and compound TBDMSCl (4.7 g, 1.2 eq, 31.03 mmol) was added in batches. The mixture was allowed to warm slowly to room temperature and stirred overnight. Ethyl acetate (200 mL) and 1 M aqueous hydrochloric acid (200 mL) were added. The mixture was stirred for 10 minutes. The organic layer was separated, washed with 1 M hydrochloric acid (100 mL), washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. A sample of the mixture was passed through a column to obtain 5 g of a colorless oil. Yield: 84%.

[0166] Step 2: Synthesis of tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)cyclohexylidene)hydrazine-1-formate compound 3-((tert-Butyldimethylsilyl)oxy)cyclohexan-1-ol (1.79 g, 7.82 mmol) and MeOH (20 mL) were added to a 100 mL two-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and NH2NHBoc compound (1.55 g, 1.5 equiv., 11.73 mmol) was added. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. Dichloromethane (100 mL) and water (100 mL) were added and stirred for 5 min. The organic layer was separated and the aqueous layer was extracted again. The organic layers were combined, washed once with saturated brine, and evaporated to dryness on a rotary evaporator. The residue was passed through a silica gel column to give 1.67 g of the desired product. Yield: 62%. LC-MS (APCI): m / z=344.0 (M+1) + .

[0167] Step 3: Synthesis of tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)hydrazine-1-formate compound In a 100 mL three-neck flask equipped with a magnetic stirrer, tert-butyl 2-(3-((tert-butyldimethylsilyl)oxy)cyclohexylidene)hydrazine-1-carboxylate (1.67 g, 4.87 mmol) and MeOH (30 mL) were added and stirred until dissolved. Acetic acid (1.0 equiv., 302 mg) was added. The mixture was stirred for 20 min, cooled to 0° C. in an ice bath, NaBH3CN (2.0 equiv., 604 mg) was added in batches and stirred at room temperature under nitrogen overnight. The reaction was confirmed to be complete by TLC. Dichloromethane (100 mL) and water (100 mL) were added and stirred for 5 min. The organic layer was separated, the aqueous layer was extracted again, the organic layers were combined, washed once with saturated brine, and evaporated to dryness on a rotary evaporator. The residue was passed through a silica gel column to give 1.6 g of the desired product. Yield: 95%. LC-MS(APCI): m / z=346.0(M+1) + .

[0168] Step 4: Synthesis of hydrochloride salt of 3-hydrazinocyclohexan-1-ol compound 2-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)hydrazine-1-carboxylate tert-butyl (1.6 g, 4.62 mmol) was dissolved in 10 mL of dichloromethane. 10 mL of 5 M isopropanol hydrochloride was slowly added under ice bath cooling, and the mixture was stirred at room temperature for 2 hours. After TLC confirmed that no raw material remained, the mixture was directly dried on a rotary evaporator and sucked dry for the next reaction.

[0169] Step 5: Synthesis of intermediate compound A-2 3-Hydrazinocyclohexan-1-ol hydrochloride obtained in the previous step, intermediate compound A-1 (378 mg, 1.45 mmol) and absolute ethanol (20 mL) were added to a two-neck flask equipped with a magnetic stirrer and a condenser. Triethylamine (586 mg, 5.8 mmol) was added while stirring. Under a nitrogen atmosphere, the temperature was raised to 80° C. and the reaction was stirred overnight. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. Saturated saline (20 mL) and ethyl acetate (30 mL) were added. The mixture was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 300 mg of a brown solid. LC-MS (APCI): m / z=361.0 (M+1) + .

[0170] Preparation of intermediate compound A-3 trans-1-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ka] A-3

[0171] The following synthetic route was chosen: [ka]

[0172] Step 1: Synthesis of cis-3-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol compound Cis-cyclohexane-1,3-diol (3.0 g, 25.86 mmol), imidazole (2.64 g, 1.5 eq, 38.79 mmol) and DMF (40 mL) were added in sequence to a 250 mL two-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and compound TBDMSCl (4.7 g, 31.03 mmol) was added in batches. The mixture was slowly warmed to room temperature and stirred overnight. Ethyl acetate (200 mL) and 1 M aqueous hydrochloric acid (200 mL) were added. The mixture was stirred for 10 minutes. The organic layer was separated, washed with 1 M hydrochloric acid (100 mL), washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. A sample of the mixture was passed through a column to obtain 5.0 g of a colorless oil. Yield: 84%.

[0173] Step 2: Synthesis of intermediate compound A-3 Cis-3-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol (1.16 g, 5.02 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.19 g, 4.57 mmol) and THF (20 mL) were added to a 100 mL two-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and Ph3P (2.39 g, 9.13 mmol) was added. Then, DIAD (1.84 g, 9.13 mmol) was slowly added dropwise and allowed to warm to room temperature and stirred overnight. Ethyl acetate (50 mL) and water (50 mL) were added and stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted again. The organic layers were combined, washed once with saturated brine and evaporated to dryness on a rotary evaporator. The residue was passed through a silica gel column to give 2.3 g of a white solid. Yield: 96.8%.

[0174] Preparation of intermediate compound A-4 5-amino-3-(4-bromophenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carbonitrile [ka] A-4

[0175] The following synthetic route was chosen: [ka]

[0176] Step 1: Synthesis of ((3,4-dihydro-2H-pyran-2-yl)methoxy)(diphenyl)(tert-butyl)silane compound (3,4-Dihydro-2H-pyran-2-yl)methanol (3 g, 26.32 mmol), imidazole (2.7 g, 39.48 mmol) and DMF (40 mL) were added in sequence to a 250 mL two-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. TBDPSCl compound (4.7 g, 28.95 mmol) was added in batches. The mixture was slowly warmed to room temperature and stirred overnight. Ethyl acetate (100 mL) and 1 M aqueous hydrochloric acid (50 mL) were added. The mixture was stirred for 10 minutes. The organic layer was separated, washed with 1 M hydrochloric acid (30 mL), washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was passed through a silica gel column to give 7.4 g of a colorless oil. Yield: 80%.

[0177] Step 2: Synthesis of 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol compound ((3,4-dihydro-2H-pyran-2-yl)methoxy)(diphenyl)(tert-butyl)silane compound (4 g, 11.33 mmol) and anhydrous THF (20 mL) were added in sequence to a 100 mL two-neck flask equipped with a magnetic stirrer and a condenser, and stirred until dissolved. The flask was evacuated and the atmosphere was replaced with nitrogen three times. BH3-THF solution (23 mL, 1 M) was slowly added dropwise under an ice bath. After the addition was complete, the mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath. 4 M NaOH aqueous solution (4 M, 12 mL) was slowly added, followed by H2O2 solution (mass fraction: 33%, 20 mL) dropwise. The temperature was raised to 50° C., and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, and the mixture was stirred for 5 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed once with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was passed through a silica gel column to obtain 1.8 g of a colorless oily substance. Yield: 43.1%, LC-MS (APCI): m / z = 371.2 (M + 1). + .

[0178] Step 3: Synthesis of 6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one compound In a 100 mL two-neck flask equipped with a magnetic stirrer, 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (1.5 g, 4.0 mmol) and DCM (20 mL) were added in sequence and stirred until dissolved. The solution was cooled to 0° C. A Dess-Martin oxidant compound (3.43 g, 8.0 mmol) was added in batches. After the addition, the mixture was warmed to room temperature and stirred overnight. Dichloromethane (50 mL) and water (50 mL) were added and stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was passed through a silica gel column to give 1.35 g of a colorless oil. Yield: 90.4%. LC-MS(APCI): m / z=369.2(M+1) + .

[0179] Step 4: Synthesis of tert-butyl 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-ylidene)hydrazine-1-formate compound 6-(((tert-Butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one (1.35 g, 3.66 mmol) and MeOH (20 mL) were added in sequence to a 100 mL two-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. NH2NHBoc compound (724 mg, 5.49 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The organic solvent was evaporated under reduced pressure and the residue was extracted with dichloromethane (30 mL×3). The organic layers were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was passed through a silica gel column to give 1.15 g of a white solid. Yield: 65%. LC-MS (APCI): m / z=483.0 (M+1) + .

[0180] Step 5: Synthesis of tert-butyl 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)hydrazine-1-formate compound tert-Butyl 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-ylidene)hydrazine-1-carboxylate (2.45 g, 5.07 mmol) and MeOH (30 mL) were added in sequence to a 100 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. Acetic acid (314 mg, 5.07 mmol) was added. The mixture was stirred for 20 min and cooled to 0° C. in an ice bath. NaBH3CN (628 mg, 10.14 mmol) was added in batches and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched by the addition of saturated sodium bicarbonate solution (30 mL). The organic solvent was evaporated under reduced pressure and the residue was extracted with DCM (30 mL×3). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was passed through a silica gel column to give 2.3 g of a white solid. Yield: 95%. LC-MS (APCI): m / z=485.0 (M+1). + .

[0181] Step 6: Synthesis of the hydrochloride salt of (6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)hydrazine compound In a 50 mL one-neck flask equipped with a magnetic stirrer, tert-butyl 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)hydrazine-1-carboxylate (2.3 g, 4.74 mmol) and dichloromethane (10 mL) were added in sequence and stirred until dissolved. Hydrochloric acid / isopropanol solution (20 mL, 5 M) was added. The mixture was stirred at room temperature for 2 h and concentrated to dryness under reduced pressure for the next step.

[0182] Step 7: Synthesis of intermediate compound A-4 Intermediate compound A-1 (1.24 g, 4.74 mmol), the hydrochloride salt of (6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)hydrazine obtained in the previous step, and absolute ethanol (20 mL) were added to a 100 mL two-neck flask equipped with a magnetic stirrer and a condenser. Triethylamine (1.44 g, 14.22 mmol) was added while stirring. The temperature was raised to 80° C. under a nitrogen atmosphere. The mixture was stirred overnight to react. After cooling to room temperature, the solvent was evaporated under reduced pressure, and saturated saline (20 mL) and ethyl acetate (30 mL) were added. The mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 1.1 g of a white solid. Yield: 61.6%, LC-MS (APCI): m / z=377.1 (M+1) + .

[0183] Preparation of intermediate compound A-5 3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)cyclohexan-1-ol [ka] A-5

[0184] The following synthetic route was chosen: [ka]

[0185] Step 1: Synthesis of 3-oxocyclohexane-1-carboxylic acid compound Ethyl 3-oxocyclohexane-1-carboxylate (1 g, 5.88 mmol), THF (10 mL), and HO (10 mL) were added in sequence to a 100 mL single-neck flask equipped with a magnetic stirrer and stirred until dissolved. LiOH (0.42 g, 17.64 mmol) was added. The mixture was stirred overnight at room temperature. The organic solvent was evaporated under reduced pressure. Dilute hydrochloric acid solution (1 M) was added slowly. The pH was adjusted to about 2. A large amount of solid precipitated, which was filtered and washed with distilled water (10 mL). The filter cake was dried under vacuum to give 800 mg of a white solid. Yield: 86.1%.

[0186] Step 2: Synthesis of N-((3-chloropyrazin-2-yl)methyl)-3-oxocyclohexane-1-carboxamide compound (3-Chloropyrazin-2-yl)methylamine hydrochloride (904 mg, 5.23 mmol), 3-oxocyclohexane-1-carboxylic acid (800 mg, 5.23 mmol) and dichloromethane (20 mL) were added in sequence to a 100 mL one-neck flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath. DIPEA (1.69 g, 13.08 mmol), EDCI (1.3 equiv, 6.80 mmol) and DMAP (124 mg, 1.05 mmol) were added under nitrogen atmosphere. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was quenched by adding water (50 mL) and stirred for 3 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 996 mg of an off-white solid. Yield: 74.3%. LC-MS(APCI):m / z=268.2(M+1) + .

[0187] Step 3: Synthesis of 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexan-1-one compound N-((3-chloropyrazin-2-yl)methyl)-3-oxocyclohexane-1-carboxamide (100 mg, 0.373 mmol), pyridine (88 mg, 1.12 mmol) and dichloromethane (10 mL) were added to a 50 mL two-neck flask equipped with a magnetic stirrer. The mixture was cooled in an ice-water bath and trifluoromethanesulfonic anhydride (316 mg, 1.12 mmol) was added dropwise under a nitrogen atmosphere. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (30 mL) and stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layers were combined, diluted with hydrochloric acid (1 M, 10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 32 mg of an off-white solid. Yield: 34.3%, LC-MS (APCI): m / z=250.1 (M+1). + .

[0188] Step 4: Synthesis of 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl-1-ol compound 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexan-1-one (530 mg, 2.12 mmol) and MeOH (20 mL) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled in an ice-water bath and NaBH4 (4.24 mmol, 161 mg) was added slowly. After the addition was complete, the reaction was stirred in the ice bath for an additional hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and stirred for 5 minutes. The organic solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness. The residue was passed through a silica gel column to give 435 mg of an off-white solid. Yield: 82.1%, LC-MS (APCI): m / z = 250.1 (M+1) + .

[0189] Step 5: Synthesis of 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl-1-ol compound 3-(8-Chloroimidaz[1,5-a]pyrazin-3-yl)cyclohexyl-1-ol (435 mg, 1.73 mmol) and acetonitrile (10 mL) were added sequentially to a 50 mL one-neck flask equipped with a magnetic stirrer. The mixture was cooled in an ice bath and NBS (323.3 mg, 1.82 mmol) was added slowly. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL) and stirred for 3 minutes. Ethyl acetate (20 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness. The residue was passed through a silica gel column to give 465 mg of an off-white solid. Yield: 81.1%, LC-MS (APCI): m / z=369.1 (M+1) + .

[0190] Step 6: Synthesis of intermediate compound A-5 3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl-1-ol (465 mg, 1.4 mmol) and ethylene glycol monomethyl ether (5 mL) were added in sequence to a 100 mL sealed tube equipped with a magnetic stirrer and stirred until dissolved. Aqueous ammonia (10 mL) was added, sealed and heated to 70° C. The reaction was stirred overnight. The mixture was cooled to room temperature. Ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 400 mg of a white solid. Yield: 92.0%, LC-MS (APCI): m / z=311.1 (M+1) + .

[0191] Preparation of intermediate compound A-6 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methylcyclohexan-1-ol [ka] A-6

[0192] The following synthetic route was chosen: [ka]

[0193] Step 1: Synthesis of 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-ol compound 3-((tert-Butyldimethylsilyl)oxy)cyclohexan-1-ol (2 g, 8.69 mmol), triphenylphosphine (6 g, 22.90 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 7.66 mmol) were added to a 100 mL three-neck flask equipped with a magnetic stirrer and a condenser. The flask was evacuated and the atmosphere replaced with nitrogen three times. Anhydrous THF (20 mL) was added under ice-water bath cooling. The mixture was stirred and dispersed. DIAD (3 g, 14.85 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and the reaction was stirred overnight. Ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, extracted with ethyl acetate (2×50 mL), washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and filtered. 4M dioxane hydrochloride solution was added to the filtrate and stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 2.1 g of a white solid. Yield: 76.36%. LC-MS (APCI): m / z=360.1 (M+1). + .

[0194] Step 2: Synthesis of 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one compound 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-ol (2.1 g, 5.85 mmol) was added to a 100 mL three-neck flask equipped with a magnetic stirrer and a condenser. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous THF (10 mL) was added under ice-water bath cooling, and stirred and dispersed. A solution of Dess-martin oxidant (4.98 g, 11.74 mmol) in DCM (30 mL) was added dropwise and the reaction was stirred for 30 minutes under ice-water bath. The mixture was allowed to warm to room temperature and reacted with stirring overnight. The reaction was quenched by adding saturated Na2S2O3 (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 50 mL). The organic layers were combined, washed with saturated NaHCO3 (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was passed through a silica gel column to give 1 g of a white solid. Yield: 47.89%. LC-MS (APCI): m / z = 358.2 (M+1). + .

[0195] Step 3: Synthesis of intermediate compound A-6 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one compound (1 g, 2.80 mmol) was added to a 100 mL three-neck flask equipped with a magnetic stirrer and a condenser. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous THF (20 mL) was added under ice-water bath cooling, and stirred and dispersed. 3M CH3MgBr (2.8 mL, 8.42 mmol) solution was added dropwise and the reaction was stirred for 30 minutes under ice-water bath cooling. The mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 924 mg of a white solid. Yield: 88.56%. LC-MS (APCI): m / z=374.3 (M+1). + .

[0196] Preparation of intermediate compound A-7 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-ol [ka] A-7

[0197] The following synthetic route was chosen: [ka]

[0198] Step 1: Synthesis of 3-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound 4-Dioxaspiro[4.5]decan-8-ol (2.9 g, 18.35 mmol), triphenylphosphine (12 g, 45.80 mmol), and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4 g, 15.32 mmol) were added to a 100 mL three-neck flask equipped with a magnetic stirrer and a condenser. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous THF (20 mL) was added under ice-water bath cooling, stirred and dispersed. DIAD (6.19 g, 30.64 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and reacted with stirring overnight. Ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, extracted with ethyl acetate (2 x 50 mL), washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 3.32 g of a white solid. Yield: 54.07%. LC-MS (APCI): m / z=402.1 (M+1). + .

[0199] Step 2: Synthesis of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one compound 3-Iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound (3.6 g, 89.78 mmol) was added to a 100 mL one-neck flask equipped with a magnetic stirrer and a condenser. Acetone (40 mL) and water (40 mL) were added at room temperature. PyTs (4.62 g, 183.84 mmol) was added. The mixture was stirred and dispersed. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was heated to 65° C. and reacted with stirring overnight. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 2.8 g of a white solid. Yield: 87.50%. LC-MS (APCI): m / z=358.5 (M+1). + .

[0200] Step 3: Synthesis of intermediate compound A-7 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one (1 g, 2.80 mmol) was added to a 50 mL three-neck flask equipped with a magnetic stirrer and a condenser tube. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous MeOH (10 mL) was added under ice-water bath cooling, stirred and dispersed. NaBH4 (43 mg, 1.12 mmol) was added and the reaction was stirred under ice-water bath for 30 minutes. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 620 mg of a white solid. Yield: 61.65%. LC-MS(APCI): m / z=360.3(M+1) + .

[0201] Preparation of intermediate compound A-8 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentan-1-ol [ka] A-8

[0202] The following synthetic route was chosen: [ka]

[0203] Step 1: Synthesis of 3-hydroxycyclopentyl methanesulfonic acid Cyclopentane-1,3-diol (1 g, 9.80 mmol) and triethylamine (1.98 g, 19.60 mmol) were added to a 50 mL two-neck flask equipped with a magnetic stirrer and a condenser tube. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Anhydrous DCM (10 mL) was added under ice-water bath cooling, stirred and dispersed. MsCl (1.12 g, 9.82 mmol) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was stirred and reacted overnight while maintaining the temperature. Ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, extracted with ethyl acetate (2 x 50 mL), washed with saturated sodium carbonate (2 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. 1.25 g of crude product was obtained. Yield: 70.83%.

[0204] Step 2: Synthesis of intermediate compound A-8 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (750 mg, 2.87 mmol) was added to a 50 mL single-neck flask equipped with a magnetic stirrer and a condenser tube. DMF (10 mL) was added at room temperature. 3-Hydroxycyclopentylmethanesulfonic acid (600 mg, 3.33 mmol) was added, followed by cesium carbonate (2.3 g, 7.08 mmol). The mixture was stirred and dispersed. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The temperature was raised to 100° C. The mixture was stirred and reacted overnight while maintaining the temperature. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 706 mg of a white solid. Yield: 71.36%. LC-MS(APCI):m / z=345.3(M+1) + .

[0205] Preparation of intermediate compound A-9 (trans-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-2-en-1-yl) acetate [ka] A-9

[0206] The following synthetic route was chosen: [ka]

[0207] A 100 mL three-neck flask equipped with a magnetic stirrer was charged with 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 7.03 mmol), (cis-4-hydroxycyclopent-2-en-1-yl)acetate (1.53 g, 5.86 mmol), Ph3P (4.61 g, 17.58 mmol), and THF (20 ml). The flask was evacuated and the atmosphere replaced with nitrogen three times. Under ice-water bath cooling, DIAD (2.37 g, 11.72 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at room temperature under nitrogen atmosphere. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.98 g of a white solid. Yield: 43.4%. LC-MS (APCI): m / z=386.0 (M+1). + .

[0208] Preparation of intermediate compound A-10 4-amino-3-(4-bromophenyl)-1-(4-hydroxycyclohexyl)-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one [ka] A-10

[0209] The following synthetic route was chosen: [ka]

[0210] Step 1: Synthesis of ethyl 4-(4-bromophenyl)-2,4-dioxobutyrate compound Ethanol (50 mL), sodium ethoxide solution (10.5 g, 20 wt%), and diethyl oxalate (4.5 g, 30.1 mmol) were added in sequence to a 250 mL two-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was reacted at room temperature for 10 minutes, and then a solution of 4-bromobenzophenone (5 g, 25 mmol) in ethanol (20 mL) was added dropwise to the above reaction solution under an ice bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. Acetic acid (1.81 g, 30.1 mmol) was added to the reaction solution and stirred at room temperature for 10 minutes. The reaction was quenched and the reaction solution was directly stored for the next step.

[0211] Step 2: Synthesis of ethyl 3-(4-bromophenyl)-1H-pyrazole-5-formate compound Hydrazine hydrate (1.25 g, 25 mmol) was added dropwise directly to the reaction solution quenched in step 1 and reacted overnight at room temperature. Water (60 mL) and ethanol (100 mL) were added. The mixture was stirred at room temperature for 10 minutes. Ethanol was removed using a rotary evaporator, and ethyl acetate (100 mL x 3) was added for extraction. The organic layers were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 7.0 g of a yellow oily substance. The combined yield of step 1 and step 2 was 94.4%. LC-MS (APCI): m / z = 296.1 (M + 1) + .

[0212] Step 3: Synthesis of ethyl 3-(4-bromophenyl)-4-iodo-1H-pyrazole-5-formate compound Anhydrous acetonitrile (60 mL), ethyl 3-(4-bromophenyl)-1H-pyrazole-5-carboxylate (7 g, 23.7 mmol), NIS (5.87 g, 26.1 mmol), and CAN (1.3 g, 2.37 mmol) were added sequentially to a 150 mL two-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was heated to 90° C. Water (60 mL) was added. The mixture was extracted with ethyl acetate (120 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 8.3 g of a yellow oily substance. Yield: 83%, LC-MS (APCI): m / z=421.2 (M+1). + .

[0213] Step 4: Synthesis of 3-(4-bromophenyl)-4-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-5-carboxylate ethyl compound Anhydrous THF (10 mL), ethyl 3-(4-bromophenyl)-4-iodo-1H-pyrazole-5-carboxylate (1 g, 2.38 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (0.47 g, 2.97 mmol), and Ph3P (1.871 g, 7.14 mmol) were added to a 50 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under ice-water bath cooling, DIAD (0.962 g, 4.76 mmol) was added dropwise, stirred and dispersed. The reaction was stirred for 10 minutes under ice-water bath and slowly warmed to room temperature. The mixture was stirred and reacted overnight while maintaining the temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.1 g of a white solid. Yield: 82%. LC-MS (APCI): m / z=560.0 (M+1). + .

[0214] Step 5: Synthesis of 3-(4-bromophenyl)-4-cyano-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-4-iodo-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-5-carboxylate (1.1 g, 1.97 mmol) and DMF (10 mL) were charged to a 50 mL one-neck flask equipped with a magnetic stirrer and condenser tube and stirred until dissolved. Copper(I) cyanide (0.26 g, 2.9 mmol), Pd2(dba)3 (0.18 g, 0.19 mmol), and Pd(dppf)Cl2 (0.16 g, 0.19 mmol) were added. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under nitrogen atmosphere, the mixture was heated to 100 °C and the reaction was stirred overnight. At room temperature, the reaction was quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.73 g of a white solid. Yield: 80%. LC-MS (APCI): m / z=460.0 (M+1). + .

[0215] Step 6: Synthesis of 3-(4-bromophenyl)-4-cyano-1-(4-oxocyclohexanyl)-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-4-cyano-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-5-carboxylate (735 mg, 1.60 mmol), acetone (5 mL), water (5 mL) and PPTS (805 mg, 3.21 mmol) were charged into a 50 mL one-neck flask equipped with a magnetic stirrer and a condenser tube. The mixture was stirred until dissolved and heated to 90° C. under nitrogen atmosphere. The mixture was stirred and reacted overnight while maintaining the temperature. The reaction was cooled to room temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL×3). The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.583 g of a white solid. Yield: 87.74%. LC-MS(APCI): m / z=416.0(M+1) + .

[0216] Step 7: Synthesis of 3-(4-bromophenyl)-4-cyano-1-(4-hydroxycyclohexanyl)-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-4-cyano-1-(4-oxocyclohexanyl)-1H-pyrazole-5-carboxylate (583 mg, 1.40 mmol) and absolute ethanol (10 mL) were charged into a 50 mL one-neck flask equipped with a magnetic stirrer. Sodium borohydride (23 mg, 0.6 mmol) was added while stirring in an ice-water bath. The mixture was warmed to room temperature and the reaction was stirred for 30 minutes. The solvent was evaporated under reduced pressure. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.492 g of a white solid. Yield: 83.99%. LC-MS (APCI): m / z=418.0 (M+1) + .

[0217] Step 8: Synthesis of intermediate compound A-10 Ethyl 3-(4-bromophenyl)-4-cyano-1-(4-hydroxycyclohexanyl)-1H-pyrazole-5-carboxylate (492 mg, 1.18 mmol) and ethanol (25 mL) were charged into a 50 mL one-neck flask equipped with a magnetic stirrer and a condenser tube, and stirred until dissolved. Hydrazine hydrate (8.5 mL) was added, and the temperature was raised to 80° C. under a nitrogen atmosphere. The mixture was stirred overnight while maintaining the temperature. The reaction was cooled to room temperature. Water (30 mL) was added to quench the reaction. Ethyl acetate (30 mL×3) was added for extraction. The organic layer was separated, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 0.171 g (low polarity) and 0.116 g (high polarity) of a white solid. Yield: 60.36%. LC-MS(APCI): m / z=404.0(M+1) + .

[0218] Preparation of intermediate compound A-11 4-amino-3-(4-bromophenyl)-1-(3-hydroxycyclopentanyl)-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one [ka] A-11

[0219] The following synthetic route was chosen: [ka]

[0220] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol compound THF (20 mL), 1,3-cyclopentanediol (1.1 g, 10.78 mmol), and imidazole (1.1 g, 16.18 mmol) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and TBDPSCl (2.97 g, 10.8 mmol) was added. The mixture was stirred for 10 min and slowly warmed to room temperature. The reaction was stirred for 2 h while maintaining the temperature. Ethyl acetate (50 mL×3) and water (50 mL) were added for extraction. The organic layer was separated, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness. The residue was passed through a column (petroleum ether / ethyl acetate (10 / 1)) to give 1.5 g of a colorless, transparent oil. Yield: 40.9%. LC-MS(APCI): m / z=341.2(M+1) + .

[0221] Step 2: Synthesis of 3-(4-bromophenyl)-1-(3-((tert-butyldiphenylsilyl)oxy)cyclopentanyl)-4-iodo-1H-pyrazole-5-carboxylate ethyl compound Anhydrous THF (20 mL), ethyl 3-(4-bromophenyl)-4-iodo-1H-pyrazole-5-carboxylate (1.5 g, 3.57 mmol), 3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol (1.21 g, 3.56 mmol), and Ph3P (2.8 g, 10.68 mmol) were added to a 50 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under ice-water bath cooling, DIAD (1.44 g, 7.13 mmol) was added dropwise, stirred and dispersed. The reaction was stirred in an ice-water bath for 10 minutes and slowly warmed to room temperature. The mixture was stirred and reacted overnight while maintaining the temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 2.3 g of a white solid. Yield: 87%. LC-MS (APCI): m / z=743.0 (M+1).+ .

[0222] Step 3: Synthesis of 3-(4-bromophenyl)-1-(3-hydroxycyclopentanyl)-4-iodo-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-1-(3-((tert-butyldiphenylsilyl)oxy)cyclopentanyl)-4-iodo-1H-pyrazole-5-carboxylate (2.3 g, 3.09 mmol) and hydrochloric acid / isopropanol solution (5 mol / L, 10 mL) were added to a 50 mL single-neck flask equipped with a magnetic stirrer and the reaction was stirred at room temperature for 0.5 h. The solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.28 g of a white solid. Yield: 82.5%. LC-MS (APCI): m / z=504.0 (M+1). + .

[0223] Step 4: Synthesis of 3-(4-bromophenyl)-4-cyano-1-(3-hydroxycyclopentanyl)-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-1-(3-hydroxycyclopentanyl)-4-iodo-1H-pyrazole-5-carboxylate (1.284 g, 2.55 mmol) and DMF (15 mL) were charged to a 50 mL one-neck flask equipped with a magnetic stirrer and condenser tube and stirred until dissolved. Copper(I) cyanide (0.343 g, 3.83 mmol), Pd2(dba)3 (0.234 g, 0.26 mmol), and Pd(dppf)Cl2 (0.208 g, 0.26 mmol) were added. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under nitrogen atmosphere, the mixture was heated to 100 °C and the reaction was stirred overnight. At room temperature, the reaction was quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was separated, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.77 g of a white solid. Yield: 75%. LC-MS (APCI): m / z=404.0 (M+1). + .

[0224] Step 5: Synthesis of intermediate compound A-11 Ethyl 3-(4-bromophenyl)-4-cyano-1-(3-hydroxycyclopentanyl)-1H-pyrazole-5-carboxylate (1 g, 2.48 mmol) and ethanol (43 mL) were charged into a 100 mL one-neck flask equipped with a magnetic stirrer and a condenser tube, and stirred until dissolved. Hydrazine hydrate (14 mL) was added, and the temperature was raised to 80° C. under a nitrogen atmosphere. The mixture was stirred overnight while maintaining the temperature. The reaction was cooled to room temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL×3). The organic layer was separated, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 0.52 g of a white solid. Yield: 54%. LC-MS (APCI): m / z=390.0 (M+1) + .

[0225] Preparation of intermediate compound A-12 4-amino-3-(4-bromophenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one [ka] A-12

[0226] The following synthetic route was chosen: [ka]

[0227] Step 1: Synthesis of 3-(4-bromophenyl)-1-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-4-iodo-1H-pyrazole-5-carboxylate ethyl compound Anhydrous tetrahydrofuran (60 mL), 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (1 g, 2.7 mmol), ethyl 3-(4-bromophenyl)-4-iodo-1H-pyrazole-5-carboxylate (1.25 g, 3.0 mmol), and triphenylphosphine (1.06 g, 4.0 mmol) were added sequentially to a 150 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The reaction was cooled in an ice bath. DIAD (0.82 g, 4.0 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature overnight. Water (60 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 1 g of a colorless, transparent oil. Yield: 47.9%. LC-MS(APCI):m / z=773.1(M+1) + .

[0228] Step 2: Synthesis of 3-(4-bromophenyl)-1-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-4-cyano-1H-pyrazole-5-carboxylate ethyl compound DMF (30 mL), ethyl 3-(4-bromophenyl)-1-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-4-iodo-1H-pyrazole-5-carboxylate (1 g, 1.3 mmol), CuCN (0.173 g, 1.43 mmol), Pd(dppf)Cl2·DCM (0.106 g, 0.13 mmol), and Pd2(dba)3 (0.118 g, 0.13 mmol) were added sequentially to a 100 mL three-neck flask equipped with a magnetic stirrer and a condenser tube. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was heated to 100 °C and reacted overnight. Water (60 mL) and ethyl acetate (120 mL × 3) were added for extraction. The organic layers were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 600 mg of a white solid. Yield: 69%, LC-MS (APCI): m / z=672.2 (M+1). + .

[0229] Step 3: Synthesis of ethyl 3-(4-bromophenyl)-4-cyano-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-5-carboxylate compound Ethyl 3-(4-bromophenyl)-1-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-4-cyano-1H-pyrazole-5-carboxylate (600 mg, 0.90 mmol) and hydrochloric acid / isopropanol solution (5 mL, 2 mol / L) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer and reacted at room temperature overnight. The solution was concentrated. The isopropanol solution was concentrated to dryness using a rotary evaporator. The pH of the concentrated solution was adjusted to 8 using saturated aqueous sodium bicarbonate. Water (20 mL) and dichloromethane (30 mL x 3) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 300 mg of a yellow solid. Yield: 77%, LC-MS (APCI): m / z = 434.2 (M + 1) + .

[0230] Step 4: Synthesis of intermediate compound A-12 Ethanol (8 mL), ethyl 3-(4-bromophenyl)-4-cyano-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-5-carboxylate (300 mg, 0.7 mmol), and hydrazine hydrate (2 mL, content 80%) were added in sequence to a 10 mL microwave tube equipped with a magnetic stirrer. The mixture was heated to 80° C. and reacted overnight while maintaining the temperature. The reaction solution was directly concentrated and passed through a silica gel column to obtain 90 mg of a white solid. Yield: 31%, LC-MS (APCI): m / z=421.1 (M+1). + .

[0231] Preparation of intermediate compound A-13 4-amino-3-(4-bromophenyl)-1-(3-hydroxycyclohexanyl)-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one [ka] A-13

[0232] The following synthetic route was chosen: [ka]

[0233] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)cyclohexan-1-ol compound THF (20 mL), 1,3-cyclohexanediol (1.25 g, 10.78 mmol), and imidazole (1.1 g, 16.18 mmol) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and TBDPSCl (2.97 g, 10.8 mmol) was added. The mixture was stirred for 10 min and slowly warmed to room temperature. The reaction was stirred for 2 h while maintaining the temperature. Ethyl acetate (50 mL×3) and water (50 mL) were added for extraction. The organic layer was separated, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness and passed through a column (petroleum ether / ethyl acetate (10 / 1)) to give 1.5 g of a colorless, transparent oil. Yield: 39.2%. LC-MS(APCI): m / z=355.2(M+1) + .

[0234] Step 2: Synthesis of 3-(4-bromophenyl)-1-(3-((tert-butyldiphenylsilyl)oxy)cyclohexanyl)-4-iodo-1H-pyrazole-5-carboxylate ethyl compound Anhydrous THF (20 mL), ethyl 3-(4-bromophenyl)-4-iodo-1H-pyrazole-5-carboxylate (1.5 g, 3.57 mmol), 3-((tert-butyldiphenylsilyl)oxy)cyclohexan-1-ol (1.26 g, 3.56 mmol), and Ph3P (2.8 g, 10.68 mmol) were added to a 50 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under ice-water bath cooling, DIAD (1.44 g, 7.13 mmol) was added dropwise, stirred and dispersed. The reaction was stirred for 10 minutes under ice-water bath and slowly warmed to room temperature. The mixture was stirred and reacted overnight while maintaining the temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 2.0 g of a white solid. Yield: 75.7%. LC-MS (APCI): m / z=741.1 (M+1).+ .

[0235] Step 3: Synthesis of 3-(4-bromophenyl)-1-(3-hydroxycyclohexanyl)-4-iodo-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-1-(3-((tert-butyldiphenylsilyl)oxy)cyclohexanyl)-4-iodo-1H-pyrazole-5-carboxylate (1.5 g, 2.02 mmol) and hydrochloric acid / isopropanol solution (5 mol / L 10 mL) were added to a 50 mL single-neck flask equipped with a magnetic stirrer and the reaction was stirred at room temperature for 0.5 h. The solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.8 g of a white solid. Yield: 76.5%. LC-MS (APCI): m / z=519.0 (M+1). + .

[0236] Step 4: Synthesis of 3-(4-bromophenyl)-4-cyano-1-(3-hydroxycyclohexanyl)-1H-pyrazole-5-carboxylate ethyl compound Ethyl 3-(4-bromophenyl)-1-(3-hydroxycyclohexanyl)-4-iodo-1H-pyrazole-5-carboxylate (0.64 g, 1.26 mmol) and DMF (8 mL) were charged to a 50 mL one-neck flask equipped with a magnetic stirrer and condenser tube and stirred until dissolved. Copper cyanide (0.17 g, 1.94 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol), and Pd(dppf)Cl2 (0.21 g, 0.13 mmol) were added. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under nitrogen atmosphere, the mixture was heated to 100 °C and the reaction was stirred overnight. At room temperature, the reaction was quenched by adding water (20 mL). Ethyl acetate (30 mL x 3) was added for extraction. The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.40 g of a white solid. Yield: 75.9%. LC-MS (APCI): m / z=418.0 (M+1). + .

[0237] Step 5: Synthesis of intermediate compound A-13 Ethyl 3-(4-bromophenyl)-4-cyano-1-(3-hydroxycyclohexanyl)-1H-pyrazole-5-carboxylate (0.4 g, 0.95 mmol) and ethanol (20 mL) were charged into a 100 mL one-neck flask equipped with a magnetic stirrer and a condenser tube, and stirred until dissolved. Hydrazine hydrate (8 mL) was added and the temperature was raised to 80° C. under a nitrogen atmosphere. The mixture was stirred overnight while maintaining the temperature. The reaction was cooled to room temperature. Water (30 mL) was added to quench the reaction. Ethyl acetate (30 mL×3) was added for extraction. The organic layer was separated, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.22 g of a white solid. Yield: 57.5%. LC-MS (APCI): m / z=403.0 (M+1) + .

[0238] Preparation of intermediate compound A-14 (cis-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-2-en-1-yl) acetate [ka] A-14

[0239] The following synthetic route was chosen: [ka]

[0240] Step 1: Synthesis of trans-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-2-en-1-ol compound Intermediate A-9 (1.5 g, 3.896 mmol), methanol (200 mL) and water (10 mL) were charged to a 100 mL three-neck flask equipped with a magnetic stirrer and stirred until dissolved. Potassium carbonate (1.61 g, 11.688 mmol) was added. The flask was evacuated and the atmosphere was replaced with nitrogen three times. Under nitrogen atmosphere, the reaction was stirred at 80° C. for 12 hours. The reaction was cooled to room temperature. Water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.0 g of a white solid. Yield: 74.8%. LC-MS (APCI): m / z=344.0 (M+1) + .

[0241] Step 2: Synthesis of intermediate A-14 Trans-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopent-2-en-1-ol (1.0 g, 2.915 mmol) and THF (20 mL) were added to a 50 mL three-necked bottle equipped with a magnetic stirrer and stirred until dissolved. Glacial acetic acid (210.0 mg, 3.498 mmol) and triphenylphosphine (2.291 g, 8.745 mmol) were added. The flask was evacuated and the atmosphere replaced with nitrogen three times. The mixture was cooled using an ice-water bath and DIAD (1.178 g, 5.830 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature under nitrogen atmosphere for 12 hours. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 400 mg of a white solid. Yield: 35.6%. LC-MS (APCI): m / z=386.0 (M+1). + .

[0242] Preparation of intermediate compound A-15 5-(4-bromophenyl)-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine [ka] A-15

[0243] The following synthetic route was chosen: [ka]

[0244] Step 1: Synthesis of (Z)-2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-ylidene)acetonitrile compound Tetrahydrofuran (170 mL) and NaH (2.1 g, 52.5 mmol, 60%) were added sequentially to a 500 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere replaced with nitrogen three times. The mixture was cooled to 0° C. and a solution of diethyl cyanomethyl phosphate (9.3 g, 52.5 mmol) in tetrahydrofuran (20 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0° C. for 30 minutes. A solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one (17.0 g, 47.7 mmol) in tetrahydrofuran (20 mL) was added dropwise and the mixture was reacted at 0° C. for 30 minutes. The mixture was allowed to warm to room temperature and react overnight. Ethyl acetate (200 mL×3) and water (100 mL) were added for extraction. The organic layer was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 13.5 g of a yellow oil. Yield: 72%. LC-MS (APCI): m / z=392 (M+1). + .

[0245] Step 2: Synthesis of 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)acetonitrile compound Ethyl acetate (100 mL), acetic acid (1 mL), (Z)-2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-ylidene)acetonitrile (13.5 g, 34.5 mmol) and Pd / C (1.35 g, 10%) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was reacted at room temperature overnight. The Pd / C was directly filtered off and the reaction solution was concentrated. After concentration, the residue was passed through a silica gel column to obtain 7.5 g of a yellow oily substance. Yield: 56%. LC-MS (APCI): m / z=394 (M+1) + . 1H NMR (500 MHz, DMSO-D6) δ (ppm): 7.63-7.60 (m, 4H), 7.45-7.40 (m, 6H), 3.67-3.61 (m, 2H), 3.58-3.52 (m, 2H), 3.45-3.41 (m, 1H), 2.70-2.62 (m, 2H), 1.95-1.90 (m, 1H), 1.80-1.68 (m, 2H), 1.51-1.43 (m, 2H), 0.98 (s, 9H).

[0246] Step 3: Synthesis of 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-3-oxopropionitrile compound Tetrahydrofuran (100 mL) and 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)acetonitrile (6.2 g, 15.8 mmol) were added sequentially to a 250 mL three-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was cooled to -78°C and a solution of LDA in tetrahydrofuran (7.9 mL, 15.8 mmol, 2 mol / L) was added dropwise. After the addition was complete, the mixture was reacted at -78°C for 30 minutes. A solution of ethyl formate (2.3 g, 31.6 mmol) in tetrahydrofuran (20 mL) was added dropwise and reacted at -78°C for 30 minutes. The mixture was warmed to room temperature and reacted overnight. Hydrochloric acid (1 mol / L) was added to adjust the pH to 3. Ethyl acetate (150 mL x 3) and water (70 mL) were added for extraction. The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 2.6 g of a yellow oil. Yield: 40%. LC-MS (APCI): m / z=422 (M+1). + .

[0247] Step 4: Synthesis of (Z)-3-((4-bromophenyl)(cyanomethyl)amino)-2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)acrylonitrile compound Toluene (15 mL), 2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-3-oxopropionitrile (359 mg, 0.85 mmol), 2-((4-bromophenyl)amino)acetonitrile (150 mg, 0.85 mmol), and p-toluenesulfonic acid (13.5 mg, 0.085 mmol) were added sequentially to a 50 mL three-neck flask equipped with a magnetic stirrer. A water separator was attached and the reaction was refluxed overnight. Saturated aqueous sodium bicarbonate was added to adjust the pH to 7-8. Ethyl acetate (30 mL x 3) and water (15 mL) were added for extraction. The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 526 mg of crude product as a yellow oil. LC-MS(APCI): m / z=614(M+1) + .

[0248] Step 5: Synthesis of 3-amino-1-(4-bromophenyl)-4-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-1H-pyrrole-2-carbonitrile compound Tert-butanol (15 mL), (Z)-3-((4-bromophenyl)(cyanomethyl)amino)-2-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)acrylonitrile (523 mg, 0.85 mmol) and a solution of potassium tert-butoxide in tert-butanol (0.9 mL, 0.9 mmol, 1 mol / L) were charged into a 50 mL three-necked flask equipped with a magnetic stirrer, heated to 80° C., and reacted for 30 minutes. The mixture was cooled to room temperature. A hydrochloric acid solution (1 mol / L) was added to adjust the pH to 7. Ethyl acetate (30 mL×3) and water (15 mL) were added for extraction. The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 50 mg of the crude product as a yellow oil. Yield: 9.5%, LC-MS (APCI): m / z=614(M+1) + .

[0249] Step 6: Synthesis of intermediate compound A-15 DME (5 mL), 3-amino-1-(4-bromophenyl)-4-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-1H-pyrrole-2-carbonitrile (50 mg, 0.081 mmol) and formamidine acetate (42 mg, 0.41 mmol) were added sequentially to a microwave reaction tube (10 mL) equipped with a magnet. The tube was filled with sufficient nitrogen. The cover of the microwave reaction tube was clamped. The microwave reaction tube was placed in a microwave reactor at 140° C. and reacted for 1 h. The reaction mixture was cooled to room temperature, directly concentrated and passed through a silica gel column to give 55 mg of a white solid. Yield: 100%, LC-MS (APCI): m / z=641 (M+1) + .

[0250] Preparation of intermediate compound A-16 6-chloro-N,N-bis(4-methoxybenzyl)-5-nitropyrimidin-4-amine [ka] A-16

[0251] The following synthetic route was chosen: [ka]

[0252] Isopropanol (50 mL), 4,6-dichloro-5-nitropyrimidine (8 g, 41.6 mmol), NH(PMB)2 (10.68 g, 41.6 mmol) and triethylamine (5.44 g, 54 mmol) were added sequentially to a 100 mL one-neck flask equipped with a magnetic stirrer. The mixture was heated to 95° C. and reacted for 4 h. The reaction mixture was directly concentrated and passed through a silica gel column to give 16.4 g of a yellow oil. Yield: 96%, LC-MS (APCI): m / z=415 (M+1). + .

[0253] Preparation of intermediate compound A-17 6-amino-7-(4-bromophenyl)-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-7,9-dihydro-8H-purin-8-one [ka] A-17

[0254] The following synthetic route was chosen: [ka]

[0255] Step 1: Synthesis of 3-((6-(bis(4-methoxybenzyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexan-1-ol compound 1,4-Dioxane (80 mL), intermediate compound A-16 (8.2 g, 19.8 mmol), 3-aminocyclohexanol (2.28 g, 19.8 mmol) and triethylamine (4.0 g, 39.6 mmol) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer, heated to 50° C. and reacted overnight. Water (100 mL) and ethyl acetate (150 mL×3) were added for extraction. The organic layers were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 8.88 g of a yellow oily substance. Yield: 91%, LC-MS (APCI): m / z=494 (M+1) + .

[0256] Process 2:N 4 -(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-N 6 ,N 6 Synthesis of -bis(4-methoxybenzyl)-5-nitropyrimidine-4,6-diamine compound THF (100 mL), 3-((6-(bis(4-methoxybenzyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexan-1-ol (7.27 g, 14.7 mmol) and imidazole (1.5 g, 22.1 mmol) were added in sequence to a 250 mL three-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and t-butyldiphenylchlorosilane (4.45 g, 16.2 mmol) was added. The mixture was stirred for 10 min. The reaction was allowed to warm slowly to room temperature and stirred for 2 h. Ethyl acetate (150 mL×3) and water (75 mL) were added for extraction. The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 10.35 g of a yellow oil. Yield: 96%. LC-MS(APCI): m / z=732(M+1) + .

[0257] Process 3:N 4 -(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-N 6 ,N 6 Synthesis of -bis(4-methoxybenzyl)pyrimidine-4,5,6-triamine compound Ethyl acetate (100 mL), N 4 -(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-N 6 ,N 6 -Bis(4-methoxybenzyl)-5-nitropyrimidine-4,6-diamine (10.35 g, 14.1 mmol), zinc powder (9.2 g, 141 mmol), and aqueous ammonium chloride solution (4.54 g, 84.9 mmol, 3.0 mol / L) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer and reacted overnight at room temperature. The reaction mixture was filtered, concentrated, and passed through a silica gel column to obtain 8.9 g of a yellow oily substance. Yield: 90%, LC-MS (APCI): m / z=702 (M+1). + .

[0258] Step 4: Synthesis of 6-(bis(4-methoxybenzyl)amino)-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-7,9-dihydro-8H-purin-8-one compound DCM (100 mL), N 4 -(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-N 6 ,N 6 -Bis(4-methoxybenzyl)pyrimidine-4,5,6-triamine (5 g, 7.1 mmol), DIPEA (2.0 g, 15.7 mmol) and triphosgene (2.1 g, 7.1 mmol, 3.0 mol / L) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer and reacted overnight at room temperature. Ethyl acetate (100 mL x 3) and water (100 mL) were added for extraction. The organic layer was separated, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 2.035 g of a yellow oily substance. Yield: 40.1%. LC-MS (APCI): m / z = 728 (M + 1) + .

[0259] Step 5: Synthesis of 6-amino-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-7,9-dihydro-8H-purin-8-one compound DCM (3 mL), 6-(bis(4-methoxybenzyl)amino)-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-7,9-dihydro-8H-purin-8-one (200 mg, 0.27 mmol) and TFA (3 mL) were sequentially charged into a 50 mL one-neck flask equipped with a magnetic stirrer, and the temperature was raised to 50° C. for 4 hours. The reaction solution was adjusted to pH 7 using a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate (30 mL×3) and water (15 mL). The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 80 mg of a yellow oily substance. Yield: 59.8%. LC-MS (APCI): m / z=488 (M+1) + .

[0260] Step 6: Synthesis of intermediate compound A-17 DCM (15 mL), 6-amino-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-7,9-dihydro-8H-purin-8-one (80 mg, 0.16 mmol), 4-bromophenylboronic acid (43 mg, 0.21 mmol), copper(II) acetate (15 mg, 0.08 mmol), TEMPO (28 mg, 0.176 mmol) and TEA (66 mg, 0.64 mmol) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with oxygen three times. The mixture was reacted at room temperature overnight. The reaction mixture was directly concentrated and passed through a silica gel column to give 15 mg of a yellow oily substance. Yield: 15%, LC-MS (APCI): m / z=642 (M+1). + .

[0261] Preparation of intermediate compound A-18 (1R,4R)-4-(6-(bis(4-methoxybenzyl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxylate ethyl compound [ka] A-18

[0262] The following synthetic route was chosen: [ka]

[0263] Step 1: Synthesis of (1R,4R)-4-((6-(bis(4-methoxybenzyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxylate ethyl compound 1,4-Dioxane (100 mL), intermediate compound A-16 (8.2 g, 19.8 mmol), (1R,4R)-ethyl 4-aminocyclohexane-1-carboxylate hydrochloride (2.38 g, 19.8 mmol) and triethylamine (6.0 g, 59.4 mmol) were added in sequence to a 250 mL one-neck flask equipped with a magnetic stirrer, heated to 50° C. and reacted overnight. Extraction was performed by adding water (100 mL) and ethyl acetate (150 mL×3). The organic layers were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 10.67 g of a yellow oily substance. Yield: 98%, LC-MS (APCI): m / z=550 (M+1) + .

[0264] Step 2: Synthesis of (1R,4R)-4-((5-amino-6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate ethyl compound Ethyl acetate (100 mL), (1R,4R)-4-((6-(bis(4-methoxybenzyl)amino)-5-nitropyrimidin-4-yl)amino)ethyl cyclohexane-1-carboxylate (10.67 g, 19.4 mmol), zinc powder (12.7 g, 194 mmol), and aqueous ammonium chloride solution (6.3 g, 117 mmol, 3.0 mol / L) were sequentially charged into a 250 mL one-neck flask equipped with a magnetic stirrer and reacted overnight at room temperature. The reaction mixture was filtered, concentrated, and passed through a silica gel column to obtain 8.7 g of a yellow oily substance. Yield: 86%, LC-MS (APCI): m / z=520 (M+1). + .

[0265] Step 3: Synthesis of intermediate compound A-18 DCM (100 mL), (1R,4R)-ethyl 4-((5-amino-6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxylate (8.7 g, 16.7 mmol), DIPEA (4.9 g, 36.9 mmol) and triphosgene (4.97 g, 16.7 mmol, 3.0 mol / L) were sequentially charged into a 250 mL one-neck flask equipped with a magnetic stirrer and reacted at room temperature overnight. Ethyl acetate (100 mL x 3) and water (100 mL) were added for extraction. The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 7.7 g of a yellow oily substance. Yield: 84%. LC-MS (APCI): m / z = 546 (M + 1) + .

[0266] Synthesis of intermediate compound A-19 1-(3-((tert-butyldimethylsilyl)oxy)cycloheptyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound [ka] A-19

[0267] The following synthetic route was chosen: [ka]

[0268] Step 1: Synthesis of 2-cyclohepten-1-ol compound 2-Cyclohepten-1-one (2.0 g, 18.16 mmol) and MeOH (20 mL) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. CeCl3-7H2O (7.44 g, 19.98 mmol) was added. The mixture was further stirred at 0°C. NaBH4 (755.7 mg, 19.98 mmol) was added in batches and stirred at room temperature overnight. The reaction was quenched by adding saturated ammonium chloride solution (20 mL). The organic solvent was removed under reduced pressure on a rotary evaporator. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.02 g of a colorless oily liquid. Yield: 50.1%. LC-MS(APCI): m / z=113.0(M+1) + . 1 H NMR (400MHz, CDCl3) δ (ppm):5.80-5.72 (m, 2H), 4.42-4.40 (m, 1H), 2.23-2.16 (m, 1H), 2.08-2.00 (m, 1H), 1.96-1.91 (m, 1H), 1.72-1.53 (m, 4H), 1.42-1.32 (m, 1H).

[0269] Step 2: Synthesis of tert-butyl(cyclohept-2-en-1-yloxy)dimethylsilane compound 2-Cyclohepten-1-ol (1.0 g, 8.90 mmol) and DCM (10 mL) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. Imidazole (908.9 mg, 13.35 mmol) and tert-butyldimethylchlorosilane (1.48 g, 9.79 mmol) were added and stirred at room temperature for 2 h. The reaction was quenched with saturated saline (10 mL) and extracted with dichloromethane (10 mL x 2). The organic layers were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.7 g of a colorless oily liquid. Yield: 84.5%. LC-MS (APCI): m / z = 227.0 (M + 1) +.

[0270] Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)cycloheptan-1-ol compound Tert-Butyl(cyclohept-2-en-1-yloxy)dimethylsilane (1.65 g, 7.3 mmol) and BH3-THF (1 M, 14.6 mL, 14.6 mmol) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred overnight at room temperature. Aqueous NaOH (3 M, 14.6 mL, 43.8 mmol) and aqueous H2O2 (6.6 mL, 58.4 mmol) were added and stirred at 55 °C for 1 h. The reaction was cooled to room temperature. Saturated saline (20 mL) was added to quench the reaction. Dichloromethane (20 mL x 2) was added for extraction. The organic layers were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 1.0 g of a colorless oily liquid. Yield: 56.1%. LC-MS(APCI): m / z=245.0(M+1) + .

[0271] Step 4: Synthesis of intermediate compound A-19 3-((Tert-butyldimethylsilyl)oxy)cycloheptan-1-ol (1.0 g, 4.1 mmol), 4-amino-3-iodo-1H-pyrrolo[3,4,b]pyrimidine (1.07 g, 4.1 mmol), TPP (2.15 g, 8.2 mmol) and THF (15 mL) were added in sequence to a 50 mL three-neck flask equipped with a magnetic stirrer and further stirred at 0° C. DIAD (1.44 mL, 8.2 mmol) was slowly added dropwise and stirred at room temperature for 6 hours. The reaction was quenched by adding saturated saline (20 mL). Ethyl acetate (20 mL×2) was added for extraction. The organic layers were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 480 mg of a white solid. Yield: 24.0%. LC-MS(APCI): m / z=488.0(M+1) + .

[0272] Preparation of intermediate compound A-20 5-bromo-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine compound [ka] A-20

[0273] The following synthetic route was chosen: [ka]

[0274] Step 1: Synthesis of tert-butyl((3,4-dihydro-2H-pyran-2-yl)methoxy)diphenylsilane compound THF (200 mL), (3,4-dihydro-2H-pyran-2-yl)methanol (20 g, 17.5 mmol) and imidazole (17.9 g, 26.3 mmol) were added in sequence to a 500 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled to 0° C. and tert-butyldiphenylchlorosilane (53.0 g, 19.3 mmol) was added. The mixture was stirred for 10 minutes and slowly warmed to room temperature. The reaction was stirred for 2 hours while maintaining the temperature. Ethyl acetate (200 mL×3) and water (100 mL) were added for extraction. The organic layer was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 60 g of a yellow oil. Yield: 97%. LC-MS (APCI): m / z=353 (M+1) + .

[0275] Step 2: Synthesis of 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol compound THF (200 mL) and tert-butyl((3,4-dihydro-2H-pyran-2-yl)methoxy)diphenylsilane (60 g, 170 mmol) were added in sequence to a 1000 mL three-neck flask equipped with a magnetic stirrer and filled and evacuated with nitrogen three times. The mixture was cooled to 0° C. and a solution of BH3 in tetrahydrofuran (255 mL, 255 mmol, 1.0 mol / L) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. The temperature was lowered to 0° C. and a mixed solution of aqueous sodium hydroxide (151 mL, 302 mmol, 2 mol / L) and aqueous hydrogen peroxide (42 mL, 414 mmol, 30%) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 0.5 h. The mixture was heated to 55° C. and allowed to react for 1 h. The mixture was cooled to room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (300 mL) and extracted with water (300 mL) and ethyl acetate (300 mL x 3). The organic layer was separated, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 45 g of a yellow oily substance. Yield: 71.5%. LC-MS (APCI): m / z = 371 (M + 1). + .

[0276] Step 3: Synthesis of 6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one compound A 500 mL three-neck flask equipped with a magnetic stirrer was charged with DCM (200 mL) and 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (45 g, 122 mmol) in that order and stirred until dissolved. The atmosphere was replaced with nitrogen three times. The mixture was cooled to 0° C. Dess-Martin oxidant (56.7 g, 133 mmol) was added in batches and stirred for 10 min, slowly warmed to room temperature, and stirred for 1 h while maintaining the temperature. DCM (200 mL×3) and water (100 mL) were added for extraction. The organic layer was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 24.6 g of a yellow oil. Yield: 55%. LC-MS (APCI): m / z=369 (M+1) + .

[0277] Step 4: Synthesis of 6-(((tert-butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-3-yl-trifluoromethanesulfonate compound THF (70 mL), 6-(((tert-butyldiphenylsilyl)oxy)methyl)dihydro-2H-pyran-3(4H)-one (5.8 g, 16.3 mmol), and OTf2 (7.22 g, 18.4 mmol) were added in sequence to a 100 mL three-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was cooled to -78 °C. KHMDS (17.9 mL, 17.9 mmol, 1 mol / L) was added dropwise. After the addition was completed, the mixture was reacted for 1 h while maintaining the temperature. The reaction was quenched by adding saturated aqueous ammonium chloride solution (126 mL). The mixture was extracted by adding ethyl acetate (100 mL x 3). The organic layer was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 3.7 g of a yellow oily substance. Yield: 45%. LC-MS(APCI):m / z=501(M+1) + .

[0278] Step 5: Synthesis of tert-butyldiphenyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-yl)methoxy)silane compound 1,4-Dioxane (50 mL), 6-(((tert-butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-3-yl-trifluoromethanesulfonate (3.7 g, 7.4 mmol), bis(pinacolato)diborane (2.25 g, 8.8 mmol), Pd(dppf)Cl2·DCM (0.6 g, 0.74 mmol) and potassium acetate (2.17 g, 22.2 mmol) were added in sequence to a 100 mL three-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was heated to 95 °C and reacted overnight while maintaining the temperature. Ethyl acetate (100 mL × 3) and water (50 mL) were added for extraction. The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 2.2 g of a yellow oil. Yield: 63%. LC-MS (APCI): m / z=479 (M+1). + . 1 H NMR (500 MHz, DMSO-D6) δ (ppm): 7.63-7.60 (m, 4H), 7.48-7.40 (m, 6H), 6.09 (s, 1H), 4.20 (s, 2H), 3.71-3.67 (m, 3H), 2.26-2.24 (m, 2H), 0.98 (s, 9H).

[0279] Step 6: Synthesis of 7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine compound 1,4-Dioxane (30 mL), water (7.5 mL), tert-butyldiphenyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-yl)methoxy)silane (2.2 g, 4.6 mmol), 4-amino-7-bromopyrrolo[2,1-F][1,2,4]triazine (0.817 g, 3.8 mmol), tetratriphenylphosphine palladium (0.22 g, 0.19 mmol), and potassium carbonate (1.57 g, 11.4 mmol) were added in sequence to a 100 mL three-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was heated to 100 °C and reacted for 4 h. Ethyl acetate (80 mL x 3) and water (50 mL) were added for extraction. The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.47 g of a yellow oil. Yield: 80%. LC-MS (APCI): m / z=485 (M+1). + .

[0280] Step 7: Synthesis of 7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine compound Methanol (10 mL), 7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)-5,6-dihydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1 g, 2.0 mmol) and Pd / C (500 mg, 10%) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was reacted at room temperature overnight. The Pd / C was directly filtered off. The reaction solution was concentrated to give 0.8 g of crude product. Yield: 80%. LC-MS (APCI): m / z=487 (M+1). + .

[0281] Step 8: Synthesis of intermediate compound A-20 DMF (10 mL) and 7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.4 g, 0.8 mmol) were added in sequence to a 50 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was cooled to -50°C. Dibromohydantoin (0.26 g, 0.9 mmol) was added, and the temperature was slowly raised to 0°C and stirred for 1 hour while maintaining the temperature. Ethyl acetate (50 mL x 3) and water (15 mL) were added for extraction. The organic layer was separated, washed with saturated saline (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 0.4 g of a yellow oily substance. Yield: 87%. LC-MS(APCI): m / z=565(M+1) + .

[0282] Preparation of intermediate compound B-1 (4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)boronic acid [ka] B-1

[0283] The following synthetic route was chosen: [ka]

[0284] Tetrahydrofuran (120 mL), (4-(aminomethyl)phenyl)boronic acid hydrochloride (12 g, 64.1 mmol) and 5-fluoro-2-methoxybenzoic acid (10.9 g, 64.1 mmol) were sequentially charged into a 500 mL one-neck flask equipped with a magnetic stirrer and a condenser tube, and stirred until dissolved. A solution of T3P in ethyl acetate (1.7 mol / L) (75.5 mL, 128.3 mmol) and DIEA (33 g, 256 mmol) were added with stirring. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The temperature was raised to 70° C. The mixture was stirred and reacted overnight while maintaining the temperature. The reaction was cooled to room temperature and concentrated under reduced pressure. Water (120 mL) and dichloromethane (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and dichloromethane (100 mL) was added. The mixture was stirred for 60 minutes and filtered. The filter cake was washed with a small amount of dichloromethane, and the solid was sucked dry using a vacuum pump to give 17.6 g of a white solid. Yield: 90.7%.

[0285] Preparation of intermediate compound B-2 potassium (5-fluoro-2-methoxybenzoylamino)methyl)trifluoroborate [ka] B-2

[0286] The following synthetic route was chosen: [ka]

[0287] Step 1: Synthesis of 5-fluoro-2-methoxybenzoyl chloride compound 5-Fluoro-2-methoxybenzoic acid (2.6 g, 15 mmol) and anhydrous dichloromethane (30 mL) were added to a 100 mL three-neck flask equipped with a magnetic stirrer and stirred until dissolved. The solution was cooled in an ice-water bath and, under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) and anhydrous DMF (110 mg, 1.5 mmol) were added. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at room temperature. The solvent and incompletely reacted oxalyl chloride were evaporated under reduced pressure and used in the subsequent step.

[0288] Step 3: Synthesis of intermediate compound B-2 2-(Bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 16.5 mmol) and anhydrous THF (30 mL) were added to a 100 mL three-necked flask equipped with a magnetic stirrer and cooled to -78°C under nitrogen atmosphere. KHMDS (16.5 mL, 1M THF solution) was added dropwise and stirred for 30 minutes while maintaining the temperature, then warmed to room temperature and stirred for 30 minutes. Anhydrous methanol (2.11 g, 66 mmol) was added. The mixture was stirred at room temperature for 1 hour. Insoluble solids were filtered off. The filtrate solvent was evaporated at 30°C or less. Anhydrous THF (20 mL) was added and then the filtrate solvent was evaporated. This procedure was repeated twice. The residue was then dissolved in anhydrous THF (20 mL). The above solution of 5-fluoro-2-methoxybenzoyl chloride in THF (20 mL) was added dropwise slowly. After the addition was complete, the reaction was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in methanol (30 mL). An aqueous solution of potassium bifluoride (6.4 g, 82.5 mmol, 20 mL) was added and the reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Toluene (50 mL) was added and the solvent was distilled off. This procedure was repeated twice. The residue was washed with MTBE and filtered. The filter cake was washed with a solution of hot methanol / acetone (1 / 3, 100 mL) and the filtrate was concentrated to dryness. The residue was slurried with MTBE. The precipitated solid was filtered and dried to give 3.5 g of a white solid. Yield: 80.7%. 1H NMR (400MHz, DMSO-D6) δ(ppm): 7.75(brs, 1H), 7.65-7.62(m, 1H), 7.30-7.25(m, 1H), 7.17-7.14(m, 1H), 3.87(s, 3H), 2.13-2.10(m, 2H).

[0289] Example 1 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide compound [ka]

[0290] The following synthetic route was chosen: [ka]

[0291] Step 1: Synthesis of N-(4-(5-amino-4-cyano-1-(3-hydroxycyclohexanyl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound Intermediate compound A-2 (150 mg, 0.414 mmol), intermediate compound B-2 (144 mg, 0.497 mmol), Cs2CO3 (325 mg, 1.242 mmol), Xphos (20 mg, 0.04 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), THF (10 mL) and water (1 mL) were added to a microwave tube. The atmosphere was replaced with nitrogen for 2 minutes and the reaction was reacted at 100 °C under microwave for 1.5 hours. The reaction was cooled to room temperature. Saturated saline (5 mL) and ethyl acetate (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.16 g of a white solid. Yield: 83.3%. LC-MS(APCI): m / z=465.2(M+1) + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.26-8.24(m, 1H), 7.98-7.95(dd, J=9.2 Hz, J=3.2 Hz, 1H), 7.88(d, J=8.0 Hz, 2H), 7.41(d, J=8.0 Hz, 2H), 7.18-7.13(m, 1H), 6.95-6.92(m, 1H), 4.71(d, J=5.6 Hz, 2H), 4.32(br s, 2H), 3.99-3.96(m, 1H), 3.93(s, 3H), 3.83-3.80(m, 1H), 2.28-2.25(m, 1H) , 2.13-2.05(m, 1H), 1.99-1.95(m, 2H), 1.91-1.87(m, 2H), 1.43-1.36(m, 2H).

[0292] Step 2: Synthesis of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide compound N-(4-(5-amino-4-cyano-1-(3-hydroxycyclohexanyl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (250 mg, 0.54 mmol), EtOH (20 mL) and DMSO (4 mL) were added in sequence to a 50 mL one-mouth bottle equipped with a magnetic stirrer and stirred until dissolved. Under ice bath, NaOH (86 mg, 2.16 mmol) was added. After the addition was complete, H2O2 (10 mL) was added dropwise slowly and the reaction was stirred at room temperature overnight. 30 mL of water was added to dilute and the mixture was extracted with dichloromethane (30 mL x 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 165 mg of a white solid. Yield: 63.5%, LC-MS (APCI): m / z=482.2 (M+1) + . 1H NMR (500 MHz, CDCl3)δ(ppm): 8.30-8.28(m, 1H), 7.98-7.95(dd, J=9.5 Hz, J=3.5 Hz, 1H), 7.54(d, J=8.0 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.19-7.15(m, 1H), 6.96-6.94(m, 1H), 5.45(br s, 2H), 4.71(d, J=6.5 Hz, 2H), 4.05-4.02(m, 1H), 3.93(s, 3H), 3.83-3.80(m, 1H), 2.28-2.25(m, 1H), 2.13-2.05(m, 1H), 1.99-1.88(m, 3H), 1.52-1.40(m, 3H).

[0293] Example 2 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide (isomer 1) compound [ka]

[0294] The compound 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm; Batch number: ADHOCE-VB150; Product number: 19325; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: methanol:n-hexane:ethanol=10:75:15.

[0295] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 62 mg of the target compound. The corresponding retention time was 12.797 min. LC-MS (APCI): m / z=482.2 (M+1). + . 1H NMR (500 MHz, CDCl3)δ(ppm): 8.30-8.28(m, 1H), 7.98-7.95(dd, J=9.5 Hz, J=3.5 Hz, 1H), 7.54(d, J=8.0 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.19-7.15(m, 1H), 6.96-6.94(m, 1H), 5.45(br s, 2H), 4.71(d, J=6.5 Hz, 2H), 4.05-4.02(m, 1H), 3.93(s, 3H), 3.83-3.80(m, 1H), 2.28-2.25(m, 1H), 2.13-2.05(m, 1H), 1.99-1.88(m, 3H), 1.52-1.40(m, 3H).

[0296] Example 3 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide compound (isomer 2) [ka]

[0297] The compound 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm; Batch number: ADHOCE-VB150; Product number: 19325; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: methanol:n-hexane:ethanol=10:75:15.

[0298] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 61 mg of the target compound. The corresponding retention time was 15.533 min. LC-MS (APCI): m / z=482.2 (M+1). + . 1H NMR (500 MHz, CDCl3)δ(ppm): 8.30-8.28(m, 1H), 7.98-7.95(dd, J=9.5 Hz, J=3.5 Hz, 1H), 7.54(d, J=8.0 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.19-7.15(m, 1H), 6.96-6.94(m, 1H), 5.45(br s, 2H), 4.71(d, J=6.5 Hz, 2H), 4.05-4.02(m, 1H), 3.93(s, 3H), 3.83-3.80(m, 1H), 2.28-2.25(m, 1H), 2.13-2.05(m, 1H), 1.99-1.88(m, 3H), 1.52-1.40(m, 3H).

[0299] Example 4 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide compound [ka]

[0300] The following synthetic route was chosen: [ka]

[0301] N-(4-(5-amino-4-cyano-1-(3-hydroxycyclohexanyl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg, 0.43 mmol), formamidine acetate (416.4 mg, 4.00 mmol) and DME (1 ml) were added to a 10 mL microwave tube equipped with a magnet and reacted in a microwave under nitrogen atmosphere at 150° C. for 2 hours. The reaction was cooled to room temperature. Water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 134 mg of a white solid. Yield: 63.6%. LC-MS (APCI): m / z=491.0 (M+1) + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.40(br s, 2H), 8.02-7.99(m, 1H), 7.71(d, J=8.0 Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.21-7.19(m, 1H), 7.01-6.98(m, 1H), 5.63(br s, 2H), 4.96-4.93(m, 1H), 4.78(d, J=6.4 Hz, 2H), 3.99(s, 3H), 3.93-3.91(m, 1H), 2.39-2.37(m, 1H), 2.22-2.18(m, 1H), 2.07-1.96(m, 4H), 1.54-=1.46(m, 1H), 0.92-0.89(m, 1H).

[0302] Example 5 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0303] The compound N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide (120 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0304] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 5 mg of the target compound. The corresponding retention time was 12.375 min. LC-MS (APCI): m / z=491.0 (M+1). + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.40(br s, 2H), 8.02-7.99(m, 1H), 7.71(d, J=8.0 Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.21-7.19(m, 1H), 7.01-6.98(m, 1H), 5.63(br s, 2H), 4.96-4.93(m, 1H), 4.78(d, J=6.4 Hz, 2H), 3.99(s, 3H), 3.93-3.91(m, 1H), 2.39-2.37(m, 1H), 2.22-2.18(m, 1H), 2.07-1.96(m, 4H), 1.54-=1.46(m, 1H), 0.92-0.89(m, 1H).

[0305] Example 6 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0306] The compound N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide (120 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0307] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 5 mg of the target compound. The corresponding retention time was 13.903 min. LC-MS (APCI): m / z=491.0 (M+1). + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.40(br s, 2H), 8.02-7.99(m, 1H), 7.71(d, J=8.0 Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.21-7.19(m, 1H), 7.01-6.98(m, 1H), 5.63(br s, 2H), 4.96-4.93(m, 1H), 4.78(d, J=6.4 Hz, 2H), 3.99(s, 3H), 3.93-3.91(m, 1H), 2.39-2.37(m, 1H), 2.22-2.18(m, 1H), 2.07-1.96(m, 4H), 1.54-=1.46(m, 1H), 0.92-0.89(m, 1H).

[0308] Example 7 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide compound (isomer 3) [ka]

[0309] The compound N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide (120 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0310] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 42 mg of the target compound. The corresponding retention time was 15.742 min. LC-MS (APCI): m / z=491.0 (M+1). + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.40(br s, 2H), 8.02-7.99(m, 1H), 7.71(d, J=8.0 Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.21-7.19(m, 1H), 7.01-6.98(m, 1H), 5.63(br s, 2H), 4.96-4.93(m, 1H), 4.78(d, J=6.4 Hz, 2H), 3.99(s, 3H), 3.93-3.91(m, 1H), 2.39-2.37(m, 1H), 2.22-2.18(m, 1H), 2.07-1.96(m, 4H), 1.54-=1.46(m, 1H), 0.92-0.89(m, 1H).

[0311] Example 8 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide compound (isomer 4) [ka]

[0312] The compound N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl-5-fluoro-2-methoxybenzamide (120 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0313] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 45 mg of the target compound. The corresponding retention time was 19.368 min. LC-MS (APCI): m / z=491.0 (M+1). + . 1H NMR (400 MHz, CDCl3)δ(ppm): 8.40(br s, 2H), 8.02-7.99(m, 1H), 7.71(d, J=8.0 Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.21-7.19(m, 1H), 7.01-6.98(m, 1H), 5.63(br s, 2H), 4.96-4.93(m, 1H), 4.78(d, J=6.4 Hz, 2H), 3.99(s, 3H), 3.93-3.91(m, 1H), 2.39-2.37(m, 1H), 2.22-2.18(m, 1H), 2.07-1.96(m, 4H), 1.54-=1.46(m, 1H), 0.92-0.89(m, 1H).

[0314] Example 9 Preparation of trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0315] The following synthetic route was chosen: [ka]

[0316] Step 1: Synthesis of trans-N-(4-(4-amino-1-(3-((tert-butyldimethylsilyl)oxy)cyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound Intermediate compound A-3 (1.0 g, 2.11 mmol), intermediate compound B-1 (833 mg, 2.75 mmol), K2CO3 (875 mg, 6.34 mmol), Pd(dppf)Cl2 (162 mg, 0.21 mmol), 1,4-dioxane (10 mL) and water (3 mL) were added to a 20 mL microwave tube. Nitrogen was bubbled through the mixture for 2 minutes. The mixture was heated to 120 °C in a microwave and reacted for 0.5 hours. The reaction was cooled to room temperature and saturated brine (5 mL) and DCM (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 1.0 g of a white solid. Yield: 80.2%. LC-MS(APCI): m / z=605.2(M+1) + .

[0317] Step 2: Synthesis of trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound Trans-N-(4-(4-amino-1-(3-((tert-butyldimethylsilyl)oxy)cyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (0.5 g, 0.828 mmol) and DCM (5 mL) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer and stirred until dissolved. In an ice bath, hydrochloric acid / isopropanol solution (5 M, 20 mL) was added dropwise and the reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. The solvent was evaporated under reduced pressure. DCM (30 mL) and saturated NaHCO3 solution (20 mL) were added and stirred for 2 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column. 373 mg of a white solid was obtained. Yield: 91.9%. LC-MS (APCI): m / z=491.2 (M+1). + .

[0318] Example 10 Preparation of trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0319] The compound trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (300 mg) was dissolved in methanol (30 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0320] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 128 mg of the target compound. The corresponding retention time was 12.877 min. LC-MS (APCI): m / z=491.2 (M+1). + .

[0321] Example 11 Preparation of trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0322] The compound trans-N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (300 mg) was dissolved in methanol (30 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=45:45:10.

[0323] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 125 mg of the target compound. The corresponding retention time was 14.505 min. LC-MS (APCI): m / z=491.2 (M+1). + .

[0324] Example 12 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide compound [ka]

[0325] The following synthetic route was chosen: [ka]

[0326] Step 1: Synthesis of N-(4-(5-amino-4-cyano-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound Intermediate compound A-4 (500 mg, 1.33 mmol), intermediate compound B-2 (461 mg, 1.60 mmol), Cs2CO3 (1.3 g, 3.99 mmol), Xphos (80 mg, 0.13 mmol), Pd(OAc)2 (30 mg, 0.07 mmol), THF (10 mL) and water (1 mL) were added in sequence to a 20 mL microwave tube and nitrogen was bubbled for 2 minutes. The mixture was heated to 100° C. in a microwave and reacted for 1.5 hours. The reaction was cooled to room temperature. The organic solvent was evaporated under reduced pressure. Saturated saline (5 mL) and ethyl acetate (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 510 mg of a white solid. Yield: 80.3%. LC-MS(APCI):m / z=480.2(M+1) + .

[0327] Step 2: Synthesis of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide compound In a 50 mL one-neck flask equipped with a magnetic stirrer, N-(4-(5-amino-4-cyano-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (320 mg, 0.667 mmol), EtOH (20 mL) and DMSO (4 mL) were added and stirred until dissolved. NaOH (2.67 mmol, 107 mg) was added under ice bath. After the addition was completed, H2O2 aqueous solution (5 mL, 33 wt%) was slowly added dropwise and the mixture was slowly warmed to room temperature and stirred overnight. The organic solvent was evaporated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 221 mg of a white solid. Yield: 66.3%, LC-MS (APCI): m / z=498.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.33-8.31(m, 1H), 7.97(dd, J=9.2 Hz, 1H), 7.53(d, J=8.0 Hz, 2H), 7.46(d, J=8.0 Hz, 2H), 7.21-7.17(m, 1H), 6.98-6.95(m, 1H), 5.59(s, 2H), 5.27(s, 2H), 4.73(d, J=5.6 Hz, 2H), 4.14-4.10(m, 1H), 4.06-4.00(m, 1H), 3.96(s, 3H), 3.85(t, J=10.4Hz, 1 H), 3.58-3.56(m, 2H), 2.38-2.34(m, 1H), 2.19-2.17(m, 2H), 1.82-1.78(m, 1H).

[0328] Example 13 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide compound (isomer 1) [ka]

[0329] The compound 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: methanol: n-hexane: ethanol = 2:63:35 (0.1% triethylamine).

[0330] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 78 mg of the target compound. The corresponding retention time was 12.033 min. LC-MS (APCI): m / z=498.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm): 8.33-8.31(m, 1H), 7.97(dd, J=9.2 Hz, 1H), 7.53(d, J=8.0 Hz, 2H), 7.46(d, J=8.0 Hz, 2H), 7.21-7.17(m, 1H), 6.98-6.95(m, 1H), 5.59(s, 2H), 5.27(s, 2H), 4.73(d, J=5.6 Hz, 2H), 4.14-4.10(m, 1H), 4.06-4.00(m, 1H), 3.96(s, 3H), 3.85(t, J=10.4Hz, 1 H), 3.58-3.56(m, 2H), 2.38-2.34(m, 1H), 2.19-2.17(m, 2H), 1.82-1.78(m, 1H).

[0331] Example 14 Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide compound (isomer 2) [ka]

[0332] The compound 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: methanol: n-hexane: ethanol = 2:63:35 (0.1% triethylamine).

[0333] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 73 mg of the target compound. The corresponding retention time was 17.875 min. LC-MS (APCI): m / z=498.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.33-8.31(m, 1H), 7.97(dd, J=9.2 Hz, 1H), 7.53(d, J=8.0 Hz, 2H), 7.46(d, J=8.0 Hz, 2H), 7.21-7.17(m, 1H), 6.98-6.95(m, 1H), 5.59(s, 2H), 5.27(s, 2H), 4.73(d, J=5.6 Hz, 2H), 4.14-4.10(m, 1H), 4.06-4.00(m, 1H), 3.96(s, 3H), 3.85(t, J=10.4Hz, 1 H), 3.58-3.56(m, 2H), 2.38-2.34(m, 1H), 2.19-2.17(m, 2H), 1.82-1.78(m, 1H).

[0334] Example 15 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0335] The following synthetic route was chosen: [ka]

[0336] N-(4-(5-amino-4-cyano-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (170 mg, 0.354 mmol) and ethylene glycol dimethyl ether (5 mL) were added in sequence to a 20 mL microwave tube and stirred until dissolved. Formamidine acetate (368 mg, 3.54 mmol) was added and the mixture was reacted in a microwave at 120° C. for 2 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. DCM (30 mL) and water (20 mL) were added to the residue. The organic layer was separated and the aqueous layer was extracted with DCM (20 mL×2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 125 mg of a white solid. Yield: 69.6%. LC-MS (APCI): m / z=507.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.37-8.35(m, 2H), 7.97-7.94(m, 1H), 7.65(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.19-7.14(m, 1H), 6.97-6.94(m, 1H), 5.73(br s, 2H), 4.98-4.91(m, 1H), 4.75(d, J=6.4 Hz, 2H), 4.18-4.15(m, 1H), 3.99(t, J=11.2) Hz, 1H), 3.95(s, 3H), 3.70-3.58(m, 3H), 2.46-2.38(m, 1H), 2.26-2.23(m, 1H), 1.82-1.79(m, 1H), 1.71-1.66(m, 1H).

[0337] Example 16 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0338] The compound N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: n-hexane:methanol:ethanol = 65:5:30 (0.1% triethylamine).

[0339] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 6 mg of the target compound. The corresponding retention time was 21.672 min. LC-MS (APCI): m / z=507.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.37-8.35(m, 2H), 7.97-7.94(m, 1H), 7.65(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.19-7.14(m, 1H), 6.97-6.94(m, 1H), 5.73(br s, 2H), 4.98-4.91(m, 1H), 4.75(d, J=6.4 Hz, 2H), 4.18-4.15(m, 1H), 3.99(t, J=11.2 Hz, 1H), 3.95(s, 3H), 3.70-3.58(m, 3H), 2.46-2.38(m, 1H), 2.26-2.23(m, 1H), 1.82-1.79(m, 1H), 1.71-1.66(m, 1H).

[0340] Example 17 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0341] The compound N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: n-hexane:methanol:ethanol = 65:5:30 (0.1% triethylamine).

[0342] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 5 mg of the target compound. The corresponding retention time was 25.023 min. LC-MS (APCI): m / z=507.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.37-8.35(m, 2H), 7.97-7.94(m, 1H), 7.65(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.19-7.14(m, 1H), 6.97-6.94(m, 1H), 5.73(br s, 2H), 4.98-4.91(m, 1H), 4.75(d, J=6.4 Hz, 2H), 4.18-4.15(m, 1H), 3.99(t, J=11.2 Hz, 1H), 3.95(s, 3H), 3.70-3.58(m, 3H), 2.46-2.38(m, 1H), 2.26-2.23(m, 1H), 1.82-1.79(m, 1H), 1.71-1.66(m, 1H).

[0343] Example 18 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 3) [ka]

[0344] The compound N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: n-hexane:methanol:ethanol = 65:5:30 (0.1% triethylamine).

[0345] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 32 mg of the target compound. The corresponding retention time was 27.823 min. LC-MS (APCI): m / z=507.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.37-8.35(m, 2H), 7.97-7.94(m, 1H), 7.65(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.19-7.14(m, 1H), 6.97-6.94(m, 1H), 5.73(br s, 2H), 4.98-4.91(m, 1H), 4.75(d, J=6.4 Hz, 2H), 4.18-4.15(m, 1H), 3.99(t, J=11.2 Hz, 1H), 3.95(s, 3H), 3.70-3.58(m, 3H), 2.46-2.38(m, 1H), 2.26-2.23(m, 1H), 1.82-1.79(m, 1H), 1.71-1.66(m, 1H).

[0346] Example 19 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 4) [ka]

[0347] The compound N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5μm;Batch number: ADHOCE-VB150;Item number: 19325; Flow rate: 4mL / min; Mobile phase: n-hexane:methanol:ethanol = 65:5:30 (0.1% triethylamine).

[0348] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 30 mg of the target compound. The corresponding retention time was 42.518 min. LC-MS (APCI): m / z=507.2 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.37-8.35(m, 2H), 7.97-7.94(m, 1H), 7.65(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.19-7.14(m, 1H), 6.97-6.94(m, 1H), 5.73(br s, 2H), 4.98-4.91(m, 1H), 4.75(d, J=6.4 Hz, 2H), 4.18-4.15(m, 1H), 3.99(t, J=11.2 Hz, 1H), 3.95(s, 3H), 3.70-3.58(m, 3H), 2.46-2.38(m, 1H), 2.26-2.23(m, 1H), 1.82-1.79(m, 1H), 1.71-1.66(m, 1H).

[0349] Example 20 Preparation of N-(4-(8-amino-3-(3-hydroxycyclohexanyl)imidazo[1,5-a]pyrazin-1-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0350] The following synthetic route was chosen: [ka]

[0351] Intermediate compound A-5 (200 mg, 0.645 mmol), intermediate compound B-1 (254 mg, 0.839 mmol), K2CO3 (267 mg, 1.935 mmol), Pd(dppf)Cl2 (43 mg, 0.06 mmol), 1,4-dioxane (10 mL), and water (3 mL) were added in sequence to a 20 mL microwave tube equipped with a magnet, and the atmosphere was replaced with nitrogen for 2 minutes. The mixture was reacted in a microwave at 120° C. for 0.5 hours. The reaction was cooled to room temperature, and saturated brine (5 mL) and DCM (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 0.27 g of a white solid. Yield: 83.3%. LC-MS(APCI): m / z=490.1(M+1) + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.29(s, 1H), 7.96(dd, J=9.2 Hz, J=3.2 Hz, 1H), 7.62(d, J=8.0 Hz, 2H), 7.45(d, J=8.0 Hz, 2H), 7.18-7.13(m, 2H), 7.07(d, J=5.2 Hz, 1H), 6.95-6.92(m, 1H), 5.16(br s, 2H), 4.72(d, J=5.6 Hz, 2H), 3.94(s, 3H), 3.93-3.90(m, 1H), 3.26-3.24(m, 1H), 2.26-2.22(m, 1H), 2.09-2.02(m, 1H), 1.90-1.83(m, 4H), 1.48-1.42(m, 1H).

[0352] Example 21 Preparation of N-(4-(8-amino-3-(3-hydroxycyclohexanyl)imidazo[1,5-a]pyrazin-1-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0353] The compound N-(4-(8-amino-3-(3-hydroxycyclohexanyl)imidazo[1,5-a]pyrazin-1-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: n-hexane:ethanol = 60:40 (0.1% triethylamine).

[0354] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 75 mg of the target compound. The corresponding retention time was 23.963 min. LC-MS (APCI): m / z=490.1 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.29(s, 1H), 7.96(dd, J=9.2 Hz, J=3.2 Hz, 1H), 7.62(d, J=8.0 Hz, 2H), 7.45(d, J=8.0 Hz, 2H), 7.18-7.13(m, 2H), 7.07(d, J=5.2 Hz, 1H), 6.95-6.92(m, 1H), 5.16(br s, 2H), 4.72(d, J=5.6 Hz, 2H), 3.94(s, 3H), 3.93-3.90(m, 1H), 3.26-3.24(m, 1H), 2.26-2.22(m, 1H), 2.09-2.02(m, 1H), 1.90-1.83(m, 4H), 1.48-1.42(m, 1H).

[0355] Example 22 Preparation of N-(4-(8-amino-3-(3-hydroxycyclohexanyl)imidazo[1,5-a]pyrazin-1-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0356] The compound N-(4-(8-amino-3-(3-hydroxycyclohexanyl)imidazo[1,5-a]pyrazin-1-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: n-hexane:ethanol = 60:40 (0.1% triethylamine).

[0357] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 81 mg of the target compound. The corresponding retention time was 27.885 min. LC-MS (APCI): m / z=490.1 (M+1). + . 1 H NMR (400 MHz, CDCl3)δ(ppm):8.29(s, 1H), 7.96(dd, J=9.2 Hz, J=3.2 Hz, 1H), 7.62(d, J=8.0 Hz, 2H), 7.45(d, J=8.0 Hz, 2H), 7.18-7.13(m, 2H), 7.07(d, J=5.2 Hz, 1H), 6.95-6.92(m, 1H), 5.16(br s, 2H), 4.72(d, J=5.6 Hz, 2H), 3.94(s, 3H), 3.93-3.90(m, 1H), 3.26-3.24(m, 1H), 2.26-2.22(m, 1H), 2.09-2.02(m, 1H), 1.90-1.83(m, 4H), 1.48-1.42(m, 1H).

[0358] Example 23 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (low polarity); and

[0359] Example 24 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (high polarity) [ka]

[0360] The following synthetic route was chosen: [ka]

[0361] Intermediate compound A-6 (400 mg, 1.07 mmol) was added to a 50 mL one-neck flask equipped with a magnetic stirrer and a condenser tube. 1,4-Dioxane (8 mL) and H2O (2 mL) were added at room temperature. Tetrakis(triphenylphosphine)palladium (123 mg, 0.106 mmol), sodium carbonate (341 mg, 3.21 mmol), and intermediate compound B-1 (389.9 mg, 1.287 mmol) were added. The mixture was stirred and dispersed. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The temperature was raised to 100 °C. The mixture was stirred and reacted overnight while maintaining the temperature. The reaction was quenched by adding aqueous solution (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to obtain 105 mg of the less polar Example 23 as a white solid (yield: 19.5%, LC-MS (APCI): m / z = 505.5 (M+1)). + ) to obtain 98 mg of highly polar Example 24 as a white solid (yield: 18.2%, LC-MS (APCI): m / z = 505.5 (M+1) + ) obtained.

[0362] Example 25 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0363] Example 23 (100 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=40:50:10.

[0364] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 38 mg of the target compound. The corresponding retention time was 16.013 min. LC-MS (APCI): m / z=505.5 (M+1). + .

[0365] Example 26 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0366] Example 23 (100 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=40:50:10.

[0367] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 42 mg of the target compound. The corresponding retention time was 20.367 min. LC-MS (APCI): m / z=505.5 (M+1). + .

[0368] Example 27 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0369] Example 24 (90 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL *5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=40:50:10.

[0370] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 35 mg of the target compound. The corresponding retention time was 13.253 min. LC-MS (APCI): m / z=505.5 (M+1). + .

[0371] Example 28 Preparation of N-(4-(4-amino-1-(3-hydroxy-3-methylcyclohexanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0372] Example 24 (100 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IC column: CHIRALPAKR IC; 4.6mm * 250mmL * 5μm;Batch number: ICOOCE-VL054;Item number: 83325; Flow rate: 4mL / min; Mobile phase: dichloromethane:n-hexane:ethanol=40:50:10.

[0373] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 32 mg of the target compound. The corresponding retention time was 14.672 min. LC-MS (APCI): m / z=505.5 (M+1). + .

[0374] Example 29 Preparation of N-(4-(4-amino-1-((1R,4R)-4-hydroxycyclohexylalkane)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound; and

[0375] Example 30 Preparation of N-(4-(4-amino-1-((1S,4S)-4-hydroxycyclohexylalkane)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0376] The following synthetic route was chosen: [ka]

[0377] Intermediate compound A-7 (500 mg, 1.39 mmol) was added to a 50 mL one-neck flask equipped with a magnetic stirrer and a condenser tube. 1,4-dioxane (8 mL) and water (2 mL) were added at room temperature. Tetrakis(triphenylphosphine)palladium (160 mg, 0.14 mmol), sodium carbonate (442.8 mg, 4.17 mmol), and intermediate compound B-1 (633 mg, 2.08 mmol) were added. The mixture was stirred and dispersed. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was heated to 100 °C. The mixture was stirred and reacted overnight while maintaining the temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 232 mg of the highly polar Example 29 as a white solid. Yield: 34.09%, LC-MS (APCI): m / z=491.0 (M+1). + . 1 H NMR (400MHz, CDCl3)δ(ppm):8.38(s, 1H), 8.37-8.34(m, 1H), 8.00-7.97(m, 1H), 7.69(d, J=8.0 Hz, 2H), 7.52(d, J=8.0 Hz, 2H), 7.20-7.16(m, 1H), 6.98-6.95(m, 1H), 5.47(br s, 2H), 4.83-4.80(m, 1H), 4.76(d, J=5.6 Hz, 2H), 4.14(s, 1H), 3.96(s, 3H), 2.54-2.51(m, 2H), 2.05-2.00(m, 2H), 1.90-1.80(m, 4H).

[0378] 75 mg of the less polar Example 30 was obtained as a white solid. Yield: 11.01%. LC-MS (APCI): m / z=491.0 (M+1). + . 11H NMR (400 MHz, CDCl3) δ (ppm): 8.38 (s, 1H), 8.37 - 8.34 (m, 1H), 8.00 - 7.97 (m, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.20 - 7.16 (m, 1H), 6.98 - 6.95 (m, 1H), 5.44 (br s, 2H), 4.83 - 4.80 (m, 1H), 4.76 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 3.83 - 3.81 (m, 1H), 2.25 - 2.00 (m, 8H).

[0379] Example 31 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (low polarity); and

[0380] Example 32 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (high polarity)

Chem.

[0381] The following synthetic route was chosen:

Chem.

[0382] Intermediate compound A-8 (500 mg, 1.44 mmol) was added to a 50 mL one-neck flask equipped with a magnetic stirrer and a condenser tube. 1,4-Dioxane (8 mL) and H2O (2 mL) were added at room temperature. Tetrakis(triphenylphosphine)palladium (160 mg, 0.14 mmol), sodium carbonate (445 mg, 4.20 mmol), and intermediate compound B-1 (640 mg, 2.11 mmol) were added. The mixture was stirred and dispersed. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The mixture was heated to 100 °C. The mixture was stirred and reacted overnight while maintaining the temperature. Water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was passed through a silica gel column to give 151 mg of the less polar Example 31 as a white solid. Yield: 21.92%. LC-MS (APCI): m / z=476.2 (M+1). + .

[0383] 45 mg of highly polar Example 32 was obtained as a white solid. Yield: 6.58%. LC-MS (APCI): m / z=476.2 (M+1). + .

[0384] Example 33 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0385] Example 31 (150 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm I.D. * 250mmL * 5μm;Batch number: IGOOCE-BR054;Item number: 87325; Flow rate: 4ml / min; Mobile phase: methyl tert-butyl ether:methanol:ethanol=95:3:2.

[0386] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 58 mg of the target compound with a corresponding retention time of 30.460 min.

[0387] Example 34 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0388] Example 31 (150 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm I.D. * 250mmL * 5μm;Batch number: IGOOCE-BR054;Item number: 87325; Flow rate: 4ml / min; Mobile phase: methyl tert-butyl ether:methanol:ethanol=95:3:2.

[0389] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 52 mg of the target compound with a corresponding retention time of 34.478 min.

[0390] Example 35 N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0391] Example 32 (40 mg) was dissolved in methanol (6 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm I.D. * 250mmL * 5μm;Batch number: IGOOCE-BR054;Item number: 87325; Flow rate: 4ml / min; Mobile phase: methyl tert-butyl ether:methanol:ethanol=95:3:2.

[0392] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 13 mg of the target compound with a corresponding retention time of 24.480 min.

[0393] Example 36 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0394] Example 32 (40 mg) was dissolved in methanol (6 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm I.D. * 250mmL * 5μm;Batch number: IGOOCE-BR054;Item number: 87325; Flow rate: 4ml / min; Mobile phase: methyl tert-butyl ether:methanol:ethanol=95:3:2.

[0395] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 15 mg of the desired compound with a corresponding retention time of 27.155 min.

[0396] Example 37 Preparation of trans-N-(4-(4-amino-1-(4-hydroxycyclopent-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1), and

[0397] Example 38 Preparation of trans-N-(4-(4-amino-1-(4-hydroxycyclopent-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0398] The following synthetic route was chosen: [ka]

[0399] Intermediate compound A-9 (0.98 g, 2.54 mmol), intermediate compound B-1 (1.15 g, 3.81 mmol), sodium carbonate (0.81 g, 7.62 mmol), Pd(pph3)4 (146.8 mg, 0.127 mmol), 1,4-dioxane (20 ml) and water (5 ml) were added to a 100 ml three-necked bottle equipped with a magnetic stirrer and a condenser tube, and the reaction was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was cooled to room temperature. Water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 71 mg of the less polar Example 37 as a white solid. Yield: 5.8%, LC-MS (APCI): m / z=475.0(M+1) + . 1 H NMR (400MHz, DMSO-D6) δ(ppm): 8.85(t, J=6.0 Hz, 1H), 8.23(s, 1H), 7.61(d, J=8.0 Hz, 2H), 7.52-7.48(m, 3H), 7.35-7.30(m, 1H), 7.19-7.16(m, 1H), 6.07-6.05(m, 1H), 5.90-5.88(m, 1H), 5.73(t, J=10.4 Hz, 1H), 5.25(d, J=6.8 Hz, 1H), 4.74-4.71(m, 1H), 4.56(d, J=6.0 Hz, 2H), 4.04-3.98(m, 1H), 3.89(s, 3H), 2.82-2.79(m, 1H).

[0400] 165 mg of highly polar Example 38 was obtained as a white solid. Yield: 13.7%, LC-MS (APCI): m / z=475.0 (M+1). + . 1H NMR (400MHz, CDCl3)δ(ppm):8.40(t, J=4.8 Hz, 1H), 8.26(s, 1H), 7.96(dd, J=9.6 Hz, J=3.2 Hz, 1H), 7.61-7.54(m, 4H), 7.20-7.16(m, 1H), 6.98-6.95(m, 1H), 6.28-6.24(m, 2H), 6.06-6.05(d, J=4.4 Hz, 1H), 5.34-5.33(m, 1H), 4.76(d, J=6.0 Hz, 2H), 3.98(s, 3H), 2.72-2.66(m, 1H), 2.43-2.37(m, 1H).

[0401] Example 39 Preparation of cis-N-(4-(4-amino-1-((1S,4S)-4-hydroxycyclohexanyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound, and

[0402] Example 40 Preparation of trans-N-(4-(4-amino-1-((1R,4R)-4-hydroxycyclohexanyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0403] The following synthetic route was chosen: [ka]

[0404] Intermediate compound A-10 (171 mg, 0.42 mmol), tetrahydrofuran (7 mL), water (0.7 mL), intermediate compound B-2 (153 mg, 0.53 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), XPhos (20 mg, 0.04 mmol), and cesium carbonate (415 mg, 0.12 mmol) were added to a 10 ml microwave tube. The atmosphere was replaced with nitrogen, and the mixture was reacted at 110° C. for 1 hour using microwave. The reaction was cooled to room temperature. Water (20 mL) was added to quench the reaction. Ethyl acetate (30 mL×3) was added for extraction. The organic layer was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 32 mg of the cis product, less polar, Example 39, as a white solid. Yield: 14.0%, LC-MS (APCI): m / z=510.0(M+1) +75 mg of the trans product, highly polar Example 40, was obtained as a white solid. Yield: 35.0%, LC-MS (APCI): m / z=510.0 (M+1). + .

[0405] Example 41 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (low polarity); and

[0406] Example 42 Preparation of N-(4-(4-amino-1-(3-hydroxycyclopentanyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (high polarity) [ka]

[0407] The following synthetic route was chosen: [ka]

[0408] Intermediate compound A-11 (156 mg, 0.4 mmol), tetrahydrofuran (7 mL), water (0.7 mL), intermediate compound B-2 (184.5 mg, 0.63 mmol), Pd(OAc)2 (9.5 mg, 0.04 mmol), XPhos (12.3 mg, 0.04 mmol), and cesium carbonate (416 mg, 0.12 mmol) were added to a 10 ml microwave tube. The atmosphere was replaced with nitrogen, and the mixture was reacted at 110° C. for 1 hour using microwave. The reaction was cooled to room temperature. Water (20 mL) was added to quench the reaction. Ethyl acetate (30 mL×3) was added for extraction. The organic layer was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 65 mg of the less polar Example 41 as a white solid. Yield: 32.8%, LC-MS (APCI): m / z=496.0(M+1) + 58 mg of highly polar Example 42 was obtained as a white solid. Yield: 29.3%, LC-MS (APCI): m / z=496.0 (M+1). + .

[0409] Example 43 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0410] The following synthetic route was chosen: [ka]

[0411] THF (10 mL), water (1 mL), intermediate compound A-12 (90 mg, 0.21 mmol), intermediate compound B-2 (80 mg, 0.27 mmol), Xphos (10.2 mg, 0.021 mmol), palladium acetate (2.4 mg, 0.01 mmol) and cesium carbonate (209 mg, 0.64 mmol) were added in sequence to a microwave reaction tube (10-20 mL) equipped with a magnet. The microwave reaction tube was filled with nitrogen and the lid was tightly clamped. The microwave reaction tube was subjected to a microwave reactor and reacted at 110 °C for 1 h. The mixture was cooled to room temperature, directly concentrated and passed through silica gel to obtain 32 mg of an off-white solid. Yield: 29.2%, LC-MS (APCI): m / z = 523.2 (M + 1) + .

[0412] Example 44 Preparation of N-(4-(4-amino-1-(3-hydroxycyclohexanyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0413] The following synthetic route was chosen: [ka]

[0414] Intermediate compound A-13 (156 mg, 0.4 mmol), tetrahydrofuran (7 mL), water (0.7 mL), intermediate compound B-2 (184.5 mg, 0.63 mmol), Pd(OAc)2 (9.5 mg, 0.04 mmol), XPhos (12.3 mg, 0.04 mmol), and cesium carbonate (41 mg, 0.12 mmol) were added to a 10 ml microwave tube. The atmosphere was replaced with nitrogen, and the mixture was reacted at 110° C. for 1 hour using a microwave. The reaction was cooled to room temperature. Water (20 mL) was added to quench the reaction. Ethyl acetate (30 mL×3) was added for extraction. The organic layer was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 124 mg of a white solid. Yield: 61.3%, LC-MS (APCI): m / z=507.0(M+1) + .

[0415] Example 45 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0416] Example 43 (25 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: methanol:methyl tert-butyl ether=8:92.

[0417] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 2 mg of the target compound with a corresponding retention time of 9.198 min.

[0418] Example 46 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0419] Example 43 (25 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: methanol:methyl tert-butyl ether=8:92.

[0420] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 2 mg of the target compound with a corresponding retention time of 9.342 min.

[0421] Example 47 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 3) [ka]

[0422] Example 43 (25 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: methanol:methyl tert-butyl ether=8:92.

[0423] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 8 mg of the target compound with a corresponding retention time of 22.452 min. 1H NMR (400 MHz, DMSO-D6)δ(ppm): 11.76(s, 1H), 8.87(t, J=6.0 Hz, 1H), 7.62(d, J=8.0 Hz, 2H), 7.53-7.48(m, 3H), 7.36-7.31(m, 1H), 7.20-7.17(m, 1H), 5.49-5.43(m, 1H), 5.07(s, 2H), 4.70(t, J=6.0 Hz, 1H), 4.57(d, J=6.0 Hz, 2H), 4.08-4.04(m, 1H), 3.89(s, 3H), 3.64(t, J=10.8 Hz, 1H), 3.44-2.35(m, 3H), 2.27-2.20(m, 2H), 1.85-1.82(m, 1H), 1.46-1.42(m, 1H).

[0424] Example 48 Preparation of N-(4-(4-amino-1-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-d]pyridazin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 4) [ka]

[0425] Example 43 (25 mg) was dissolved in methanol (10 mL) and the chiral preparation was carried out using the following conditions: IG column: CHIRALPAKR IG; 4.6mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: methanol:methyl tert-butyl ether=8:92.

[0426] The corresponding fractions were collected and evaporated to dryness on a rotary evaporator to give 8 mg of the target compound with a corresponding retention time of 27.243 min. 11H NMR (400 MHz, DMSO-D6) δ (ppm): 11.76 (s, 1H), 8.87 (t, J = 6.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.53 - 7.48 (m, 3H), 7.36 - 7.31 (m, 1H), 7.20 - 7.17 (m, 1H), 5.49 - 5.43 (m, 1H), 5.07 (s, 2H), 4.70 (t, J = 6.0 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.08 - 4.04 (m, 1H), 3.89 (s, 3H), 3.64 (t, J = 10.8 Hz, 1H), 3.44 - 2.35 (m, 3H), 2.27 - 2.20 (m, 2H), 1.85 - 1.82 (m, 1H), 1.46 - 1.42 (m, 1H).

[0427] Example 49 Preparation of trans-N-(4-(4-amino-1-(4-hydroxycyclopent-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1), and

[0428] Example 50 Preparation of trans-N-(4-(4-amino-1-(4-hydroxycyclopent-2-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2)

Chem.

[0429] The following synthetic route was chosen:

Chem.

[0430] Intermediate A-14 (400 mg, 1.039 mmol), Intermediate B-1 (377.8 mg, 1.247 mmol), sodium carbonate (330.4 mg, 3.117 mmol), tetrakistriphenylphosphine palladium (120.1 mg, 0.104 mmol), 1,4-dioxane (8 mL) and water (2 mL) were added to a 50 mL three-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 100° C. under nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature. Extraction was performed by adding water (50 mL) and ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 20 mg of the less polar Example 49 as a white solid. LC-MS(APCI): m / z=475.0(M+1) + . 1 H NMR (400 MHz, DMSO-d6): 8.87(t, J=6.0 Hz, 1H), 8.25(s, 1H), 7.63(d, J=8.0 Hz, 2H), 7.54-7.49(m, 3H), 7.37-7.32(m, 1H), 7.21-7.17(m, 1H), 6.08-6.06(m, 1H), 5.92-5.90(m, 1H), 5.75(t, J=10.4 Hz, 1H), 5.27(d, J=6.8 Hz, 1H), 4.74-4.71(m, 1H), 4.56(d, J=6.0 Hz, 2H), 4.04-3.98(m, 1H), 3.90(s, 3H), 2.84-2.81(m, 1H), 2.02-1.95(m, 1H).

[0431] 80 mg of highly polar Example 50 was obtained as a white solid. LC-MS (APCI): m / z=475.0 (M+1). + . 1H NMR (400 MHz, DMSO-d6): 8.85(t, J=6.0 Hz, 1H), 8.24(s, 1H), 7.59(d, J=8.8 Hz, 2H), 7.53-7.47(m, 3H), 7.35-7.30(m, 1H), 7.19-7.16(m, 1H), 6.10-6.05(m, 2H), 5.94-5.92(m, 1H), 4.99-4.97(m, 2H), 4.56(d, J=6.0 Hz, 2H), 3.98(s, 3H), 2.43-2.39(m, 1H), 2.17-2.13(m, 1H).

[0432] Example 51 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1), and

[0433] Example 52 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0434] The following synthetic route was chosen: [ka]

[0435] Step 1: Synthesis of N-(4-(4-amino-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound THF (10 mL), water (1 mL), intermediate compound A-15 (55 mg, 0.081 mmol), intermediate compound B-2 (30 mg, 0.106 mmol), Xphos (4 mg, 0.008 mmol), palladium acetate (1.83 mg, 0.008 mmol) and cesium carbonate (80 mg, 0.24 mmol) were added in sequence to a microwave reaction tube (10-20 mL) equipped with a magnet. The microwave reaction tube was filled with nitrogen and the lid was tightly clamped. The microwave reaction tube was subjected to a microwave reactor at 110 °C and reacted for 1 h. The mixture was cooled to room temperature, directly concentrated and passed through a silica gel column to obtain 54 mg of an off-white solid. Yield: 90%, LC-MS (APCI): m / z = 744 (M + 1) + .

[0436] Step 2: Synthesis of the compound of Example 51 (isomer 1) and the compound of Example 52 (isomer 2) Hydrochloric acid / isopropanol solution (5 mol / L, 5 mL) and N-(4-(4-amino-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide (54 mg, 0.072 mmol) were added in sequence to a 25 mL one-neck flask equipped with a magnetic stirrer and stirred at room temperature for 1 hour. The pH was adjusted to 7 using saturated aqueous sodium bicarbonate. Ethyl acetate (20 mL x 3) and water (10 mL) were added for extraction. The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 10 mg of the less polar Example 51 as a yellow solid. Yield: 27.4%, LC-MS (APCI): m / z=506 (M+1) + , 1H NMR (400 MHz, DMSO-D6) δ (ppm): 8.88 (t, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.52-7.48 (m, 4H), 7.41 (d, J=8.4 Hz, 2H), 7.34-7.31 (m, 1H), 7.20-7.16 (m, 1H), 5.71 (br s, 2H), 4.61 (t, J=6.4 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.12-4.09 (m, 1H), 3.89 (s, 3H), 3.44-3.38 (m, 2H), 3.35-3.33 (m, 1H), 3.08-3.00 (m, 1H), 2.11-2.05 (m, 1H), 1.88-1.82 (m, 1H), 1.74-1.70 (m, 1H), 1.39-1.32, (m, 1H).

[0437] High polarity Example 52 was obtained at 8mg. Yield: 22.0%, LC-MS (APCI): m / z=506 (M+1) + . 1 H NMR (400 MHz, DMSO-D6) δ (ppm): 8.89 (t, J=6.0 Hz, 1H), 8.20 (s, 1H), 7.58 (s, 1H), 7.53-7.50 (m, 3H), 7.43 (d, J=8.0 Hz, 2H), 7.36-7.31 (m, 1H), 7.20-7.16 (m, 1H), 5.76 (br s, 2H), 4.59-4.56 (m, 3H), 4.12 (d, J=10.4 Hz, 1H), 3.89 (s, 3H), 3.75 (dd, J=10.4 Hz, J=2.4 Hz, 1H), 3.41-3.34 (m, 3H), 3.22-3.20 (m, 1H), 2.02-1.96 (m, 2H), 1.52-1.39 (m, 2H).

[0438] Example 53 Preparation of N-(4-(6-amino-9-(3-hydroxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)benzyl)-5-fluoro-2-methoxybenzamide compound

change

[0439] The following synthetic route was chosen:

change

[0440] Step 1: Synthesis of N-(4-(6-amino-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)benzyl)-5-fluoro-2-methoxybenzamide compound THF (10 mL), water (1 mL), intermediate compound A-17 (15 mg, 0.023 mmol), intermediate compound B-2 (9 mg, 0.03 mmol), Xphos (1.0 mg, 0.0023 mmol), palladium acetate (0.5 mg, 0.0023 mmol) and cesium carbonate (22.5 mg, 0.069 mmol) were added in sequence to a microwave reaction tube (10-20 mL) equipped with a magnet. The lid of the microwave reaction tube was clamped. The microwave reaction tube was subjected to a microwave reactor at 110 °C and reacted for 1 h. The mixture was cooled to room temperature, directly concentrated and passed through a silica gel column to obtain 12 mg of an off-white solid. Yield: 70%, LC-MS (APCI): m / z = 745 (M + 1) + .

[0441] Step 2: Synthesis of the compound of Example 53 Hydrochloric acid / isopropanol solution (5 mol / L, 5 mL) and N-(4-(6-amino-9-(3-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)benzyl)-5-fluoro-2-methoxybenzamide (12 mg, 0.016 mmol) were added in sequence to a 25 mL one-neck flask equipped with a magnetic stirrer and stirred at room temperature for 1 hour. The pH was adjusted to 7 using saturated aqueous sodium bicarbonate. Ethyl acetate (20 mL x 3) and water (10 mL) were added for extraction. The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 5 mg of a white solid. Yield: 61%. LC-MS (APCI): m / z = 507 (M + 1) + .

[0442] Example 54 Preparation of N-(4-(6-amino-9-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0443] The following synthetic route was chosen: [ka]

[0444] Step 1: Synthesis of (1R,4R)-4-(6-(bis(4-methoxybenzyl)amino)-7-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxylate ethyl compound DCM (15 mL), intermediate compound A-18 (7.7 g, 14.1 mmol), intermediate compound B-1 (5.5 g, 18.3 mmol), copper acetate (1.28 g, 7.0 mmol), TEMPO (2.4 g, 15.5 mmol) and TEA (5.7 g, 56.5 mmol) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer. The flask was evacuated and the atmosphere was replaced with oxygen three times. The mixture was reacted at room temperature overnight. The reaction mixture was directly concentrated and passed through a silica gel column to give 1.13 g of a yellow oily substance. Yield: 10%, LC-MS (APCI): m / z=803 (M+1). + .

[0445] Step 2: Synthesis of (1R,4R)-4-(6-amino-7-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxylate ethyl compound DCM (5 mL), (1R,4R)-4-(6-(bis(4-methoxybenzyl)amino)-7-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl cyclohexane-1-carboxylate (1.13 g, 1.4 mmol) and TFA (5 mL) were added in sequence to a 50 mL one-neck flask equipped with a magnetic stirrer, and the mixture was heated to 50° C. and reacted for 4 hours. The pH was adjusted to 7 using saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL×3) and water (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 0.34 g of a yellow oily substance. Yield: 43.0%. LC-MS (APCI): m / z=563 (M+1) + .

[0446] Step 3: Synthesis of the compound of Example 54 Anhydrous tetrahydrofuran (10 mL) and (1R,4R)-4-(6-amino-7-(4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-ethyl carboxylate (340 mg, 0.6 mmol) were added in sequence to a 25 mL two-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was cooled to 0° C. Lithium aluminum hydride (91 mg, 2.4 mmol) was added and reacted at 0° C. for 1 hour. Water (30 mL) was added to quench the reaction, and the mixture was filtered. The filtrate was washed with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 165 mg of a white solid. Yield: 52%, LC-MS (APCI): m / z=521 (M+1). + . 1H NMR (400 MHz, DMSO-D6) δ (ppm): 8.89 (t, J=6.0 Hz, 1H), 8.13 (s, 1H), 7.54-7.49 (m, 3H), 7.43-7.41 (m, 2H), 7.37-7.32 (m, 1H), 7.21-7.17 (m, 1H), 5.57 (br s, 2H), 4.58 (d, J=6.0 Hz, 2H), 4.45 (t, J=6.0 Hz, 1H), 4.24-4.18 (m, 1H), 3.90 (s, 2H), 3.28-3.24 (m, 2H), 2.38-2.29 (m, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.78 (d, J=10.4 Hz, 2H), 1.45-1.42 (m, 1H), 1.10-1.01 (m, 2H).

[0447] Example 55 Preparation of cis-N-(4-(4-amino-1-((1S,4S)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0448] The following synthetic route was chosen: [ka]

[0449] Step 1: Preparation of cis-(1S,4S)-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl-1-carboxylate ethyl compound 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound (2.0 g, 7.66 mmol), ethyl trans-4-hydroxycyclohexylcarboxylate (1.45 g, 8.43 mmol) and anhydrous THF (30 mL) were added in sequence to a 100 mL three-necked flask equipped with a magnetic stirrer and stirred until dissolved. Ph3P (4.01 g, 15.32 mmol) was added and the mixture was cooled to 0°C. DIAD (3.09 g, 15.32 mmol) was slowly added dropwise and stirred at room temperature overnight after the addition was complete. The reaction was quenched by adding saturated saline (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and passed through a silica gel column to give 2.5 g of the title product. Yield: 78.6%, LC-MS (APCI): m / z=416.0(M+1) + .

[0450] Step 2: Synthesis of (1s,4s)-4-(4-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexane-1-carboxylate ethyl compound Cis-(1S,4S)-ethyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl-1-carboxylate (1 g, 2.41 mmol) and boronic acid (2.89 mmol, 876 mg) were dissolved in 30 mL of DME / H2O (V / V=3 / 1) solution. K2CO3 (7.23 mmol, 997 mg) was added followed immediately by Pd(PPh3)4 (0.241 mmol, 278 mg) and intermediate compound B-1 (1.1 g, 3.62 mmol). The atmosphere was replaced with nitrogen three times. The mixture was heated to 100° C. and stirred for 4 h. The reaction mixture was cooled to room temperature. Dichloromethane (40 mL) and water (30 mL) were added and stirred. The layers were separated. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 630 mg of the desired product. Yield: 48.1%. LC-MS (APCI): m / z = 547.2 (M + 1). + .

[0451] Step 3: Synthesis of the compound of Example 55 (1S,4S)-4-(4-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexane-1-carboxylate (300 mg, 0.548 mmol) was dissolved in 20 mL of anhydrous THF. LiAlH4 (1.10 mmol, 42 mg) was added at 0°C. After the addition was complete, the mixture was stirred for 2 hours while maintaining the temperature. The reaction was quenched by adding sodium sulfate decahydrate (10 g) under ice-water bath. Ethyl acetate (20 mL) was added and the mixture was filtered. The filtrate was concentrated and passed through a silica gel column to obtain 110 mg of the desired product. Yield: 39.7%, LC-MS (APCI): m / z=505.1 (M+1) + . 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.86 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.53-7.48 (m, 3H), 7.35-7.31 (m, 1H), 7.20-7.16 (m, 1H), 4.76-4.74 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.52-4.46 (m, 1H), 3.91 (s, 3H), 3.47 (d, J=6.8 Hz, 2H), 2.13-2.08 (m, 2H), 1.82-1.73 (m, 5H), 1.65-1.60 (m, 1H).

[0452] Example 56 Preparation of trans-N-(4-(4-amino-1-((1R,4R)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0453] Following the synthesis route of Example 55, the raw material trans-4-hydroxycyclohexyl ethyl carboxylate was replaced with cis-4-hydroxycyclohexyl ethyl carboxylate to obtain the compound of Example 56, which is in the trans configuration. LC-MS (APCI): m / z=505.1 (M+1). + . 1 H NMR (400 MHz, MeOH-d4) δ (ppm): 8.86 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.53-7.48 (m, 3H), 7.35-7.31 (m, 1H), 7.20-7.16 (m, 1H), 4.65-4.60 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.51-4.45 (m, 1H), 3.89 (s, 3H), 3.38-3.25 (m, 2H), 1.99-1.87 (m, 6H), 1.43-1.41 (m, 1H), 1.15-1.11 (m, 2H).

[0454] Example 57 Preparation of N-(4-(4-amino-1-(3-hydroxycycloheptyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0455] The following synthetic route was chosen: [ka]

[0456] Step 1: Synthesis of N-(4-(4-amino-1-(3-((tert-butyldimethylsilyl)oxy)cycloheptyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide compound Intermediate compound A-19 (400 mg, 0.82 mmol), intermediate compound B-1 (300 mg, 0.99 mmol), Pd(PPh3)4 (95 mg, 0.082 mmol), Na2CO3 (261 mg, 2.46 mmol), DMF (6 mL), and H2O (2 mL) were added in sequence to a 50 mL three-neck flask equipped with a magnetic stirrer. The system was evacuated. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 100 °C for 6 h. The reaction was cooled to room temperature. The reaction was quenched by adding saturated saline (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 410 mg of a white solid. Yield: 82.8%. LC-MS(APCI): m / z=619.0(M+1) + .

[0457] Step 2: Synthesis of the compound of Example 57 N-(4-(4-amino-1-(3-((tert-butyldimethylsilyl)oxy)cycloheptyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)-5-fluoro-2-methoxybenzamide (200 mg, 0.32 mmol) and HCl / ethyl acetate (4 M, 4 mL) were added in sequence to a 50 mL three-necked flask equipped with a magnetic stirrer and stirred at room temperature for 1 h. The mixture was cooled to 0° C. Saturated Na2CO3 was added to adjust the pH to 10, and the mixture was extracted with ethyl acetate (10 mL×2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to give 120 mg of a white solid. Yield: 74.4%. LC-MS (APCI): m / z=505.0 (M+1) + . 1 H NMR (400MHz, DMSO-D6) δ (ppm): 8.87 (t, J=6.0 Hz, 1H), 8.23 ​​(s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.54-7.49 (m, 3H), 7.35-7.30 (m, 1H), 7.21-7.18 (m, 1H), 4.88-4.85 (m, 1H), 4.61 (d, J=4.4 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.32-2.22 (m, 2H), 2.12-2.05 (m, 2H), 1.98-1.90 (m, 3H), 1.76-1.73 (m, 1H), 1.63-1.53 ​​(m, 3H).

[0458] Example 58 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound [ka]

[0459] The following synthetic route was chosen: [ka]

[0460] Step 1: Synthesis of N-(4-(4-amino-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound 1,4-Dioxane (20 mL), water (5 mL), intermediate compound A-20 (0.4 g, 0.7 mmol), intermediate compound B-1 (0.28 mg, 0.9 mmol), tetrakistriphenylphosphine palladium (0.16 g, 0.14 mmol), and sodium carbonate (0.23 g, 2.0 mmol) were sequentially charged into a 25 mL three-neck flask equipped with a magnetic stirrer. The atmosphere was replaced with nitrogen three times. The mixture was heated to 100° C. and reacted overnight. Ethyl acetate (80 mL×3) and water (50 mL) were added for extraction. The organic layer was separated, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 0.43 g of a yellow oily substance. Yield: 82%. LC-MS (APCI): m / z=744 (M+1) + .

[0461] Step 2: Synthesis of the compound of Example 58 Hydrochloric acid / isopropanol solution (5 mL) and N-(4-(4-amino-7-(6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide (430 mg, 0.57 mmol) were added in sequence to a 25 mL one-neck flask equipped with a magnetic stirrer and stirred at room temperature for 1 hour. The pH was adjusted to 7 using saturated aqueous sodium bicarbonate. Extraction was performed by adding ethyl acetate (20 mL x 3) and water (10 mL). The organic layer was separated, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and passed through a silica gel column to obtain 119 mg of a yellow solid. Yield: 41%. LC-MS (APCI): m / z = 506 (M + 1) + .

[0462] Example 59 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 1) [ka]

[0463] Example 58 (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: (ethyl acetate: n-hexane:ethanol = 18:72:10) + 0.1% triethylamine.

[0464] The retention time of the target compound was 28.923 minutes, and the weight obtained was 31 mg. LC-MS (APCI): m / z=506 (M+1) + . 1 H NMR (400 MHz, DMSO-D6): 8.84 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.53-7.49 (m, 1H), 7.43 (s, 4H), 7.36-7.30 (m, 1H), 7.19-7.16 (m, 1H), 6.77 (s, 1H), 4.59 (br s, 1H), 4.54 (d, J=6.4 Hz, 2H), 4.18 (d, J=11.2 Hz, 1H), 3.89 (s, 3H), 3.81-3.78 (m, 1H), 3.41-3.39 (m, 3H), 2.01-1.87 (m, 3H), 1.44-1.38 (m, 2H).

[0465] Example 60 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 2) [ka]

[0466] Example 58 (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL* 5 μm; Flow rate: 4ml / min; Mobile phase: (ethyl acetate: n-hexane:ethanol = 18:72:10) + 0.1% triethylamine.

[0467] The peak time of the target compound was 31.673 min, and the weight obtained was 30 mg. LC-MS (APCI): m / z=506 (M+1) + . 1 H NMR (400 MHz, DMSO-D6): 8.84 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.53-7.49 (m, 1H), 7.43 (s, 4H), 7.36-7.30 (m, 1H), 7.19-7.16 (m, 1H), 6.77 (s, 1H), 4.59 (br s, 1H), 4.54 (d, J=6.4 Hz, 2H), 4.13 (d, J=11.6 Hz, 1H), 3.89 (s, 3H), 3.81-3.78 (m, 1H), 3.41-3.39 (m, 3H), 2.01-1.87 (m, 3H), 1.44-1.38 (m, 2H).

[0468] Example 61 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 3) [ka]

[0469] Example 58 (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: (ethyl acetate: n-hexane:ethanol = 18:72:10) + 0.1% triethylamine.

[0470] The peak time of the target compound was 40.873 min, and the weight obtained was 20 mg. LC-MS (APCI): m / z=506 (M+1) + . 1H NMR (400 MHz, DMSO-D6): 8.84 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.53-7.49 (m, 1H), 7.43 (s, 4H), 7.36-7.30 (m, 1H), 7.19-7.16 (m, 1H), 6.55 (s, 1H), 4.66 (br s, 1H), 4.54 (d, J=6.4 Hz, 2H), 4.13 (d, J=6.0 Hz, 1H), 3.89 (s, 3H), 3.42-3.39 (m, 2H), 3.41-3.39 (m, 3H), 2.13-1.10 (m, 1H), 1.83-1.73 (m, 3H), 1.38-1.35 (m, 1H).

[0471] Example 62 Preparation of N-(4-(4-amino-7-(6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)benzyl)-5-fluoro-2-methoxybenzamide compound (isomer 4) [ka]

[0472] Example 58 (150 mg) was dissolved in methanol (15 mL) and the chiral preparation was carried out using the following conditions: AD-H column: CHIRALPAKR AD-H; 4.6 mm * 250mmL * 5 μm; Flow rate: 4ml / min; Mobile phase: (ethyl acetate: n-hexane:ethanol = 18:72:10) + 0.1% triethylamine.

[0473] The peak time of the target compound was 47.310 min, and the weight obtained was 21 mg. LC-MS (APCI): m / z=506 (M+1) + . 1 H NMR (400 MHz, DMSO-D6): 1H NMR (400 MHz, DMSO-D6) δ (ppm): 8.84 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.53-7.49 (m, 1H), 7.43 (s, 4H), 7.36-7.30 (m, 1H), 7.19-7.16 (m, 1H), 6.55 (s, 1H), 4.64 (br s, 1H), 4.54 (d, J=6.4 Hz, 2H), 4.10 (d, J=6.0 Hz, 1H), 3.89 (s, 3H), 3.42-3.39 (m, 2H), 3.41-3.39 (m, 3H), 2.13-1.10 (m, 1H), 1.83-1.73 (m, 3H), 1.38-1.35 (m, 1H).

[0474] Biological Activity Assay (1) Kinase activity inhibition assay In this assay, an HTRF TK kit from Cisbio (catalog number: 62TKOPEC) was used to detect the inhibitory activity of compounds against BTK kinase and BTK C481S kinase, as well as the selectivity of compounds against EGFR, ITK and TEC kinases.

[0475] Reagents and consumables: BTK kinase (Invitrogen, Catalog Number: PV3587), BTK C481S (Carna, Catalog Number: 08-547), ITK (Carna, Catalog Number: 08-181), EGFR (Carna, Catalog Number: 08-115), TEC (Carna, Catalog Number: 08-182), HTRF-TK kit (Cisbio, Catalog Number: 62TK0PEC), MgCl2 (Sigma, Catalog Number: M1028), MnCl2 (Sigma, Catalog Number: M1787), DTT (Sigma, Catalog Number: D0632), ATP (Sigma, Catalog Number: A7699-1g), DMSO (Sigma, Catalog Number: D2650), 384-well plates (PE, Catalog Number: 6008280).

[0476] Kinase activity assay: The required compounds were prepared, and the final DMSO concentration in the kinase detection system was less than 1%. All operation steps were performed on ice, and the total reaction volume was 10 μL. Compounds (4 μL), substrate and ATP (4 μL), and kinase (2 μL) were added sequentially to a 384-well plate and shaken for 30 seconds. After an appropriate time at room temperature, detection reagents were added. After 1 hour at room temperature, the plate was detected by a microplate reader. The specific steps were as follows: a) The 1× kinase buffer solution required for kinase detection was calculated according to the amount of detection compound and prepared as necessary; b) 100x gradient solutions of compounds were diluted 40x to prepare compounds at the desired concentrations, 2.5x working concentration, mixed well and added to each well at 4μL / well; c) 5x working concentrations of substrate and ATP were prepared and mixed in a 1:1 ratio before adding to the 384-well plate, and added to each well at 4 μL / well; d) 5x working concentration of kinase was prepared and 2μL was added to each well; e) The plate was shaken on a microplate oscillator for 30 seconds, sealed with a sealing membrane, and allowed to react for an appropriate time at room temperature; f) 4x working concentration of streptavidin XL-665 and TK antibody cryptate compounds were prepared and mixed in a 1:1 ratio before adding to the 384-well plate, and 10 μL / well was added to each well; g) After 1 hour reaction at room temperature, the plate was read; h) Wells containing only substrate, ATP, and 1% DMSO but no kinase served as blank control wells, and wells containing only substrate, ATP, 1% DMSO, and kinase served as positive control wells. Reading: Using a BioTek Synerg Neo2 microplate reader, values ​​were read at 620 nm (cryptate) and 665 nm (XL665), the 665 / 620 ratio was calculated for each well, and the data was exported. Data analysis: IC was analyzed using GraphPad Prism 7.0 software. 50 was calculated. The IC of the compound was calculated using the following nonlinear fitting equation: 50 (50% inhibitory concentration) was obtained: Y = Lower limit + (Upper limit - Lower limit) / (1 + 10^((LogIC 50 -X) * HillSlope) X: Logarithm of compound concentration Y: Inhibition rate (% inhibition) Kinase inhibition rate (% inhibition) was calculated as follows: Inhibition rate % = (1-(wells of each concentration - blank wells) / (positive control wells - blank wells)) * 100%.

[0477] The results of this assay show that the compounds of the present disclosure have strong activity against both wild-type BTK kinase and the drug-resistant mutant BTK C481S kinase, as well as superior selectivity over EGFR, ITK, and TEC kinases. The results of representative example compounds are summarized in Table 1 below (where A is the IC 50 ≦10nM, B is IC 50 is 10-50nM, and C is IC 50 is 50-100nM, and D is IC 50 is 100-1000nM, and E is IC 50 represents an IC of 1000 to 10000 nM, and F represents an IC 50 >10000nM). [Table 1]

[0478] (2) Cell proliferation inhibition assay In this assay, the CellTiter-Glo (registered trademark) Luminescent Cell Viability Detection Kit, a uniform cell viability detection method provided by Promega, was used. The cell viability of cultured cells (TMD-8 cells: human diffuse large B-cell lymphoma cell line, REC1 cells: human mantle cell lymphoma cells, DOHH2 cells: human follicular lymphoma cells, Pfeiffer cells: human diffuse large B-cell lymphoma cells, Raji cells: human Burkitt lymphoma cells, RPMI-8226 cells: human multiple myeloma cells) was measured by quantifying ATP. The specific assay steps were as follows: a) Logarithmic growth phase cells were collected, a cell suspension was prepared, the cell number was counted, and the cell concentration was calculated. b) The cell suspension was diluted to the required concentration and then added to the central wells of a 96-well plate, and PBS was added to the edge wells. Wells without cells and wells containing only culture medium served as blank controls. c) In addition to the cell plate used for compound analysis, another 96-well plate was prepared as a T0 plate, and 3-6 blank wells and 3-6 cell wells were added. The next day, cell viability was detected using CTG as the T0 viability of cells. d) The cell plates were cultured overnight in a 37° C., 5% CO2 incubator. e) The next day, serial dilutions of compounds were added and the cell plates were cultured for 72 hours in a 5% CO2 incubator at 37°C. Wells containing only 0.5% DMSO without compound were used as positive controls for cell proliferation. f) CTG reagent (CellTiter-Glo kit) was added according to the manufacturer's instructions to detect cell viability. g) The plate was read on a Biotek cytation 3.0 microplate reader and the data exported. h) Using GraphPad Prism 7.0 software, IC 50 was calculated. The IC of the compound was calculated using the following nonlinear fitting equation: 50 (50% inhibitory concentration) was obtained: Y = Lower limit + (Upper limit - Lower limit) / (1 + 10^((LogIC 50 -X) * HillSlope) X: Logarithm of compound concentration Y: Inhibition rate (% inhibition) The formula for calculating the cell inhibition rate (% inhibition) was: Inhibition rate %=1−(luminescence of test drug−luminescence of vehicle control group) / (luminescence of cell control group−luminescence of vehicle control group)×100%.

[0479] The results of this assay show that the compounds of the present disclosure have relatively strong activity against TMD-8 cells, REC1 cells, DOHH2 cells, Pfeiffer cells, Raji cells, and RPMI-8226 cells.

[0480] (3) Phosphor-BTK(Y223) assay The purpose of this assay is to simply, quickly and directly detect the internal levels of BTK in cells. The specific assay steps are as follows: Day 1: NIH / 3T3 BTK WT cells (7.5k / well) and NIH / 3T3 BTK C481S cells (10k / well) were plated in a 96-well plate and cultured overnight at 37°C under 5% CO2. Day 2: 1. A 3-fold final concentration gradient dilution of the compound was prepared and 50 μL was added to 100 μL of cell culture medium; 0.5% DMSO was used as a positive control for cell proliferation. 2. The plates were incubated at 37° C. under 5% CO2 for 0.5 hours. 3. Na3VO4 was added to a final concentration of 1 mM, and the cells were cultured at 37°C under 5% CO2 for 2 hours. 4. During incubation, prepare the following reagents: 1x Additive Lysis Buffer: 3vol ddH2O + 1vol 4x Lysis Buffer + 100x Blocking Reagent Standard solutions of p-BTK(Y223) cryptate antibody and p-BTK(Y223)d2-antibody: Frozen antibodies (stored at -20°C) were added to 19-fold the volume of assay buffer (stored at 4°C). 5. After incubation, the medium was removed and 50 μL of 1× supplemented lysis buffer was added; the mixture was centrifuged at 500 rpm for 30 minutes at room temperature. 6. The lysate was mixed thoroughly and 16 μL was transferred to a 384-well plate; 1× added lysis buffer was used as a blank control. 7. 4 μL of a premixed standard solution of the two antibodies (cryptate Ab:d2 Ab=1:1) was added and the plate was sealed. 8. The plates were incubated overnight at room temperature. Day 3: Plates were read at 665 nm and 620 nm using a Biotek cytation 3.0 microplate reader and the 665 / 620 nm ratio was calculated for each well. Data Analysis: IC was analyzed using GraphPad Prism 7.0 software. 50 was calculated. Calculate the phosphorylated BTK Y223 IC of the compound using the following nonlinear fitting equation: 50 (50% phosphorylation inhibitory concentration) was obtained: Y = Lower limit + (Upper limit - Lower limit) / (1 + 10^((LogIC 50 -X) * HillSlope) X: Logarithm of compound concentration Y: Inhibition rate (% inhibition) The formula for calculating the cellular phosphorylation inhibition rate (% inhibition) was as follows: % Inhibition = 1-(wells of each concentration - blank wells) / (positive control wells - blank wells)

[0481] The results of the Phosphor-BTK(Y223) assay described above are summarized in Table 2 below (where A is IC 50 ≦25nM, and B is IC 50 is 25-50 nM, and C is the IC50 is 50-100 nM, and D is the IC 50 (Indicates that the concentration is 100-500 nM.) [Table 2] [Table 3]

[0482] (4) Metabolic stability evaluation Metabolic stability is generally used to describe the rate and extent to which a compound is metabolized, and is one of the major factors that affect pharmacokinetic properties. Many compounds are substrates for CYP450 enzymes and other drug metabolizing enzymes, and liver microsomes are rich in CYP450. The purpose of this assay is to detect the in vitro metabolic stability of the compounds disclosed herein by incubating them with human and SD rat liver microsomes, and detecting the remaining rate of the compounds by LC-MS / MS. 1) Preparation of solutions Phosphate buffer solution (PBS): 150 mL of the previously prepared K2HPO4 (0.5 M) solution was mixed with 700 mL of K2HPO4 (0.5 M) solution; then, the pH of the mixed solution was adjusted to 7.4 using K2HPO4 (0.5 M) solution. The mixed solution was used as 5x concentrated PBS and stored at 4°C until use. Before use, the mixed solution was diluted 5x with ultrapure water and 3.3 mM magnesium chloride was added to obtain phosphate buffer solution PBS (100 mM).

[0483] NADPH regeneration system solution: An NADPH solution containing 6.5 mM NADP, 16.5 mM glucose-6-phosphate, and 3 U / mL glucose-6-phosphate dehydrogenase was prepared using 5 mL of PBS.

[0484] Internal standard stop solution: 50 ng / mL propranolol hydrochloride and 200 ng / mL tolbutamide were prepared as a standard solution of the internal standard using acetonitrile.

[0485] Human liver microsome solution: 0.31 mL of human liver microsomes (25 mg / mL) was added to 0.961 mL of PBS (pH 7.4) and mixed thoroughly to obtain a human liver microsome dilution with a protein concentration of 0.625 mg / mL.

[0486] SD rat liver microsome solution: 0.31 mL of SD rat liver microsomes (25 mg / mL) was added to 0.961 mL of PBS (pH 7.4) and mixed thoroughly to obtain a SD rat liver microsome dilution with a protein concentration of 0.625 mg / mL.

[0487] Sample standard solution: The powder of the compound of the present disclosure, the positive control dextromethorphan powder and omeprazole powder were prepared in DMSO to prepare 10 mM sample stock solutions, which were then diluted with 70% acetonitrile-water to obtain 0.25 mM sample standard solutions.

[0488] 2) Sample culture 398 μL of the human liver microsome dilution was added to a 96-well culture plate (N=2); 2 μL each of 0.25 mM test compound and dextromethorphan was added and mixed thoroughly.

[0489] 398 μL of the diluted SD rat liver microsomes was added to a 96-well culture plate (N=2); 2 μL each of 0.25 mM test compound and omeprazole was added and mixed thoroughly.

[0490] 300 μL of pre-chilled stopping solution was added to each well of a 96-well deep well plate serving as a stopping plate, and the plate was placed on ice.

[0491] The 96-well culture plate and NADPH regeneration system were placed in a 37°C water bath, shaken at 100 rpm, and pre-cultured for 5 minutes. 80 μL of culture medium was removed from each well of the culture plate, added to the stop plate, and mixed thoroughly. 20 μL of NADPH regeneration system solution was added as a 0-minute sample. Then, 80 μL of NADPH regeneration system solution was added to each well of the culture plate. The reaction was started and timing was started. The reaction concentration of the compound to be tested was 1 μM, and the protein concentration was 0.5 mg / mL.

[0492] At 10, 30, and 90 minutes into the reaction, 100 μL of the reaction solution was added to a stop plate and vortexed for 3 minutes to stop the reaction.

[0493] The stopped plate was centrifuged at 5000 rpm for 15 minutes at 4° C. 200 μL of the supernatant was added to a 96-well plate containing 200 μL of ultrapure water and mixed thoroughly. Sample analysis was performed using LC-MS / MS, with 10 μL injected.

[0494] 3) How to analyze the samples In this assay, the peak areas of the tested compounds, dextromethorphan, omeprazole and the internal standard, were detected using an LC-MS / MS system, and the peak area ratios of the compounds to the internal standard were calculated. 4) Data processing Peak areas of samples and internal standards were acquired using a mass spectrometer and Analyst software. The substrate removal rate constant K was obtained by plotting the remaining amount of compound (R%) versus time using a single exponential degradation model in Graphpad prism 7.0 software. Ct / C0=exp(-K * t)

[0495] Half-life T 1 / 2 and intrinsic clearance CL int was calculated according to the following formula, where V / M is equal to 1 / C(protein):

number

[0496] The results of this assay demonstrate that the compounds of the present disclosure have excellent metabolic stability.

[0497] (5) Pharmacokinetic assay in rats Six male Sprague-Dawley rats (7-8 weeks old, weighing approximately 210 g) were divided into two groups (three rats per group). A unit dose of the compound (10 mg / kg orally) was administered intravenously or orally. The pharmacokinetic differences were compared.

[0498] Rats were fed standard chow and provided with water. Fasting began 16 hours before the study. Drugs were dissolved with PEG400 and dimethylsulfoxide. Blood was collected from the orbit. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dosing.

[0499] The rats were temporarily anesthetized by inhaling ether, and 300 μL of blood samples were collected from the orbit into test tubes containing 30 μL of 1% heparin saline solution. The tubes were dried overnight at 60°C before use. After the blood samples were collected at the final time point, the rats were sacrificed after ether anesthesia.

[0500] Immediately after blood samples were collected, the tubes were mixed thoroughly by gently inverting at least 5 times and placed on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4°C to separate plasma and red blood cells. 100 μL of plasma was added to a clean plastic centrifuge tube using a pipette. The compound name and the time point of sampling were recorded. Plasma was stored at -80°C until analysis. The concentration of the compounds of the present disclosure in plasma was determined by LC-MS / MS. Pharmacokinetic parameters were calculated based on the plasma drug concentration of each animal at different time points.

[0501] The results of this assay demonstrate that the compounds of the present disclosure have relatively excellent pharmacokinetic properties in animals and therefore relatively excellent pharmacodynamics and therapeutic efficacy.

[0502] The above contents are further detailed descriptions of the present disclosure in combination with certain other embodiments, and the specific implementation of the present disclosure is not deemed to be limited to these descriptions. For those skilled in the art to which the present disclosure belongs, some easy deductions or substitutions can be made without departing from the concept of the present disclosure, and they should be considered to belong to the scope of protection of the present disclosure.

Claims

1. Formula (I): 【Chemistry 1】 (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, Ring A has the structure: 【Chemistry 2】 and X １ ~X ５ is located on an aromatic ring; X １ is N, CD or CH; X ２ is a N atom or a C atom; X ３ is a N atom or a C atom; X ４ is a N atom or a C atom; X ５ is a N atom or a C atom; Y １ is O, S, NH or C(R Ｙ１ ) ２ where R Ｙ１ are independently H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ are independently H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; Y ３ is N, CD or CH; Z １ is C(O)NH ２ and Z ２ NH ２ and Or Z. １ and Z ２ together with the atoms to which they are attached form the structure: 【Chemistry 3】 Forming Here, X ６ is N, CD, CH or C—OH; X ７ is N, CD or CH; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D, OH or NH ２ and R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - or -C(R １ ) (R １ ')-C(R ２ ) (R ２ ')- together form -CH=CH-; Or, R １ and R ２ is combined with C １～４ Forming an alkylene; R ４ H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; R ４ ' is H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; R ｓ H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; R ｔ H, D, halogen, C １～６ Alkyl or C １～６ haloalkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; In the above group, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 3- to 7-membered heterocyclyl and C １～４ One or more H in the alkylene may be replaced with D until fully deuterized; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

2. Ring A has the structure: 【Chemistry 4】 or the structure: 【Chemistry 5】 or further alternatively the structure: 【Chemistry 6】 2. The compound of claim 1, wherein:

3. Ring A has the structure: 【Chemistry 7】 or the structure: 【Chemistry 8】 or further alternatively the structure: 【Chemistry 9】 2. The compound of claim 1, wherein:

4. Y １ is O, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

5. Y １ C (RY １ ) ２ , or C.H. ２ 4. The compound of any one of claims 1 to 3, wherein:

6. Y ２ is a bond, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

7. Y ２ C(R Ｙ２ ) ２ Or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ , or C.H. ２ Or CH ２ CH ２ 6. The compound of any one of claims 1 to 5, wherein:

8. Y ３ is CH, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

9. R ２ is OH and R ３ is H, or R ２ is H and R ３ is OH, or R ２ is H and R ３ CH ２ 9. The compound of any one of claims 1 to 8, wherein R is 0, R is 1 or R is 2. OH, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

10. 10. The compound of any one of claims 1 to 9, wherein R is F, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

11. 11. The compound of any one of claims 1 to 10, or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein R' is methyl.

12. The following general formula: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 wherein each group is as defined in any one of claims 1 to 11.

12. The compound of any one of claims 1 to 11, having the formula:

13. Formula (II): 【Chemistry 14】 (II) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ are independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

14. Formula (II-1): 【Chemistry 15】 (II-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OH.

15. X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is F; R' is methyl; However, R ２ and R ３ At least one of is OH or CH ２ OH, 15. The compound of claim 14, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

16. Formula (III): 【Chemistry 16】 (III) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X ２ is N, CD or CH; X ５ is N, CD or CH; X ６ is N, CD, CH or C—OH; X ７ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ 1 is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

17. Formula (III-1): 【Chemistry 17】 (III-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X ２ is N, CD or CH; X ５ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

18. Formula (III-2): 【Chemistry 18】 (III-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X ２ is N, CD or CH; X ５ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OH.

19. X ２ is N; X ５ is N; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is F; R' is methyl; However, R ２ and R ３ At least one of is OH or CH ２ OH, 20. The compound of claim 18, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

20. Formula (IV): 【Chemistry 19】 (IV) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ ~X ５ is located on an aromatic ring; X １ is N, CD or CH; X ２ is a N atom or a C atom; X ３ is a N atom or a C atom; X ４ is a N atom or a C atom; X ５ is a N atom or a C atom; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

21. Formula (IV-1): 【Chemistry 20】 (IV-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ , X ２ and X ５ is located on an aromatic ring; X １ is N, CD or CH; X ２ is a N atom or a C atom; X ５ is a N atom or a C atom; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

22. Formula (IV-2): 【Chemistry 21】 (IV-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ , X ２ and X ５ is located on an aromatic ring; X １ is N, CD or CH; X ２ is a N atom or a C atom; X ５ is a N atom or a C atom; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OH.

23. X １ , X ２ and X ５ is an aromatic ring; X １ is N, CD or CH; X ２ is a N atom or a C atom; X ５ is a N atom or a C atom; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is F; R' is methyl; However, R ２ and R ３ At least one of is OH or CH ２ OH, 23. The compound of claim 22, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

24. Formula (V): 【Chemical 22】 (V) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

25. Formula (VI): 【Chemistry 23】 (VI) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

26. Formula (VI-1): 【Chemistry 24】 (VI-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OH.

27. X １ is N, CD or CH; X ６ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond or C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ３ is H, D, OH or CH ２ OH; R is F; R' is methyl; However, R ２ and R ３ At least one of is OH or CH ２ OH, 27. The compound of claim 26, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

28. Formula (VII): 【Chemistry 25】 (VII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; Y １ is O; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; Alternatively, -C(R １ ) (R １ ')-C(R ２ ) (R ２ ') together form -CH=CH-; Or, R １ and R ２ is bonded to -CH ２ - forming; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl and -CH ２ One or more H in - may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

29. Formula (VII-1): 【Chemistry 26】 (VII-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OH; R ３ ' is H or D; Or, R １ and R ２ is bonded to -CH ２ - forming; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and -CH ２ One or more H in - may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OH.

30. X １ is N; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H or D; R ３ is H, D, OH or CH ２ OH; R ３ ' is H or D; Or, R １ and R ２ is bonded to -CH ２ - forming; R is F; R' is methyl; However, R ２ and R ３ At least one of is OH or CH ２ OH, 30. The compound of claim 29, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

31. Formula (VII): 【Chemistry 27】 (VII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; Y １ is C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - taken together form -CH=CH-; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

32. Formula (VII-2): 【Chemistry 28】 (VII-2) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; Y １ is C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H or D; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - taken together form -CH=CH-; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

33. X １ is N; Y １ C(R Ｙ１ ) ２ where R Ｙ１ is independently H or D; Y ２ is bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H or D; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - taken together to form -CH=CH-; R is F; R' is methyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ That is, 33. The compound of claim 32, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

34. Formula (VIII): 【Chemical 29】 (VIII) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; Y １ is O or C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is a bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl or 3- to 7-membered heterocyclyl; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - or -C(R １ ) (R １ ')-C(R ２ ) (R ２ ')- together form -CH=CH-; Or, R １ and R ２ is combined with C １～４ Forming an alkylene; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 3- to 7-membered heterocyclyl and C １～４ One or more H in the alkylene may be replaced with D until fully deuterized; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ is.]

35. X １ is N, CD or CH; Y １ is O; Y ２ is bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ is haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; Alternatively, -C(R １ ) (R １ ')-C(R ２ ) (R ２ ') together form -CH=CH-; Or, R １ and R ２ is bonded to -CH ２ - forming; R is halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ That is, 35. The compound of claim 34, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

36. X １ is N, CD or CH; Y １ C(R Ｙ１ ) ２ where R Ｙ１ is independently H, D or halogen; Y ２ is bond, C(R Ｙ２ ) ２ or C(R Ｙ２ ) ２ C(R Ｙ２ ) ２ where R Ｙ２ is independently H, D or halogen; R １ is H, D, halogen or OH; R １ ' is H, D or halogen; R ２ is H, D or OH; R ２ ' is H, D, C １～６ Alkyl or C １～６ haloalkyl; R ３ is H, D, OH or CH ２ OR ａ where R ａ is H, C １～６ Alkyl or C １～６ haloalkyl; R ３ ' is H, D, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ is cycloalkyl; Alternatively, -C(R ３ ) (R ３ ')-C(R Ｙ１ ) ２ - taken together to form -CH=CH-; R is halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl, C １～６ Haloalkyl and C ３～６ One or more H in the cycloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ At least one of is OH or CH ２ OR ａ That is, 35. The compound of claim 34, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

37. Formula (VIII-1): 【Chemistry 30】 (VIII-1) or a tautomer, stereoisomer, prodrug, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [In the formula, X １ is N, CD or CH; Y １ O, CHD, CD ２ or CH ２ and R ２ is H, D or OH; R ３ is H, D or CH ２ OH; R is a halogen; R' is C １～６ Alkyl or C １～６ haloalkyl; Here, C in the above group １～６ Alkyl and C １～６ One or more H in the haloalkyl may be replaced with D until fully deuterated; However, R ２ and R ３ Neither is H.

38. X １ is N; Y １ O, CHD, CD ２ or CH ２ and R ２ is H, D or OH; R ３ is H, D or CH ２ OH; R is F; R' is methyl; However, R ２ and R ３ But neither of them are H.

38. The compound of claim 37, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

39. The following structure: 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemistry 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Chemistry 60】 【Chemistry 61】 【Chemistry 62】 【Chemistry 63】 【Chemistry 64】 【Chemistry 65】 【Chemistry 66】 【Chemistry 67】 【Chemistry 68】 or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

40. 40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, and a pharma- ceutically acceptable excipient, optionally including other therapeutic agents.

41. 47. Use of a compound of any one of claims 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of claim 40, in the manufacture of a medicament for treating and / or preventing a wild-type and / or mutant BTK kinase mediated disease, wherein the mutant BTK kinase is optionally selected from C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G and BTK C481W, optionally BTK C481S.

42. 41. A method of treating and / or preventing a wild-type and / or mutant BTK kinase mediated disease in a subject, comprising administering to the subject a compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a pharmaceutical composition of claim 40, wherein the mutant BTK kinase is selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G, and BTK C481W, and optionally is BTK C481S.

43. 47. A compound according to any one of claims 1 to 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 40, wherein the mutant BTK kinase is optionally selected from BTK C481S, BTK C481F, BTK C481Y, BTK C481R, BTK C481T, BTK C481G and BTK C481W, and optionally is BTK C481S, for use in the treatment and / or prevention of a wild-type and / or mutant BTK kinase mediated disease.

44. 44. The use of claim 41, or the method of claim 42, or the compound or composition for use of claim 43, wherein the BTK mediated disease is selected from an allergic disease, an autoimmune disease, an inflammatory disease, and cancer.

45. 44. The use of claim 41 , or the method of claim 42 , or the compound or composition for use of claim 43 , wherein the BTK mediated disorder is a B cell proliferative disorder selected from chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with myelodysplastic disorders in three lineages, mixed lineage leukemia, myelodysplastic syndromes, myeloproliferative disorders, marginal zone lymphoma, and Waldenstrom's macroglobulinemia.

46. 44. The use of claim 41 or the method of claim 42 or the compound or composition for use of claim 43, wherein the BTK mediated disease is multiple myeloma.

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