Heteroaryl heterocyclic compound and use thereof

Abstract

The present invention relates to heteroaryl heterocyclic compounds of formula (I) wherein the variables are as defined in the description, pharmaceutical compositions comprising them, and processes for their preparation and use. # imgabs0 #

Description

[0001] This application is a divisional application. The application number of the original application is 202180015458.2, the application date is February 19, 2021, the earliest priority date is February 20, 2020, and the name of the invention is “Heteroaryl heterocyclic compounds and their uses”. Technical Field

[0002] The present invention relates to heteroaryl heterocyclic compounds, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Background Art

[0003] Bruton's Tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine proteins (including BTK, LTK, TEC, BMX and TXK, etc.). It is widely expressed in hematopoietic cells except T cells, NK cells and differentiated plasma cells. BTK plays a vital role in signal transduction through B cell antigen receptor (BCR) and Fcγ receptor (FcγR) in B cells and myeloid cells. It is a key regulator of B cell development, activation, signal transduction and survival. It can control the development and differentiation of B cells by activating cell cycle positive regulatory factors and differentiation factors, and can also control the survival and proliferation of B cells by regulating the expression of pro-apoptotic and anti-apoptotic proteins. BTK also plays an important role in the migration and adhesion of B lymphoma cells. In addition, BTK plays a role in numerous other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FceRI) signaling in mast cells, inhibition of Fas / API-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.

[0004] In humans, mutations in the BTK gene lead to the inherited immunodeficiency disease X-linked agammaglobulinaemia (XLA). Human XLA patients involve point mutations in the BTK gene, which are associated with extremely low BTK mRNA levels and BTK protein expression. Therefore, the loss of BTK kinase activity leads to an almost complete lack of mature B cells and immunoglobulins, as well as a significant attenuation of sustained calcium signals in response to BCR stimulation. The effects of BTK mutations are limited to the B cell population, and no significant developmental defects of other immune cells have been found in XLA patients. Spontaneous mutations in the BTK gene have also been found in X-linked immunodeficiency (xid) mice, showing similar but less severe phenotypes. In xid mice or mutation-induced BTK knockout mice, B cell differentiation is partially blocked, the number of mature B cells in the blood circulation is reduced, and resistance to collagen-induced arthritis and staphylococcal-induced arthritis models is shown. A large amount of evidence shows that BTK is highly expressed in peripheral B cells of patients with autoimmune diseases such as rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), as well as in B cell leukemia and lymphoma. Abnormal activation of BCR signaling has been confirmed in these autoimmune diseases and B cell-related diseases, and inhibition of B cells, BCR signaling pathways and BTK can slow down the progression of the disease to varying degrees.

[0005] Based on the key role of BTK in B cell development and function, BTK is considered a potential target for the treatment of B cell malignancies and autoimmune diseases. A variety of BTK inhibitors are being developed for clinical studies of hematological malignancies and autoimmune diseases. Small molecule BTK inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, PRN1008, GDC-0853) have shown relatively effective therapeutic effects. For example, the irreversible BTK inhibitor ibrutinib has shown high durable efficacy and low toxicity in clinical studies. It was approved by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of relapsed mantle cell lymphoma (MCL), in 2014 for chronic lymphocytic leukemia (CLL), and in 2015 for In 2017, it was approved for the treatment of relapsed / refractory marginal zone lymphoma (MZL). In particular, it expanded its approval indication to chronic graft-versus-host disease (GVHD) in 2017, demonstrating the mechanism of BTK in the treatment of chronic autoimmune diseases. In addition, the irreversible BTK inhibitor acalabrutinib was also approved for adult MCL in 2017 and CLL in 2019; zanubrutinib was approved by the FDA for MCL in November 2019; PRN1008 is undergoing a phase 3 study for pemphigus. Some irreversible BTK inhibitors (tirabrutinib, spebrutinib, evobrutinib) and reversible BTK inhibitors (GDC-0853, ARQ-531 and LOXO-305) are undergoing preclinical and clinical stage development.

[0006] Therefore, BTK inhibitors represent an attractive approach for development for the treatment of relevant diseases, in particular for the treatment of cancer, inflammatory diseases or autoimmune diseases. Brief description of the invention

[0008] The present invention provides a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0011] X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl;

[0012] X3 and X4 are independently C or N;

[0013] Y1 and Y2 are independently CR 10 or N;

[0014] R1 and R2 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and phenyl; or R1, R2 together with the carbon atom to which they are attached form the following structure:

[0015] Wherein: R6 is independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl and C 1-6 or two R6 together with the carbon atom to which they are commonly attached form a 3-6 membered cyclic hydrocarbon group; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; Z is N or CR7; R7 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogen and C 1-6 Haloalkyl;

[0016] Or R1, R2 together with the carbon atom to which they are attached form Provided that R3 is halogen or X1 and X2 are not CH at the same time;

[0017] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0018] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, -(C 1-3 Alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 Alkyl or C 1-3 The alkyl groups are each optionally substituted with one or more deuterium or halogen;

[0019] Cy Where: R 11 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more deuterium or halogen;

[0020] U, V and W are each independently N or CR 12 ; R 12 is hydrogen, deuterium or a halogen;

[0021] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, -C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted with one or more groups selected from the following:

[0022] 1) Halogen;

[0023] 2) Oxo;

[0024] 3)-CN;

[0025] 4) C 1-6 alkyl;

[0026] 5) C 2-6 alkenyl;

[0027] 6) C 2-6 Alkynyl;

[0028] 7) C 1-6 Alkoxy;

[0029] 8) C 1-6 Haloalkyl;

[0030] 9)-(C 1-6 Alkyl)-OH;

[0031] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0032] 11) C 3-6 Cycloalkyl;

[0033] 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclyl groups are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, -NH2, -OH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2 and -NH(C 3-6 Cycloalkyl);

[0034] 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more groups selected from the following: halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0035] 14) phenyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N-(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0036] 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e"Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0037] 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by one or more groups selected from the following: deuterium, halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cyclic hydrocarbon), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH; and

[0038] 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 Alkyl)-OH and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0039] R 10 For hydrogen, deuterium, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0040] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0041] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

[0042] The above-mentioned compounds and the active compounds disclosed in the context of the present invention (including general compounds and specific compounds), as well as pharmaceutically acceptable salts thereof, or their solvates, racemic mixtures, enantiomers, diastereomers or tautomers, are referred to herein as "compounds of the present invention".

[0043] The present invention also provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0044] The present invention also provides a method for inhibiting BTK activity in vivo or in vitro, comprising contacting an effective amount of the compound of the present invention with BTK.

[0045] The present invention also provides a method for treating or preventing a disease mediated by BTK or at least in part by BTK, comprising administering an effective amount of a compound of the present invention to a subject in need thereof.

[0046] The present invention also provides a method for treating or preventing cancer, inflammatory diseases or autoimmune diseases, which comprises administering an effective amount of the compound of the present invention to an individual in need thereof.

[0047] The present invention also provides the use of the compounds of the present invention in the treatment or prevention of diseases mediated or at least partially mediated by BTK.

[0048] The present invention also provides use of the compound of the present invention in treating or preventing cancer, inflammatory diseases or autoimmune diseases.

[0049] The present invention also provides the use of the compound of the present invention in the preparation of a medicament for treating or preventing a disease mediated by BTK or at least partially mediated by BTK.

[0050] The present invention also provides use of the compound of the present invention in preparing a medicament for treating or preventing cancer, inflammatory diseases or autoimmune diseases.

[0051] The present invention also provides compounds of the present invention for use in inhibiting BTK activity in vivo or in vitro.

[0052] The present invention also provides a compound of the invention for use as a medicament.

[0053] The present invention also provides a compound of the present invention for use as a medicament for the treatment or prevention of a disease mediated or at least partly mediated by BTK, in particular for the treatment or prevention of cancer, inflammatory diseases or autoimmune diseases.

[0054] The present invention also provides a drug combination comprising a compound of the present invention and at least one additional therapeutic agent, wherein the therapeutic agent is preferably selected from: an anti-inflammatory agent, an immunomodulator or an anti-tumor agent, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0055] The present invention also provides a kit for treating or preventing a disease mediated or at least partially mediated by BTK. The kit may include a pharmaceutical composition of the present invention and instructions for use, wherein the pharmaceutical composition includes a compound of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 :The growth curve of TMD8 subcutaneous transplanted tumor.

[0057] Figure 2 : The inhibitory effect of the compounds of the present invention on B cell activation in whole blood of mice induced by anti-IgD antibodies.

[0058] Figure 3 : The inhibitory effect of the compounds of the present invention on B cell activation in whole blood of mice induced by anti-IgD antibodies.

[0059] Figure 4 : Effects of the compounds of the present invention on the joint paw volume of CIA (collagen-induced arthritis) rats (the hind paw volume was measured using a paw volume meter, and the data were expressed as mean ± standard error, and the groups were normal group, vehicle control group (i.e., the model group in the accompanying drawings), different doses of compound 19QD groups, and 4 mg / kg GDC-0853 group (normal group: n=3, other groups: n=8). DETAILED DESCRIPTION OF THE INVENTION

[0061] definition

[0062] The following words, phrases and symbols used in this application have the meanings described below, unless the context in which they are used indicates otherwise.

[0063] A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -OR 3 Refers to R 3 It is connected to the rest of the molecule through the oxygen atom.

[0064] The term "alkyl" as used herein refers to a group having 1 to 18 carbon atoms (C 1-18 ), preferably 1 to 10 carbon atoms (C 1-10 ), particularly preferably 1 to 6 carbon atoms (C 1-6 ), more preferably 1 to 4 carbon atoms (C 1-4 ) or 1-3 carbon atoms (C 1-3) is a straight or branched saturated hydrocarbon group. When the term "alkyl" is prefixed with "C", it indicates the number of carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms, "C 1-3 "Alkyl" means an alkyl group having 1 to 3 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, and the like.

[0065] The term "alkenyl" as used herein refers to a group having 2 to 18 carbon atoms (C=C) containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (C=C). 2-18 ), preferably 2 to 10 carbon atoms (C 2-10 ), more preferably 2 to 6 carbon atoms (C 2-6 ), more preferably 2 to 4 carbon atoms (C 2-4 ) is a straight or branched unsaturated hydrocarbon group. When the term "alkenyl" is prefixed with "C", it indicates the number of carbon atoms. For example, "C 2-6 "Alkenyl" means an alkenyl group having 2 to 6 carbon atoms, "C 2-4 "Alkenyl" means an alkenyl group having 2 to 4 carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (eg, 2-propenyl), butenyl (eg, 2-butenyl), etc. The point of attachment of the alkenyl group may or may not be on the double bond.

[0066] The term "alkynyl" as used herein refers to a moiety having 2 to 18 carbon atoms (C≡C) that contains one or more, for example 1, 2 or 3, carbon-carbon triple bonds (C≡C). 2-18 ), preferably 2 to 10 carbon atoms (C 2-10 ), more preferably 2 to 6 carbon atoms (C 2-6 ), more preferably 2 to 4 carbon atoms (C 2-4 ) is a straight or branched unsaturated hydrocarbon group. When the term "alkynyl" is prefixed with "C", it indicates the number of carbon atoms. For example, "C 2-6 "Alkynyl" means an alkynyl group having 2 to 6 carbon atoms, "C 2-4 "Alkynyl" means an alkynyl group having 2 to 4 carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl (eg, 2-propynyl), butynyl (eg, 2-butynyl), etc. The point of attachment of the alkynyl group may or may not be on a triple bond.

[0067] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

[0068] The term "haloalkyl" as used herein refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. When the term "haloalkyl" is prefixed with "C", it indicates the number of carbon atoms. For example, "C 1-6 "Haloalkyl" means a haloalkyl group as defined above having 1 to 6 carbon atoms, "C 1-4 "Haloalkyl" means a haloalkyl group as defined above having 1 to 4 carbon atoms. 1-6 Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH(CF3)2, and the like.

[0069] The term "cycloalkyl" as used herein refers to a cyclic hydrocarbon group containing 3 to 12 ring carbon atoms (C 3-12 )(e.g. 3-8 ring carbon atoms (C 3-8 ), 5-7 ring carbon atoms (C 5-7 ), 4-7 ring carbon atoms (C 4-7 ) or 3-6 ring carbon atoms (C 3-6 )) is a saturated or partially unsaturated cyclic hydrocarbon group; it may have one or more rings, such as 1, 2 or 3, preferably 1 or 2 rings. When the term "cyclic hydrocarbon group" is prefixed with "C", it indicates the number of carbon atoms. For example, "C 3-6 "Cycloalkyl" or "3-6 membered cycloalkyl" means a cycloalkyl having 3-6 ring carbon atoms. The cycloalkyl may include fused or bridged rings and spiro rings. The ring of the cycloalkyl may be saturated, and may contain one or more, for example one or two, double bonds (i.e., partially unsaturated) on the ring, but it is not completely conjugated and is not an "aryl" as defined in the present invention. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentanyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and the like.

[0070] The terms "heterocyclyl" or "heterocycle" as used herein are used interchangeably and refer to: a saturated or partially unsaturated ring having 3-12 ring atoms (e.g., 3-8 ring atoms, 4-8 ring atoms, 4-6 ring atoms, or 4-5 ring atoms), wherein the ring atoms include one or more (e.g., 1, 2 or 3, preferably 1 or 2) heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as 1, 2 or 3, preferably 1 or 2 rings. Wherein, N and S may be optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl group may be on the N heteroatom or on a carbon atom. For example, "4-8 membered heterocyclyl" means a heterocyclyl having 4-8 (4, 5, 6, 7 or 8) ring atoms, which contains at least one, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S; "4-6 membered heterocyclyl" means a heterocyclyl having 4-6 (4, 5 or 6) ring atoms, which contains at least one, preferably 1 or 2 heteroatoms independently selected from N, O and S (preferably N and O), which is preferably a monocyclic ring; "4-5 membered heterocyclyl" means a heterocyclyl having 4-5 ring atoms, which contains at least one, preferably 1 or 2 heteroatoms independently selected from N, O and S (preferably N and O), which is a monocyclic ring. Heterocyclyls may include fused or bridged rings as well as spirocycles. The ring of the heterocyclic group may be saturated, and may also contain one or more, for example one or two, double bonds (i.e., partially unsaturated), but it is not completely conjugated, and is not a "heteroaryl" as defined in the present invention. Examples of heterocyclic groups include, but are not limited to, 4-8-membered heterocyclic groups, 4-6-membered heterocyclic groups, and 4-5-membered heterocyclic groups, such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, pyrazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl, preferably oxetanyl (e.g., oxetan-3-yl), azetidinyl, tetrahydropyranyl, morpholinyl (e.g., morpholino), piperazinyl (e.g., piperazin-1-yl), and tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl).

[0071] The term "aryl" or "aromatic ring" as used herein can be used interchangeably and refers to a carbocyclic hydrocarbon group having 6 to 14 carbon atoms consisting of one ring or multiple rings such as two condensed rings, wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthrenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.

[0072] As used herein, the terms "heteroaryl" and "heteroaromatic ring" are used interchangeably and refer to a mono-, bi- or tricyclic ring system having 5-15, preferably 5-12, more preferably 5-10, most preferably 5-6 or 8-10 ring atoms, wherein at least one ring is a 5- or 6-membered aromatic ring containing one or more, for example 1 to 4, heteroatoms selected from N, O and S, wherein S and N may be optionally oxidized to various oxidation states. When the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other. Preferably, the heteroaryl is a 5-12 membered heteroaryl. For example, the heteroaryl includes:

[0073] 5-6 membered monocyclic heteroaryl, i.e., a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, wherein the ring atoms include one or more, for example, 1, 2 or 3, heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon atoms; it is preferably triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, triazinyl, oxazolyl, thiadiazolyl, pyridazinyl, more preferably triazolyl (e.g. 1H-1,2,3-triazole), pyridyl (e.g. pyridin-2-yl), pyrazinyl, pyrimidinyl, and

[0074] 8-10 membered bicyclic heteroaryl, i.e., a bicyclic aromatic hydrocarbon group having 8, 9 or 10 ring atoms, wherein the ring atoms include one or more, for example 1, 2, 3 or 4, preferably 1, 2 or 3, heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring; it is preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, for example 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-yl.

[0075] Examples of heteroaryl groups include, but are not limited to, 5-6 membered monocyclic heteroaryl groups such as pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, and 1,3,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furanyl, pyranyl, pyrrolyl, pyridazinyl, and 8-10 membered bicyclic heteroaryl groups such as benzoxazolyl, benzisoxazolyl, benzothienyl, benzisothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl), imidazopyridazinyl (e.g., imidazo[1, 2-b]pyridazinyl), pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl), pyrrolopyrimidinyl (e.g., pyrrolo[3,4-d]pyrimidinyl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl), pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyridinyl (e.g., [1,2,4]triazolo[4,3-a]pyridinyl and [1,2,4]triazolo[1,5-a]pyridinyl), tetraazolopyridinyl (e.g., tetrazolo[1,5-a]pyridinyl), benzofuranyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine.

[0076] The term "-OH" as described herein refers to a hydroxyl group.

[0077] As used herein, the term "-CN" refers to a cyano group.

[0078] The term "oxo" as used herein refers to =0.

[0079] Any asymmetric atom (e.g., carbon, etc.) of the compound of formula (I) may be in a racemic or enantiomerically enriched form, for example, in (R)-, (S)-, or (RS)-configuration. In some embodiments, the asymmetric atom in the (R)- or (S)-configuration each has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100% enantiomeric excess.

[0080] If a structural formula or chemical name herein contains "(RS)", it means a mixture of the (R) configuration and the (S) configuration of the compound in any ratio.

[0081] As used herein, the terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted with one or more..." includes unsubstituted and substituted with 1, 2, 3 or more of the described substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and / or inherently unstable substitution patterns.

[0082] As used herein, the term "substituted" or "substituted by..." means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a given atom or group are replaced by one or more (e.g., 1, 2, 3, or 4) substituents, preferably substituents selected from a given substituent group or group group, provided that the normal valence of the given atom is not exceeded, and the substituents may be the same or different from each other. As used herein, the term "substituted by one or more groups selected from..." or "substituted by one or more..." means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more groups selected from a given substituent group or group group, wherein the groups may be the same or different from each other. Preferably, "substituted by one or more groups selected from..." or "substituted by one or more..." means that a given atom or group is replaced by 1, 2, 3, or 4 groups independently selected from a given substituent group or group group, wherein the groups may be the same or different from each other. In some embodiments, when the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced. The optional substituents may be various groups, provided that the combination of substituents and / or variables produces a chemically correct and stable compound. Chemically correct and stable compounds mean compounds that are sufficiently stable to be isolated from a reaction mixture. Preferably, the substituents are those implemented in the example compounds of the present application.

[0083] Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl portion.

[0084] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers, and therefore there are two or more stereoisomers. Racemic mixtures of these isomers, single isomers and mixtures enriched in one enantiomer, and diastereomers and mixtures partially enriched in specific diastereomers when there are two chiral centers are all within the scope of the present invention. It will also be appreciated by those skilled in the art that the present invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

[0085] The racemic mixture can be used in its own form or can be resolved into its individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture as follows: diastereomeric salts are formed with chiral acids (e.g., individual enantiomers of 10-camphorsulfonate, camphorate, α-bromocamphorate, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of the salts, and then one or both of the resolved bases are liberated, and this process is optionally repeated to obtain one or two isomers that are substantially free of the other isomer, i.e., isomers with an optical purity of >95%. Alternatively, the racemate can be covalently linked to a chiral compound (auxiliary) to obtain diastereomers, which can be separated by chromatography or fractional crystallization, and then the chiral auxiliary is chemically removed to obtain the pure enantiomers.

[0086] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. Tautomers can be interconverted, for example, the enol form and the keto form are typical tautomers.

[0087] "Pharmaceutically acceptable salt" refers to a salt of a free acid or base of a compound of formula (I) that is non-toxic, biologically tolerable or otherwise biologically suitable for administration to treat or prevent an individual. For example, acid addition salts include, for example, addition salts derived from inorganic acids and organic acids, the inorganic acids including, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid, the organic acids including, for example, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. For a general description of pharmaceutically acceptable salts, see, for example, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, ed., Wiley-VCH and VHCA, Zurich, 2002.

[0088] In addition, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

[0089] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (D).

[0090] The term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to entrain a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate. When the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more or less than one molecule of water with one molecule of the substance, wherein the water retains its molecular state of H2O, and such a combination can form one or more hydrates, such as hemihydrates, monohydrates and dihydrates.

[0091] As used herein, the terms "group" and "radical" are synonymous and are used to indicate a functional group or a molecular fragment that can be attached to other molecular fragments.

[0092] The term "active ingredient" is used to refer to a chemical substance that has biological activity. In some embodiments, the "active ingredient" is a chemical substance that has pharmaceutical use.

[0093] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining two or more active ingredients, including fixed and non-fixed combinations of active ingredients, such as kits, pharmaceutical compositions. The term "fixed combination" means that two or more active ingredients (e.g., a compound of the invention and an additional therapeutic agent) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that two or more active ingredients (e.g., a compound of the invention and an additional therapeutic agent) are administered to a patient simultaneously, concurrently or sequentially as separate entities, wherein the administration provides a therapeutically effective level of the compound in the patient's body.

[0094] The terms "treating" or "treatment" or "preventing" a disease or disorder refer to the administration of one or more pharmaceutical substances, particularly compounds of the invention, to an individual suffering from the disease or disorder, or having symptoms of the disease or disorder, or having a predisposition to the disease or disorder, in order to cure, heal, alleviate, relieve, alter, cure, improve, ameliorate or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition to the disease or disorder. In some embodiments, the disease or disorder is cancer, such as a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma. In other embodiments, the disease or disorder is an inflammatory disease or an autoimmune disease.

[0095] When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction to produce the indicated and / or desired product may not necessarily come directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0096] The term "effective amount" as used herein refers to an amount or dosage of a BTK inhibitor that is generally sufficient to produce a beneficial effect on a patient who needs to treat or prevent a disease or disorder mediated by BTK activity or at least in part mediated by BTK. The effective amount or dosage of the active ingredient in the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., the mode or route of administration or administration, the pharmacokinetics of the drug ingredient, the severity and course of the disease or disorder, the individual's previous or ongoing treatment, the individual's health status and response to the drug, and the judgment of the attending physician).

[0097] Typical dosage range is from about 0.0001 to about 200 milligrams of active ingredient per kilogram of individual body weight every day, for example, about 0.001 to 100 mg / kg / day, or about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg, once a day or divided dose unit taking (for example, twice a day, three times a day, four times a day). For 70 kilograms of people, the example range of suitable dosage is about 0.05 to about 7 grams / day, or about 0.2 to about 5 grams / day. Once the patient's disease or disorder improves, the dosage can be adjusted to maintain the effect. For example, the dosage or the number of administrations or the dosage and the number of administrations can be reduced to the level of maintaining the desired treatment or preventive effect according to the change of symptoms. Of course, if the symptoms are alleviated to an appropriate level, treatment can be stopped. However, for the recurrence of symptoms, the patient may need intermittent long-term treatment.

[0098] The term "inhibit" refers to a reduction in the baseline activity of a biological activity or process. The term "inhibit BTK activity" is the actual drug activity for the purposes of the present invention, and refers to a reduction in BTK activity caused by a direct or indirect response to the presence of a compound of the present invention relative to the BTK activity in the absence of the compound of the present invention. The reduction in activity can be caused by a direct interaction between the compound of the present invention and BTK, or by an interaction between the compound of the present invention and one or more other factors that affect BTK activity. For example, the compounds of the present invention can reduce the activity of BTK by directly binding to BTK, can reduce the activity of BTK by directly or indirectly affecting another factor, or can reduce the activity of BTK by directly or indirectly reducing the amount of BTK present in a cell or body.

[0099] As used herein, the term "subject" or "patient" refers to mammals and non-mammals. Mammals refer to any member of the class mammals, including but not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats and pigs; livestock, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds, etc. The term "subject" or "patient" does not limit a particular age or gender. In some embodiments, the subject or patient is a human.

[0100] In general, the term "about" is used herein to modify a stated numerical value by 20% above or below that value.

[0101] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0102] All numerical ranges herein should be understood to disclose every value and subset of values ​​within the range, regardless of whether they are specifically disclosed otherwise. For example, when any numerical range is mentioned, it should be considered to mention every value within the numerical range, such as every integer within the numerical range, such as C in this article. 1-6 It means including 1, 2, 3, 4, 5 or 6 C. The present invention relates to all values ​​falling within these ranges, all smaller ranges and upper or lower limits of numerical ranges. Specific implementation method one:

[0104] Embodiment 1. Compound of formula (I):

[0105]

[0106] or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0107] X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 C 1-6 alkyl;

[0108] X3 and X4 are independently C or N;

[0109] Y1 and Y2 are independently CR 10 or N;

[0110] R1 and R2 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and phenyl;

[0111] Or R1, R2 together with the carbon atoms to which they are attached form the following structure:

[0112] Wherein: R6 is independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl and C 1-6 or two R6 together with the carbon atom to which they are commonly attached form a 3-6 membered cyclic hydrocarbon group; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; Z is N or CR7; R7 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogen and C 1-6 Haloalkyl;

[0113] Or R1, R2 together with the carbon atom to which they are attached form Provided that R3 is halogen or X1 and X2 are not CH at the same time;

[0114] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0115] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, -(C 1-3 Alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 Alkyl or C 1-3 The alkyl groups are each optionally substituted with one or more deuterium or halogen;

[0116] Cy Where: R 11 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more deuterium or halogen;

[0117] U, V and W are each independently N or CR 12 ; R 12 is hydrogen, deuterium or a halogen;

[0118] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, -C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted with one or more groups selected from the following:

[0119] 1) Halogen;

[0120] 2) Oxo;

[0121] 3) – CN;

[0122] 4) C 1-6 alkyl;

[0123] 5) C 2-6 alkenyl;

[0124] 6) C 2-6 Alkynyl;

[0125] 7) C 1-6 Alkoxy;

[0126] 8) C 1-6 Haloalkyl;

[0127] 9)-(C 1-6 Alkyl)-OH;

[0128] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0129] 11) C 3-6 Cycloalkyl;

[0130] 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclyl groups are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, -NH2, -OH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2 and -NH(C 3-6 Cycloalkyl);

[0131] 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more groups selected from the following: halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0132] 14) phenyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N-(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0133] 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0134] 16)-C(O)NR b 'R b ”, where R b ' and Rb "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by one or more groups selected from the following: deuterium, halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cyclic hydrocarbon), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH; and

[0135] 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 Alkyl)-OH and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0136] R 10 For hydrogen, deuterium, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0137] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0138] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl;

[0139] For example, X1 and X2 are independently CH or N; or, X1 is N, and X2 is CR 14 , where R 14 C 1-6 alkyl;

[0140] X3 is N, and X4 is C;

[0141] Y1 and Y2 are both CH;

[0142] R3 is hydrogen, deuterium or halogen;

[0143] R1, R2 together with the carbon atoms to which they are attached form the following structure:

[0144] Wherein: R6 is independently selected from halogen, hydroxyl, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2; p is 1, 2 or 3;

[0145] Or R1, R2 together with the carbon atom to which they are attached form Provided that R3 is halogen or X1 and X2 are not CH at the same time;

[0146] R4 is -(C 1-3 Alkyl)-OH;

[0147] Cy Where: R 11 It is C 1-6 alkyl;

[0148] U and V are both CH; and

[0149] R5 is selected from

[0150]

[0151] in:

[0152] R 21 Selected from C 1-6 alkyl;

[0153] R 22 Independently selected from C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 Alkyl) or 4-6 membered heterocyclic group;

[0154] A1, A2 and A3 are each independently CH; and R 13 is a 6-membered heterocyclic group, which is optionally substituted by one or more selected from C 1-6 Alkyl and 4-membered heterocyclic substituents;

[0155] Provided that the 6-membered heterocyclic group, when substituted, is not substituted by C at both the 2-position and the 6-position 1-6 Alkyl substituted piperazin-1-yl;

[0156] Preferably, R1, R2 together with the carbon atoms to which they are attached form Provided that R3 is halogen or X1 and X2 are not CH at the same time;

[0157] For example, or R1, R2 together with the carbon atom to which they are attached form the following structure:

[0158] Wherein: R6 is independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2;

[0159] Preferably, m is 0.

[0160] Embodiment 2. The compound as described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0161] A racemic mixture, enantiomers, diastereomers or tautomers, wherein R1, R2 together with the carbon atoms to which they are attached form That is, the compound is a compound of formula (IA):

[0162]

[0163] Embodiment 3. The compound as described in Embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0164] A racemic mixture, enantiomers, diastereomers or tautomers, wherein R1, R2 together with the carbon atoms to which they are attached form X3 is N, X4 is C, Y1 is CH, Cy is And the compound is a compound of formula (II):

[0165]

[0166] in:

[0167] X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl;

[0168] Y2 is CH or N;

[0169] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0170] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0171] W is N or CR 12 , R 12 is hydrogen or halogen;

[0172] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following:

[0173] 1) Halogen;

[0174] 2) Oxo;

[0175] 3) – CN;

[0176] 4) C 1-6 alkyl;

[0177] 5) C 2-6 alkenyl;

[0178] 6) C 2-6 Alkynyl;

[0179] 7) C 1-6 Alkoxy;

[0180] 8) C 1-6 Haloalkyl;

[0181] 9)-(C 1-6 Alkyl)-OH;

[0182] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0183] 11) C 3-6 Cycloalkyl;

[0184] 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups;

[0185] 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0186] 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0187] 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0188] 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0189] 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0190] R6 is halogen, C 1-6 Alkyl or hydroxyl; and

[0191] m is 0, 1, 2 or 3;

[0192] Preferably, W is N or CR 12 , R 12 is a halogen; and / or

[0193] Preferably, R5 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, which is optionally substituted by one or more groups selected from the following:

[0194] 1) C 1-6 Alkyl; and

[0195] 2) 4-6 membered heterocycloalkyl, which is optionally substituted by C 1-6 Alkyl and 4-6 membered heterocyclic substitution;

[0196] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0197] Preferably, the 8-10 membered bicyclic heteroaryl is an 8 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0198] Embodiment 4. The compound as described in Embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof,

[0199] A racemic mixture, enantiomers, diastereomers or tautomers, wherein R1, R2 together with the carbon atoms to which they are attached form X3 is N, X4 is C, Y1 is CH, Cy is And the compound is a compound of formula (III):

[0200]

[0201] in:

[0202] X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl;

[0203] Y2 is CH or N;

[0204] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0205] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0206] U and V are each independently selected from N or CH;

[0207] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following:

[0208] 1) Halogen;

[0209] 2) Oxo;

[0210] 3) – CN;

[0211] 4) C 1-6 alkyl;

[0212] 5) C 2-6 alkenyl;

[0213] 6) C 2-6 Alkynyl;

[0214] 7) C 1-6 Alkoxy;

[0215] 8) C 1-6 Haloalkyl;

[0216] 9)-(C 1-6 Alkyl)-OH;

[0217] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0218] 11) C 3-6 Cycloalkyl;

[0219] 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups;

[0220] 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0221] 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0222] 15)-NR a 'R a”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0223] 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0224] 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0225] R6 is halogen, C 1-6 Alkyl or hydroxyl;

[0226] m is 0, 1, 2 or 3; and

[0227] R 11 For hydrogen, C 1-6 Alkyl or C 1-6Deuterated alkyl;

[0228] Provided that the 3-12 membered heterocyclic group, when substituted, is not substituted by C at both the 2-position and the 6-position 1-6 Alkyl substituted piperazin-1-yl;

[0229] Preferably, U is CH, and V is N or CH; more preferably, U and V are both CH;

[0230] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0231] Preferably, the 5-6 membered monocyclic heteroaryl is a 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl, pyrimidinyl;

[0232] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0233] Preferably, the 8-10 membered bicyclic heteroaryl is a 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; and / or

[0234] Preferably, the 3-12 membered heterocyclyl is a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl, provided that the 3-12 membered heterocyclyl, when substituted, is not substituted by C at both the 2 and 6 positions. 1-6 Alkyl substituted piperazin-1-yl;

[0235] More preferably, the 3-12 membered heterocyclic group is oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or tetrahydropyridinyl, provided that the 3-12 membered heterocyclic group, when substituted, is not substituted by C at both the 2- and 6-positions. 1-6 Alkyl substituted piperazin-1-yl.

[0236] Embodiment 5. A compound as described in any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein both X1 and X2 are CH, or one of X1 and X2 is N and the other is CH;

[0237] Preferably, X1 and X2 are both CH.

[0238] Embodiment 6. A compound as described in any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl.

[0239] Embodiment 7. A compound as described in any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein Y2 is CH.

[0240] Embodiment 8. A compound as described in any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R3 is hydrogen or halogen.

[0241] Embodiment 9. A compound as described in any one of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R4 is C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 alkyl) or -CHO, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0242] Preferably, R4 is C 1-6 Alkyl or -(C 1-3 alkyl)-O-(C 1-3 alkyl), wherein the C 1-6 The alkyl group is substituted with one or more halogens;

[0243] Preferably, R4 is hydroxymethyl, hydroxydeuterated methyl, hydroxyethyl, methoxymethyl or fluoromethyl;

[0244] More preferably, R4 is hydroxymethyl or hydroxydeuterated methyl;

[0245] More preferably, R4 is hydroxymethyl.

[0246] Embodiment 10. A compound as described in any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R3 is hydrogen, and R4 is -(C 1-3 Alkyl)-OH.

[0247] Embodiment 11. A compound as described in any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is hydrogen, -C(O)-(C 1-6 alkyl), -C(O)-(C3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl) or -C(O)N(C 1-6 Alkyl)2.

[0248] Embodiment 12. A compound as described in any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or the 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups selected from the following:

[0249] C 3-6 Cycloalkyl;

[0250] 3-12 membered heterocyclic group, which is optionally substituted by one or more C 1-6 Alkyl substituted, wherein the C 1-6 The alkyl group is substituted with one or more -OH groups; and

[0251] -NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by -NR e 'R e "Replace, R e ' and R e " are independently selected from C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0252] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0253] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

[0254] Embodiment 13. A compound as described in any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from

[0255] Preferably, R5 is

[0256] in:

[0257] R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0258] n is 0, 1 or 2;

[0259] R 22 and R 23 are independently selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0260] R 24 Selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), or -C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0261] A1, A2 and A3 are each independently CH or N; and R 13 Selected from:

[0262] 1) Hydrogen;

[0263] 2) C 1-6 alkyl;

[0264] 3) C 1-6 Alkoxy;

[0265] 4) Halogen;

[0266] 5) C 3-6 Cycloalkyl;

[0267] 6) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, -CN, C 1-6 Alkyl, C1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups;

[0268] 7) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups;

[0269] 8)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by -(C 1-6 Alkyl)-OH substituted, the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; and

[0270] 9)–C(O)NR b 'R b ”, where R b ' and R b " together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0271] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0272] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

[0273] Embodiment 14. The compound according to Embodiment 13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R 13is a 3-12 membered heterocyclic group, preferably

[0274] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0275] And the Cy is hour,

[0276] The 3-12 membered heterocyclic group, when substituted, is not substituted by C at both the 2-position and the 6-position 1-6 Alkyl substituted piperazin-1-yl.

[0277] Embodiment 15. The compound of Embodiment 13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R 13 is piperazinyl, which is optionally substituted by one or more selected from C 1-6 Alkyl and 4-5 membered heterocyclic groups are substituted by substituents;

[0278] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0279] And the Cy is When the piperazinyl group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

[0280] Embodiment 16. A compound as described in any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from

[0281]

[0282] Where: R 24 , R 24 '、R 25 , R 25 '、R 27 and R 27 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0283] R 26 C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) or tetrahydrofuranyl;

[0284] R 28 C 1-6 Alkoxy; R29 is hydrogen or -(C 1-6 Alkyl)-OH;

[0285] R 30 C 1-6 alkyl;

[0286] A1, A2 and A3 are each independently CH or N;

[0287] Preferably, A1 and A2 are both CH, or one of A1 and A2 is N and the other is CH;

[0288] More preferably, A1 and A2 are both CH.

[0289] Embodiment 17. A compound as described in any one of Embodiments 1-16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is

[0290] Wherein: A1, A2 and A3 are independently CH or N, and R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0291] Preferably, when R 24 C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), R5 is preferably

[0292] wherein A1, A2 and A3 are independently CH or N, and R 24 ' is C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), more preferably

[0293] Embodiment 18. The compound of Embodiment 16 or 17, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

[0294] Embodiment 19. A compound as described in any one of Embodiments 13-18, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: A1, A2 and A3 are all CH, or A1 is N and A2 and A3 are all CH, or A3 is N and A1 and A2 are all CH.

[0295] Embodiment 20. A compound according to any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from:

[0296]

[0297] Among them, R 21 C 1-6 Alkyl; R 22 Selected from hydrogen, C 1-6 alkyl and 4-membered heterocyclic group; A1 and A2 are CH; and R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

[0298] Embodiment 21. A compound as described in any one of Embodiments 4-20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: yes Where R 11 C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0299] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0300] Preferably, R 11 C 1-3 Deuterated alkyl, preferably trideuterated methyl.

[0301] Embodiment 22. A compound as described in any one of Embodiments 4-21, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 alkyl)-OH; U is CH, V is N or CH, and R 11 C 1-3 Alkyl; R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 Alkyl, A1 and A2 are both CH, or A1 is N and A2 is CH; R6 is C 1-6 alkyl; and m is 0 or 2.

[0302] Embodiment 23. A compound as described in any one of Embodiments 4-22, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein U and V are both CH, and R 11 It is methyl.

[0303] Embodiment 24. A compound as described in any one of Embodiments 1-23, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 is C 1-3 An alkyl group; and m is 2.

[0304] Embodiment 25. A compound as described in any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 is C 1-3 An alkyl group; and m is 1.

[0305] Embodiment 26. A compound as described in any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 is C 1-6 alkyl or hydroxy; and m is 3.

[0306] Embodiment 27. A compound as described in any one of Embodiments 1-26, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 together with the five-membered ring to which it is attached forms

[0307] Embodiment 28. A compound as described in any one of Embodiments 1-27, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the 3-12 membered heterocyclyl is selected from oxetanyl, azetidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, tetrahydropyridinyl, azaoxaspiro[5.3]nonanyl, diazabicyclo[2.2.1]heptanyl, diazaspiro[5.2]octanyl, diazaoxabicyclo[4.4.0]decanyl, azaoxaspiro[5.4]decanyl and diazabicyclo[3.1.1]heptanyl, provided that when R1, R2 are taken together with the carbon atom to which they are attached, they form the following structure:

[0308] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl;

[0309] Preferably, the 3-12 membered heterocyclic group is selected from:

[0310]

[0311] Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure:

[0312] And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

[0313] Embodiment 29. The compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X1 and X2 are both CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 alkyl)-OH; U and V are both CH, and R 11 is methyl; R5 is selected from Where: R 24 C 1-3 Alkyl, A1 and A2 are CH; R6 together with the five-membered ring to which it is connected forms

[0314] Embodiment 30. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IB)

[0315]

[0316] Embodiment 31. A compound as described in Embodiment 30, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IV):

[0317]

[0318] in:

[0319] X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl;

[0320] Y2 is CH or N;

[0321] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0322] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0323] U and V are each independently selected from N or CH;

[0324] Z is N or CH;

[0325] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following:

[0326] 1) Halogen;

[0327] 2) Oxo;

[0328] 3) – CN;

[0329] 4) C 1-6 alkyl;

[0330] 5) C 2-6 alkenyl;

[0331] 6) C 2-6 Alkynyl;

[0332] 7) C 1-6 Alkoxy;

[0333] 8) C 1-6 Haloalkyl;

[0334] 9)-(C 1-6 Alkyl)-OH;

[0335] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0336] 11) C 3-6 Cycloalkyl;

[0337] 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups;

[0338] 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0339] 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0340] 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group;

[0341] 16)-C(O)NR b 'Rb ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0342] 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0343] R6 is halogen, C 1-6 Alkyl or hydroxyl;

[0344] m is 0, 1, 2 or 3; and

[0345] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0346] Preferably, X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH;

[0347] Preferably, X1 and X2 are both CH;

[0348] Preferably, Y2 is CH;

[0349] Preferably, R3 is hydrogen or halogen;

[0350] Preferably, R4 is C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 alkyl) or -CHO, wherein the C 1-6 Alkyl is optionally substituted by one or more halogens; more preferably R4 is -(C 1-3Alkyl)-OH;

[0351] Preferably, R4 is C 1-6 Alkyl or -(C 1-3 alkyl)-O-(C 1-3 alkyl), wherein the C 1-6 The alkyl group is substituted with one or more halogens;

[0352] Preferably, R4 is hydroxymethyl, hydroxydeuterated methyl, hydroxyethyl, methoxymethyl or fluoromethyl; More preferably, R4 is hydroxymethyl;

[0353] Preferably, R3 is hydrogen, and R4 is -(C 1-3 Alkyl)-OH;

[0354] Preferably, yes Where R 11 C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0355] Preferably, Z is CH;

[0356] Preferably, U is CH, and V is N or CH; more preferably, U and V are both CH;

[0357] Preferably, U and V are both CH, and R 11 is methyl;

[0358] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0359] Preferably, R 11 C 1-3 Deuterated alkyl, preferably trideuterated methyl;

[0360] Preferably, R6 is halogen;

[0361] Preferably, R6 is C 1-3 alkyl;

[0362] Preferably, m is 0 or 1;

[0363] Preferably, the 5-6 membered monocyclic heteroaryl is a 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl, pyrimidinyl;

[0364] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0365] Preferably, the 8-10 membered bicyclic heteroaryl is a 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; and / or

[0366] Preferably, the 3-12 membered heterocyclic group is a 4-6 membered heterocyclic group, more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyranyl group, a morpholinyl group, a piperazinyl group or a tetrahydropyridinyl group.

[0367] Embodiment 32. A compound as described in any of Embodiments 30-31, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein Y2 is CH.

[0368] Embodiment 33. A compound as described in any one of Embodiments 30-32, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is hydrogen, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl) or -C(O)N(C 1-6 Alkyl)2.

[0369] Embodiment 34. A compound as described in any one of Embodiments 30-32, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl or the 8-10 membered bicyclic heteroaryl is each optionally substituted with one or more groups selected from the following:

[0370] C 3-6 Cycloalkyl;

[0371] 3-12 membered heterocyclic group, which is optionally substituted by one or more C 1-6 Alkyl substituted, wherein the C 1-6 The alkyl group is substituted with one or more -OH groups; and

[0372] -NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally replaced by -NR e 'R e "Replace, R e ' and R e " are independently selected from C 1-6 Alkyl, -(C1-6 alkyl)-OH and 4-6 membered heterocyclic groups.

[0373] Embodiment 35. A compound as described in any one of Embodiments 30-34, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from:

[0374]

[0375] in:

[0376] R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0377] n is 0, 1 or 2;

[0378] R 22 and R 23 are independently selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0379] R 24 Selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), or -C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0380] A1, A2 and A3 are each independently CH or N; and

[0381] R 13 Selected from:

[0382] 1) Hydrogen;

[0383] 2) C 1-6 alkyl;

[0384] 3) C1-6 Alkoxy;

[0385] 4) Halogen;

[0386] 5) C 3-6 Cycloalkyl;

[0387] 6) 4-8 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups;

[0388] 7) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups;

[0389] 8)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 Alkyl)-OH substituted, the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; and

[0390] 9)-C(O)NR b 'R b ”, where R b ' and R b " together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0391] Preferably, R5 is wherein A1 and A2 are independently CH or N, and R 13 is a 4-6 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, C 1-6Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic group;

[0392] Preferably, R5 is wherein A1 and A2 are independently CH or N; R a ' and R a "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Substitution of alkoxy and 4-6 membered heterocyclic groups;

[0393] Preferably, R5 is Where R 22 Selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0394] Preferably, R 13 is piperazinyl, which is optionally substituted by one or more selected from C 1-6 Alkyl and 4-5 membered heterocyclic groups are substituted by substituents;

[0395] Preferably, R5 is selected from:

[0396]

[0397] Where: R 24 , R 24 '、R 25 , R 25 '、R 27 and R 27 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0398] R 26 C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) or tetrahydrofuranyl;

[0399] R 28 C 1-6 Alkoxy; R29 is hydrogen or -(C 1-6 Alkyl)-OH;

[0400] R 30 C 1-6 alkyl; and

[0401] A1, A2 and A3 are each independently CH or N;

[0402] Preferably, R5 is Wherein: A1, A2 and A3 are independently CH or N, and R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0403] More preferably, when R 24 C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), R5 is preferably wherein A1, A2 and A3 are independently CH or N, and R 24 ' is C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), more preferably

[0404] Preferably, R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl;

[0405] Preferably, A1, A2 and A3 are all CH, or A1 is N and A2 and A3 are all CH, or A3 is N and

[0406] A1 and A2 are both CH;

[0407] Preferably, A1, A2 and A3 are all CH.

[0408] Embodiment 36. A compound as described in any one of Embodiments 30-35, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0409] X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH;

[0410] Y2 is CH;

[0411] R3 is hydrogen;

[0412] R4 is -(C 1-3 Alkyl)-OH;

[0413] Z is CH;

[0414] U is CH, V is N or CH;

[0415] R5 is wherein A1 and A2 are independently CH or N, and R 13 is a 4-6 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and a 4-6 membered heterocyclic group; R 22 Selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0416] R6 is hydrogen or halogen;

[0417] m is 0, 1 or 2; and

[0418] R 11 C 1-3 alkyl;

[0419] Preferably, R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 Alkyl, A1 and A2 are both CH, or A1 is N and A2 is CH;

[0420] More preferably, A1 and A2 are both CH.

[0421] Embodiment 37. A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from:

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444] Embodiment 38. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-37 and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

[0445] Embodiment 39. A method for inhibiting BTK activity in vivo or in vitro, comprising contacting BTK with an effective amount of the compound described in any one of Embodiments 1-37 and / or a pharmaceutically acceptable salt thereof.

[0446] Embodiment 40. Use of a compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-37 for preparing a medicament for treating or preventing a disease mediated or at least partially mediated by BTK, wherein the medicament is preferably used to treat or prevent cancer, inflammatory diseases or autoimmune diseases; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt's high grade B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, The inflammatory disease or autoimmune disease is preferably selected from the group consisting of systemic inflammation, local inflammation, arthritis, and so on. , rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma (also known as systemic sclerosis), multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, herpes vulgaris, and diseases related to kidney transplantation.

[0447] Embodiment 41. A method for treating or preventing a disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound and / or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-37, wherein the disease is mediated by BTK or at least partially mediated by BTK; the disease is preferably cancer, an inflammatory disease, or an autoimmune disease; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia, and myeloma; the cancer is more preferably selected from B-cell malignancies. lymphoma, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia disease (AML), chronic myeloid leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (e.g., high-risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (e.g., multiple myeloma) or transplantation versus host disease; the inflammatory disease or autoimmune disease is preferably selected from: systemic inflammation Inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, herpes vulgaris, and diseases related to kidney transplantation.

[0448] Embodiment 42. A compound according to any one of Embodiments 1-37 and / or a pharmaceutically acceptable salt thereof for use as a medicament.

[0449] Embodiment 43. A compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-37, for use in treating or preventing a disease mediated or at least partially mediated by BTK, preferably for treating or preventing cancer, inflammatory diseases or autoimmune diseases; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt's high-grade B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, The inflammatory disease or autoimmune disease is preferably selected from the group consisting of systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, pityriasis vulgaris, and diseases associated with kidney transplantation.

[0450] Embodiment 44. A drug combination comprising a compound described in any one of Embodiments 1-37 and / or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably selected from: an anti-inflammatory agent, an immunomodulatory agent or an anti-tumor agent, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0451] Embodiment 45. Compound of formula (VI):

[0452]

[0453] or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0454] X1, X2, X3, X4, R1, R2 and R3 are as defined in any one of Embodiments 1-37;

[0455] R 31’ -CHO, -C 1-3 Alkyl-OH, -C 1-3 Alkyl-OAc, C 1-3 Alkyl, -C(O)-C 1-3 Alkyl or C 1-3 a haloalkyl group, and

[0456] R 32 Halogen, -B(OH)2, -B(OC 1-6 Alkyl)2, R d is hydrogen or C 1-6 alkyl.

[0457] Embodiment 46. The compound according to Embodiment 45, which is:

[0458] Wherein: Z is N or CR7; R7 and R8 are independently hydrogen or halogen; R9 is halogen or C 1-6 Alkyl; n is 1 or 2.

[0459] Embodiment 47. A compound according to Embodiment 45, which is selected from:

[0460]

[0461] Specific implementation method 2:

[0463] Embodiment 1. Compound of formula (I):

[0464]

[0465] or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0466] X1 and X2 are independently CH or N; X3 and X4 are independently C or N;

[0467] Y1 and Y2 are independently CR 10 or N;

[0468] R1 and R2 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl and phenyl; or R1, R2 together with the carbon atom to which they are attached form the following structure:

[0469] Wherein: R6 is independently selected from deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl and C 1-6 or two R6 together with the carbon atom to which they are commonly attached form a 3-6 membered cyclic hydrocarbon group; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; Z is N or CR7; R7 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogen and C 1-6 Haloalkyl;

[0470] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0471] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, -(C 1-3 Alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 Alkyl or C 1-3 The alkyl groups are each optionally substituted with one or more deuterium or halogen;

[0472] Cy Where: R 11 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more deuterium or halogen;

[0473] U, V and W are each independently N or CR 12 ; R 12 is hydrogen, deuterium or a halogen;

[0474] R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted with one or more groups selected from the following:

[0475] 1) Halogen;

[0476] 2) Oxo;

[0477] 3) – CN;

[0478] 4) C 1-6 alkyl;

[0479] 5) C 2-6 alkenyl;

[0480] 6) C 2-6 Alkynyl;

[0481] 7) C 1-6 Alkoxy;

[0482] 8) C 1-6 Haloalkyl;

[0483] 9)-(C 1-6 Alkyl)-OH;

[0484] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0485] 11) 4-8 membered heterocyclic group, which is optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclyl groups are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2 and -NH(C 3-6 Cycloalkyl);

[0486] 12) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more groups selected from the following: halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0487] 13) phenyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N-(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0488] 14)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent;

[0489] 15)-C(O)NR b 'R b ”, where Rb ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by one or more groups selected from the following: deuterium, halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cyclic hydrocarbon), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH; and

[0490] 16)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 Alkyl)-OH and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0491] R 10 For hydrogen, deuterium, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0492] Embodiment 2. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IA):

[0493]

[0494] Embodiment 3. The compound as described in Embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (II):

[0495]

[0496] in:

[0497] X1 and X2 are independently CH or N;

[0498] Y2 is CH or N;

[0499] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0500] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl;

[0501] W is N or CR 12 , R 12 is hydrogen or halogen;

[0502] R5 is C 1-6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted by one or more groups selected from the following:

[0503] 1) Halogen;

[0504] 2) Oxo;

[0505] 3) – CN;

[0506] 4) C 1-6 alkyl;

[0507] 5) C 2-6 alkenyl;

[0508] 6) C 2-6 Alkynyl;

[0509] 7) C 1-6 Alkoxy;

[0510] 8) C 1-6 Haloalkyl;

[0511] 9)-(C 1-6 Alkyl)-OH;

[0512] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0513] 11) 4-8 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and 4-6 membered fluorinated heterocyclic group;

[0514] 12) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0515] 13) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0516] 14)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent;

[0517] 15)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0518] 16)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0519] R6 is halogen or C 1-6 alkyl; and

[0520] m is 0, 1 or 2;

[0521] Preferably, W is N or CR 12 , R 12 is a halogen;

[0522] Preferably, R5 is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, which is optionally substituted by one or more groups selected from the following:

[0523] 1) C 1-6 Alkyl; and

[0524] 2) 4-6 membered heterocycloalkyl, which is optionally substituted by C 1-6 Alkyl and 4-6 membered heterocyclic substitution;

[0525] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0526] Preferably, the 8-10 membered bicyclic heteroaryl is an 8 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0527] Embodiment 4. The compound according to Embodiment 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (III):

[0528]

[0529] in:

[0530] X1 and X2 are independently CH or N;

[0531] Y2 is CH or N;

[0532] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0533] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl;

[0534] U and V are each independently selected from N or CH;

[0535] R5 is C 1-6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted by one or more groups selected from the following:

[0536] 1) Halogen;

[0537] 2) Oxo;

[0538] 3) – CN;

[0539] 4) C 1-6 alkyl;

[0540] 5) C 2-6 alkenyl;

[0541] 6) C 2-6 Alkynyl;

[0542] 7) C 1-6 Alkoxy;

[0543] 8) C 1-6 Haloalkyl;

[0544] 9)-(C 1-6 Alkyl)-OH;

[0545] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0546] 11) 4-8 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and 4-6 membered fluorinated heterocyclic group;

[0547] 12) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0548] 13) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0549] 14)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent;

[0550] 15)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0551] 16)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0552] R6 is halogen or C 1-6 alkyl;

[0553] m is 0, 1 or 2; and

[0554] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0555] Preferably, U is CH, and V is N or CH; more preferably, U and V are both CH;

[0556] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0557] Preferably, the 5-6 membered monocyclic heteroaryl is a 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl, pyrimidinyl;

[0558] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0559] Preferably, the 8-10 membered bicyclic heteroaryl is a 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl;

[0560] Preferably, the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group, more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyranyl group, a morpholinyl group, a piperazinyl group or a tetrahydropyridinyl group.

[0561] Embodiment 5. A compound as described in any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH;

[0562] Preferably, X1 and X2 are both CH.

[0563] Embodiment 6. A compound as described in any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein Y2 is CH.

[0564] Embodiment 7. A compound as described in any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R3 is hydrogen or halogen.

[0565] Embodiment 8. A compound as described in any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R4 is C1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl) -OH or -CHO;

[0566] Preferably, R4 is hydroxymethyl or hydroxydeuteratedmethyl.

[0567] Embodiment 9. A compound as described in any one of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R3 is hydrogen, and R4 is -(C 1-3 Alkyl)-OH.

[0568] Embodiment 10. A compound as described in any one of Embodiments 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from

[0569]

[0570] in:

[0571] R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0572] n is 0, 1 or 2;

[0573] R 22 and R 23 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0574] A1 and A2 are each independently CH or N; and R 13 Selected from:

[0575] 1) Hydrogen;

[0576] 2) C 1-6 alkyl;

[0577] 3) 4-6 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic group;

[0578] 4) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups;

[0579] 5)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by -(C 1-6 alkyl)-OH; and

[0580] 6)–C(O)NR b 'R b ”, where R b ' and R b " together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0581] Preferably, R5 is

[0582] Embodiment 11. The compound according to Embodiment 10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R 13 is piperazinyl, which is optionally substituted by one or more selected from C 1-6 The substituents of the alkyl group and the 4-5-membered heterocyclic group are substituted.

[0583] Embodiment 12. A compound as described in any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from

[0584]

[0585] Where: R 24 , R 24 '、R 25 , R 25 '、R 27 and R27 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0586] R 26 C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) or tetrahydrofuranyl;

[0587] R 28 C 1-6 Alkoxy; R 29 is hydrogen or -(C 1-6 Alkyl)-OH;

[0588] R 30 C 1-6 alkyl;

[0589] A1 and A2 are independently CH or N;

[0590] Preferably, A1 and A2 are both CH, or one of A1 and A2 is N and the other is CH;

[0591] More preferably, A1 and A2 are both CH.

[0592] Embodiment 13. A compound as described in any one of Embodiments 1-12, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0593] Preferably, when R 24 C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), Preferably Where R 24 ' is C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), more preferably

[0594] Embodiment 14. The compound of Embodiment 12 or 13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

[0595] Embodiment 15. A compound as described in any one of Embodiments 10-14, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: A1 and A2 are both CH, or A1 is N and A2 is CH.

[0596] Embodiment 16. A compound according to any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from:

[0597]

[0598] Among them, R 21 C 1-6 Alkyl; R 22 Selected from hydrogen, C 1-6 alkyl and 4-membered heterocyclic group; A1 and A2 are CH; and R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

[0599] Embodiment 17. A compound as described in any one of Embodiments 4-16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0600] Where R 11 C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0601] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0602] Preferably, R 11 C 1-3 Deuterated alkyl, preferably trideuterated methyl.

[0603] Embodiment 18. A compound as described in any one of Embodiments 4-17, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 alkyl)-OH; U is CH, V is N or CH, and R 11 C 1-3 Alkyl; R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 Alkyl, A1 and A2 are both CH, or A1 is N and

[0604] A2 is CH; R6 is C 1-6 alkyl; and m is 0 or 2.

[0605] Embodiment 19. The compound of any one of Embodiments 4-18, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein U and V are both CH, and R 11 It is methyl.

[0606] Embodiment 20. A compound as described in any one of Embodiments 1-19, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 is C 1-3 An alkyl group; and m is 2.

[0607] Embodiment 21. A compound as described in any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R6 together with the five-membered ring to which it is attached forms

[0608] Embodiment 22. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IB)

[0609]

[0610] Embodiment 23. The compound according to Embodiment 22, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IV):

[0611]

[0612] in:

[0613] X1 and X2 are independently CH or N;

[0614] Y2 is CH or N;

[0615] R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl;

[0616] R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl;

[0617] U and V are each independently selected from N or CH;

[0618] Z is N or CH;

[0619] R5 is C 1-6 alkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, each of which is optionally substituted by one or more groups selected from the following:

[0620] 1) Halogen;

[0621] 2) Oxo;

[0622] 3) – CN;

[0623] 4) C 1-6 alkyl;

[0624] 5) C 2-6 alkenyl;

[0625] 6) C 2-6 Alkynyl;

[0626] 7) C 1-6 Alkoxy;

[0627] 8) C 1-6 Haloalkyl;

[0628] 9)-(C 1-6 Alkyl)-OH;

[0629] 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0630] 11) 4-8 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and 4-6 membered fluorinated heterocyclic group;

[0631] 12) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0632] 13) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group;

[0633] 14)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent;

[0634] 15)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and

[0635] 16)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0636] R6 is halogen or C 1-6 alkyl;

[0637] m is 0, 1 or 2; and

[0638] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0639] Preferably, X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH;

[0640] Preferably, X1 and X2 are both CH;

[0641] Preferably, Y2 is CH;

[0642] Preferably, R3 is hydrogen or halogen;

[0643] Preferably, R4 is C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3deuterated alkyl)-OH or -CHO; more preferably R4 is -(C 1-3 Alkyl)-OH;

[0644] Preferably, R4 is hydroxymethyl or hydroxydeuterated methyl;

[0645] Preferably, R3 is hydrogen, and R4 is -(C 1-3 Alkyl)-OH;

[0646] Preferably, yes Where R 11 C 1-6 Alkyl or C 1-6 Deuterated alkyl;

[0647] Preferably, Z is CH;

[0648] Preferably, U is CH, and V is N or CH; more preferably, U and V are both CH;

[0649] Preferably, U and V are both CH, and R 11 is methyl;

[0650] Preferably, R 11 C 1-3 Alkyl, preferably methyl or ethyl, more preferably methyl;

[0651] Preferably, R 11 C 1-3 Deuterated alkyl, preferably trideuterated methyl;

[0652] Preferably, R6 is halogen;

[0653] Preferably, m is 0 or 1;

[0654] Preferably, the 5-6 membered monocyclic heteroaryl is a 6 membered monocyclic heteroaryl, more preferably pyridyl, pyrazinyl, pyrimidinyl;

[0655] Preferably, the 5-6 membered monocyclic heteroaryl is a 5 membered monocyclic heteroaryl, more preferably a triazolyl;

[0656] Preferably, the 8-10 membered bicyclic heteroaryl is a 9 membered bicyclic heteroaryl, more preferably 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl;

[0657] Preferably, the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group, more preferably an oxetanyl group, an azetidinyl group, a tetrahydropyranyl group, a morpholinyl group, a piperazinyl group or a tetrahydropyridinyl group.

[0658] Embodiment 24. A compound as described in any of Embodiments 22-23, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein Y2 is CH.

[0659] Embodiment 25. A compound as described in any one of Embodiments 22-24, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R5 is selected from:

[0660]

[0661] in:

[0662] R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0663] n is 0, 1 or 2;

[0664] R 22 and R 23 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl);

[0665] A1 and A2 are each independently CH or N; and

[0666] R 13 Selected from:

[0667] 1) Hydrogen;

[0668] 2) C 1-6 alkyl;

[0669] 3) 4-6 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic group;

[0670] 4) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups;

[0671] 5)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 alkyl)-OH; and

[0672] 6)-C(O)NR b 'R b ”, where R b ' and R b " together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution;

[0673] Preferably, R5 is wherein A1 and A2 are independently CH or N; R a ' and R a "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Substitution of alkoxy and 4-6 membered heterocyclic groups;

[0674] Preferably, R 13 is piperazinyl, which is optionally substituted by one or more selected from C 1-6 Alkyl and 4-5 membered heterocyclic groups are substituted by substituents;

[0675] Preferably, R5 is selected from:

[0676]

[0677] Where: R 24 , R 24 '、R 25 , R 25 '、R 27 and R 27 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0678] R 26 C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6alkyl) or tetrahydrofuranyl;

[0679] R 28 C 1-6 Alkoxy; R 29 is hydrogen or -(C 1-6 Alkyl)-OH;

[0680] R 30 C 1-6 alkyl; and

[0681] A1 and A2 are independently CH or N;

[0682] Preferably, R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 alkyl;

[0683] More preferably, when R 24 C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), Preferably Where R 24 ' is C 1-6 Alkyl (e.g. C 1-3 alkyl, more preferably methyl), more preferably

[0684] Preferably, R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl;

[0685] Preferably, one of A1 and A2 is N, and the other is CH;

[0686] Preferably, A1 is N and A2 is CH;

[0687] Preferably, A1 and A2 are both CH.

[0688] Embodiment 26. A compound as described in any one of Embodiments 22-25, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0689] X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH;

[0690] Y2 is CH;

[0691] R3 is hydrogen;

[0692] R4 is -(C 1-3Alkyl)-OH;

[0693] Z is CH;

[0694] U is CH, V is N or CH;

[0695] R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 Alkyl, A1

[0696] and A2 are both CH, or A1 is N and A2 is CH;

[0697] R6 is hydrogen or halogen;

[0698] m is 0, 1 or 2; and

[0699] R 11 C 1-3 alkyl;

[0700] Preferably, A1 and A2 are both CH.

[0701] Embodiment 27. A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from:

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710] Embodiment 28. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-27 and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

[0711] Embodiment 29. A method for inhibiting BTK activity in vivo or in vitro, comprising contacting BTK with an effective amount of the compound described in any one of Embodiments 1-27 and / or a pharmaceutically acceptable salt thereof.

[0712] Embodiment 30. Use of a compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27 for preparing a medicament for treating or preventing a disease mediated or at least partially mediated by BTK, wherein the medicament is preferably used to treat or prevent cancer, inflammatory diseases or autoimmune diseases; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt's high-grade malignant B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, The inflammatory disease or autoimmune disease is preferably selected from the group consisting of systemic inflammation, local inflammation, arthritis, and so on. , rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma (also known as systemic sclerosis), multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, herpes vulgaris, and diseases related to kidney transplantation.

[0713] Embodiment 31. A method for treating or preventing a disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound and / or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-27, wherein the disease is mediated by BTK or at least partially mediated by BTK; the disease is preferably cancer, an inflammatory disease, or an autoimmune disease; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia, and myeloma; the cancer is more preferably selected from B-cell malignancies. lymphoma, diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia disease (AML), chronic myeloid leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (e.g., high-risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (e.g., multiple myeloma) or transplantation versus host disease; the inflammatory disease or autoimmune disease is preferably selected from: systemic inflammation Inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, herpes vulgaris, and diseases related to kidney transplantation.

[0714] Embodiment 32. A compound according to any one of Embodiments 1-27 and / or a pharmaceutically acceptable salt thereof for use as a medicament.

[0715] Embodiment 33. A compound and / or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27, for use in treating or preventing a disease mediated or at least partially mediated by BTK, preferably for treating or preventing cancer, inflammatory diseases or autoimmune diseases; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt's high-grade malignant B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, The inflammatory disease or autoimmune disease is preferably selected from the group consisting of systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, pityriasis vulgaris, and diseases associated with kidney transplantation.

[0716] Embodiment 34. A drug combination comprising a compound and / or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-27, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably selected from: an anti-inflammatory agent, an immunomodulatory agent or an anti-tumor agent, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0717] Embodiment 35. Compound of formula (V):

[0718]

[0719] or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, wherein:

[0720] X1, X2, X3, X4, R1, R2 and R3 are as defined in any one of Embodiments 1-27;

[0721] R 31 is -OH, oxo (=O), or -O-(C 1-6 alkyl), and

[0722] R 32 Halogen, -B(OH)2, -B(OC 1-6 Alkyl)2, R d is hydrogen or C 1-6 alkyl.

[0723] Embodiment 36. The compound according to Embodiment 35, which is:

[0724] Z is N or CR7; R7 and R8 are independently hydrogen or halogen; R9 is halogen or C 1-6 Alkyl; n is 1 or 2.

[0725] Embodiment 37. A compound selected from:

[0726]

[0727]

[0728] The various embodiments described in the present invention (including the examples below) and the features in the various embodiments should be understood to be able to be combined with each other arbitrarily, and the various schemes obtained by these combinations are included in the scope of the present invention, just as the schemes obtained by these combinations are specifically and one by one listed in this document, unless the context clearly shows otherwise.

[0729] General synthetic method

[0730] The compounds of formula (I) described herein and / or pharmaceutically acceptable salts thereof can be synthesized using commercially available raw materials, by methods known in the art, or by methods disclosed in this patent application. The synthetic routes shown in Schemes 1 to 2 illustrate the general synthetic methods of the compounds of the present invention, and the synthetic routes shown in Schemes 3 to 6 illustrate the general synthetic methods of the raw materials 1-1 used in Schemes 1 to 2.

[0731] Process 1:

[0732]

[0733] As shown in Scheme 1, the compound of Formula 1-1 reacts with the dihaloaromatic aldehyde compound of Formula 1-2 under the catalysis of cuprous iodide to obtain the compound of Formula 1-3. The carbon-nitrogen coupling reaction catalyzed by cuprous iodide is carried out under suitable conditions, and the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, etc., and the base used can be selected from Cs2CO3, Na2CO3, K3PO4, etc. Under suitable conditions, the compound of Formula 1-3 is reduced to obtain the compound of Formula 1-4 of the present invention. The reducing agent used can be selected from sodium borohydride, potassium borohydride, lithium borohydride, etc., and the solvent used can be selected from polar solvents such as methanol, ethanol or a mixed solvent of methanol and dichloromethane, etc. The hydroxyl group on the compound of Formula 1-4 is acetylated to obtain the compound of Formula 1-5. The compound of Formula 1-5 reacts with biboric acid pinacol ester under suitable conditions to obtain the boric acid or boric acid ester compound of Formula 1-6. The compound of formula 1-6 is reacted with the halide of formula 1-7 by Suzuki coupling reaction under the catalysis of an appropriate palladium reagent to obtain a compound of formula 1-8. The palladium-catalyzed Suzuki coupling reaction is carried out under appropriate conditions, and the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF or a mixed solvent of 1,4-dioxane and water, the base used can be selected from Cs2CO3, Na2CO3, K3PO4, etc., and the catalyst used can be selected from Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)4, Pd(OAc)2, etc. The compound of formula 1-8 is deacetylated under appropriate alkaline conditions to obtain a compound of formula (I-1) of the present invention. The base used can be selected from potassium carbonate, sodium carbonate, lithium hydroxide, etc., and the solvent used can be selected from polar solvents such as methanol, ethanol or a mixed solvent of methanol and water, etc.

[0734] Process 2:

[0735]

[0736] As shown in Scheme 2, the compound of Formula 1-3 is reacted with the boric acid or boric ester of Formula 2-1 by Suzuki coupling reaction under the catalysis of an appropriate palladium reagent to obtain the compound of Formula 2-2. The palladium-catalyzed Suzuki coupling reaction is carried out under appropriate conditions, and the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF or a mixed solvent of 1,4-dioxane and water, etc., the base used can be selected from Cs2CO3, Na2CO3, K3PO4, etc., and the catalyst used can be selected from Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)4, Pd(OAc)2, etc. Under appropriate conditions, the compound of Formula 2-2 is reduced to obtain the compound of Formula (I-1) of the present invention. The reducing agent used can be selected from sodium borohydride, potassium borohydride, lithium borohydride, etc., and the solvent used can be selected from polar solvents such as methanol, ethanol or a mixed solvent of methanol and dichloromethane, etc.

[0737] Process 3:

[0738]

[0739] As shown in Flow 3, the compound of formula 3-1 undergoes a substitution reaction with bromoacetaldehyde diethyl acetal under appropriate conditions to obtain a compound of formula 3-2. The base used can be selected from cesium carbonate, etc., and the solvent used can be selected from polar solvents such as DMF or 1,4-dioxane. The compound of formula 3-2 is hydrolyzed in an alkaline solution to obtain a compound of formula 3-3. The base used can be selected from lithium hydroxide, potassium carbonate, sodium carbonate, etc., and the solvent used can be selected from polar solvents such as methanol, ethanol or a mixed solvent of methanol and water. The compound of formula 3-3 undergoes a condensation reaction with HATU and ammonia water to obtain a compound of formula 3-4. The compound of formula 3-4 is ring-closed in acetic acid to obtain a compound of formula 3-5.

[0740] Process 4:

[0741]

[0742] As shown in Scheme 4, the compound of Formula 3-2 can undergo a ring-closure reaction with ammonium acetate in acetic acid to obtain a compound of Formula 3-5.

[0743] Process 5:

[0744]

[0745] As shown in Scheme 5, the compound of Formula 3-1 reacts with O-(2,4-dinitrophenyl)hydroxylamine to obtain the compound of Formula 5-1. The compound of Formula 5-1 reacts with ammonium acetate in a formamide solution to undergo a ring-closing reaction to obtain the compound of Formula 5-2.

[0746] Process 6:

[0747]

[0748] As shown in Scheme 6, the compound of Formula 3-1 undergoes a substitution reaction with hydrazine hydrate to obtain a compound of Formula 6-1. The compound of Formula 6-1 undergoes a ring-closure reaction with triethyl orthoformate in a DMF solution to obtain a compound of Formula 6-2.

[0749] The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. Synthetic chemical transformation methods can be referenced, for example, in: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

[0750] Before use, the compounds of the present invention may be purified by column chromatography, high performance liquid chromatography, crystallization or other appropriate methods.

[0751] Pharmaceutical compositions and uses

[0752] The compounds of the present invention (e.g., any of the compounds of the embodiments herein) can be formulated into pharmaceutical compositions alone or in combination with one or more additional therapeutic agents. The pharmaceutical compositions include: (a) an effective amount of a compound of the present invention; (b) a pharmaceutically acceptable excipient (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0753] A pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient in the composition (in some embodiments, can stabilize the active ingredient) and is harmless to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with the compounds of the present invention) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other excipients include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable excipients are disclosed in the standard reference book in the art (Remington's Pharmaceutical Sciences, A. Osol).

[0754] The pharmaceutical composition containing the compound of the present invention can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation, etc. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

[0755] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, bagged granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories. In some embodiments, the pharmaceutical compositions comprising the compounds of the present invention can be formulated for intravenous infusion, topical administration or oral administration.

[0756] The composition for oral administration can be in any oral acceptable dosage form, including but not limited to: tablets, capsules, emulsions and aqueous suspensions, dispersants and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in capsule form, useful diluents include lactose and dry corn starch. When administered orally in the form of an aqueous suspension or emulsion, an emulsifier or suspending agent can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweeteners, flavoring agents or pigments can also be added.

[0757] In some embodiments, the amount of the compound of the present invention in tablets can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg. In some embodiments, the amount of the compound of the present invention in capsules can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg.

[0758] Sterile injectable compositions (such as aqueous or oily suspensions) can be prepared according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents can be used, in particular, mannitol, water, Ringer's solution, and saline. In addition, sterile, nonvolatile oils such as synthetic mono- or diglycerides are commonly used as solvents or suspending media. Fatty acids such as oleic acid and its glyceride derivatives and natural pharmaceutically acceptable oils such as olive oil or castor oil (especially its polyoxyethylated form) are commonly used as injectable media. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0759] The inhalation composition may be prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, using absorption promoters to improve bioavailability, using fluorocarbons and / or other solubilizing or dispersing agents known in the art, or it may be prepared as a solution in saline.

[0760] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable oils or mineral oils, white vaseline (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with carbon atoms greater than 12). In some embodiments, a pharmaceutically acceptable carrier is a carrier in which the active ingredient can be dissolved. If necessary, the composition may also include an emulsifier, a stabilizer, a wetting agent, and an antioxidant, as well as a substance that imparts color or fragrance to it. In addition, a transdermal penetration enhancer may also be added to the topical preparation. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0761] Creams can be prepared from a mixture of mineral oil, self-emulsifying beeswax and water, with the active ingredient dissolved in a small amount of fat, such as almond oil, mixed therein. An example of a cream comprises about 40 parts of water, about 20 parts of beeswax, about 40 parts of mineral oil, and about 1 part of almond oil by weight. Ointments can be prepared by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture. An example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.

[0762] Suitable in vitro experiments can be used to evaluate the effect of the compounds of the present invention on inhibiting BTK activity. The other effects of the compounds of the present invention in preventing or treating cancer can be further detected by in vivo tests. For example, the compounds of the present invention can be administered to animals (such as mouse models) suffering from cancer, and then their therapeutic effects are evaluated. If the results of the preclinical test are successful, the dosage range and administration route for animals such as humans can also be predicted.

[0763] The compounds of the invention show sufficient preclinical utility to warrant clinical trials and are expected to show beneficial therapeutic or prophylactic effects, for example, in individuals suffering from cancer.

[0764] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growth foci at other sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies (e.g., leukemias, lymphomas, or myelomas). The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary cancers and metastatic cancers, recurrent cancers, and refractory cancers.

[0765] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, melanoma and basal carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; sarcomas, including, for example, Kaposi's sarcoma (Kaposi's sarcoma); adrenal cancer; mesothelial carcinoma; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

[0766] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL), including high-risk CLL; human acute monocytic leukemia (M(5)); hairy cell leukemia; lymphocytic leukemia; chronic lymphoid leukemia; myeloid leukemia; myelodysplastic syndrome or acute lymphoblastic leukemia; small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); follicular lymphoma; mantle cell lymphoma The following are myeloproliferative syndromes: (a) refractory anemia (RA), (b) refractory anemia with ringed sideroblasts (RARS), (c) refractory anemia with excess blasts (RAEB), and (d) refractory anemia with excess blasts with acute transformation (RAEB-T); and (e) myeloproliferative syndromes.

[0767] In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma.

[0768] The compounds of the invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual suffering from cancer.

[0769] The compounds of the invention may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject suffering from an autoimmune disease or in a subject suffering from an inflammatory disease.

[0770] The term "autoimmune disease" refers to a disease or condition caused by an immune response to self-antigens that results in damage to one's own tissues or organs. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, Sjögren's syndrome, multiple sclerosis (MS), scleroderma (also known as systemic sclerosis), multiple sclerosis osteoporosis, arthritis (e.g., rheumatoid arthritis (RA), collagen-induced arthritis), psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, Sjögren's syndrome, herpes vulgaris, diseases associated with kidney transplantation, and myeloproliferative diseases, such as myelofibrosis, post-polycythemia vera / essential thrombocytosis myelofibrosis (post-PV / ET myelofibrosis). In some embodiments, the autoimmune disease is selected from arthritis, such as rheumatoid arthritis, collagen-induced arthritis, and the like.

[0771] The term "inflammatory disease" or "inflammatory condition" refers to a pathological state that results in inflammation, particularly due to neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic and local inflammation, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD, such as Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and abnormal contractile response of coronary vessels after percutaneous coronary angioplasty, tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; cerebral edema secondary to stroke; cranial trauma, hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS) S); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjorgen's syndrome, vasculitis; diseases involving leukocyte infiltration; central nervous system (CNS) inflammatory diseases secondary to sepsis or trauma, multiple organ injury syndrome; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis; sepsis; sarcoidosis; immunopathological reactions caused by tissue / organ transplantation; lung inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis. Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other joint disorders, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic inflammatory lung disease, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and pyresis, as well as any disease associated with inflammation and related disorders.

[0772] In addition, the compounds of the present invention (e.g., any of the example compounds herein) can be used in combination with additional therapeutic agents for the treatment of diseases or conditions described herein, such as cancer, inflammatory diseases, or autoimmune diseases. Additional therapeutic agents can be administered separately from the compounds of the present invention, or can be included in a pharmaceutical composition according to the present disclosure, such as a fixed-dose combination drug. In some embodiments, additional therapeutic agents are those known or have been found to be effective for treating diseases mediated by BTK or at least partially mediated by BTK, such as other BTK inhibitors or compounds that can effectively antagonize other targets associated with the specific disease. Combination therapy can be used to improve the efficacy (e.g., by including a compound that can enhance the efficacy or effectiveness of the compounds of the present invention in the combination therapy), reduce one or more side effects, or reduce the required dose of the compound of the present invention.

[0773] In some embodiments, the compounds of the present invention (e.g., any compound herein) may be used in combination with another therapeutic agent, such as an anti-inflammatory agent, an immunomodulator, or an anti-tumor agent, including a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent. The term "anti-tumor agent" as used herein refers to any agent administered to a subject with cancer for the purpose of treating cancer, such as a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0774] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, desmethoxydaunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosocarbamide, lomustine, methyllomustine, streptozotocin, decarbazine, methotrexate, mitomycin C and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); and free radical generators such as bleomycin; as well as nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea), paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; sedatives and related analogs (e.g., CC-5013 and CC-4047).

[0775] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, such as anti-PD-1 antibodies, e.g., pembrolizumab and nivolumab; PD-L1 inhibitors, such as anti-PD-L1 antibodies, e.g., atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, e.g., ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and the like.

[0776] Targeted therapeutic agents include various small molecule or macromolecular targeted therapeutic agents, non-limiting examples of which include: protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; PI3Kδ inhibitors; SYK inhibitors; Bcl2 inhibitors; antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication, such as anti-CD20 antibodies (e.g., rituximab, ibritumomab tiuxetan, tositumomab), anti-Her2 monoclonal antibodies (trastuzumab), anti-EGFR antibodies (cetuximab) and anti-VEGFR antibodies (bevacizumab); anti-angiogenic drugs, such as lenalidomide, etc.; and other protein or enzyme inhibitors, which are known to be upregulated, overexpressed or activated in cancer, and whose inhibition can downregulate cell replication. Example

[0777] The following examples are illustrative of the present invention and are not intended to limit the present invention in any way. The data provided (e.g., amount, temperature, etc.) strive to ensure its accuracy, but those skilled in the art will appreciate that there will be some experimental errors and deviations. Unless otherwise stated, all parts are parts by weight, the temperature is Celsius, and the pressure is atmospheric pressure or near atmospheric pressure. All mass spectrometry data are measured by Agilent 6120 and 1100. All nuclear magnetic resonance data are measured by Varian 400MR. Except for the intermediates synthesized, all reagents and raw materials used in the present invention are obtained from commercial channels. Reference GDC-0853 (fenebrutinib) is purchased from Shanghai Lingkai Pharmaceutical Technology Co., Ltd. The names of all compounds except reagents are generated by Chemdraw 16.0.

[0778] In any structural formula herein, if there are vacant valencies on any atom, the vacant valencies are actually hydrogen atoms which are not specifically depicted for the sake of simplicity.

[0779] In this application, if both the name and structural formula of a compound are given, in the event of inconsistency between the two, the structure of the compound shall prevail unless the context indicates that the structure of the compound is incorrect and the name is correct.

[0780] The following is a list of abbreviations used in the examples:

[0781] Ac Acetyl

[0782] AcOK Potassium Acetate

[0783] BINAP Bis-(diphenylphosphino)-1,1'-binaphthyl

[0784] CDI N,N'-Carbonyldiimidazole

[0785] CD3OD Deuterated methanol

[0786] DCM Dichloromethane

[0787] DIAD Diisopropyl azodicarboxylate

[0788] DIEA N,N-Diisopropylethylamine

[0789] DMF N,N-Dimethylformamide

[0790] DMSO Dimethyl sulfoxide

[0791] DMSO-d6 Deuterated dimethyl sulfoxide

[0792] EA / EtOAc Ethyl acetate

[0793] Et3N Triethylamine

[0794] EtOH

[0795] g

[0796] HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0797] HMDSLi Hexamethyldisilazide Lithium

[0798] L Liter

[0799] M mole / liter

[0800] MeOH Methanol

[0801] mg milligram

[0802] mL milliliters

[0803] mmol millimole

[0804] mol mole

[0805] NBS N-Bromosuccinimide

[0806] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0807] Pd(dppf)Cl2CH2Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex

[0808] PE Petroleum Ether

[0809] TFA Trifluoroacetic acid

[0810] THF Tetrahydrofuran

[0811] Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0812] Xant-phos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

[0813] Example 1 Synthesis of Compounds

[0814] Intermediate I-1

[0815] 4-Chloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde

[0816] Step 1: 2-Chlorocyclopentane-1-ene-1-carbaldehyde

[0817] Phosphorus oxychloride (4.45 mL, 47.7 mmol) was added dropwise to DMF (4.6 mL, 59.6 mmol) at 0-5 °C under nitrogen protection. The reaction solution was stirred at 0-5 °C for 10 minutes, and then stirred at room temperature for 15 minutes. Cyclopentanone (2.5 g, 29.8 mmol) was added dropwise to the above reaction solution at 0-5 °C, reacted at room temperature for 1 hour, then poured into ice water, adjusted the pH value to 5 with sodium carbonate aqueous solution, and added 100 mL of water. Extracted with petroleum ether / ethyl acetate = 10 / 1 (100 mL x 2), the organic phases were collected and combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the target product (2.4 g, yield 62%), which was directly used in the next step.

[0818] Step 2: (E)-ethyl 3-(2-chlorocyclopent-1-en-1-yl)acrylate

[0819] Under nitrogen protection, 2-chlorocyclopentane-1-ene-1-carboxaldehyde (2.4 g, 18.4 mmol) and ethoxycarbonylmethylenetriphenylphosphine (6.4 g, 18.4 mmol) were placed in dichloromethane (30 mL) and reacted at reflux temperature for 6 hours. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.3 g, yield 89%). [M+H] + 201.1

[0820] Step 3: Ethyl 1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate

[0821] Under nitrogen protection, sodium azide (1.6 g, 24 mmol) was added to a solution of (E)-3-(2-chlorocyclopent-1-en-1-yl) ethyl acrylate (3.3 g, 16.5 mmol) in DMSO (20 mL), and the mixture was reacted at 65 ° C for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were collected and combined, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (700 mg, yield 24%). [M+H] + 180.1. 1 H NMR (400MHz, CDCl3): δ8.81(s,1H),6.65(s,1H),4.30-4.26(m,2H),2.75-2.55(m,4H),2.42-2.40(m,2H),1.35-1.31(m,3H).

[0822] Step 4: Ethyl 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate

[0823] To a solution of 1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester (700 mg, 3.9 mmol) in DMF (5 mL), add cesium carbonate (3.2 g, 9.7 mmol) and bromoacetaldehyde diethyl acetal (1.55 g, 7.8 mmol) and react at 100 ° C for 16 hours. Add water (50 mL) to the reaction solution and extract with ethyl acetate (20 mL x 2). Collect and combine the organic phases, concentrate under vacuum, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.0 g, yield 92%). [M+Na] + 318.1

[0824] Step 5: 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid

[0825] To a solution of 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester (1.0 g, 3.6 mmol) in ethanol (10 mL) and water (10 mL), lithium hydroxide monohydrate (650 mg, 14.4 mmol) was added and reacted at 80°C for 12 hours. The ethanol was removed under vacuum, the pH value was adjusted to 5-6 with concentrated hydrochloric acid, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target product (800 mg, yield 83%). [MH] - 266.1

[0826] Step 6: 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide

[0827] At 0-5°C, under nitrogen protection, triethylamine (0.84 mL, 6 mmol) and HATU (1.7 g, 4.5 mmol) were added to a DMF (5 mL) solution of 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (800 mg, 3 mmol) at room temperature for 30 minutes. The reaction solution was poured into concentrated ammonia (20 mL) and stirred for 10 minutes. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were collected and combined, and concentrated to obtain the target product (1.0 g, yield 125%), which was directly used for the next step.

[0828] Step 7: 7,8-Dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0829] Dissolve 1-(2,2-diethoxyethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide (1.0 g, 3.75 mmol) in acetic acid (10 mL), react at 100 ° C for 4 hours, remove acetic acid under vacuum, adjust the pH to 8 with ammonia water, add water (20 mL), and extract with dichloromethane (20 mL x 2). Collect and combine the organic phases, concentrate under vacuum, and purify the residue by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (600 mg, yield 92%). [M+H] + 175.1

[0830] Step 8: 4-Chloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde

[0831] Under nitrogen protection, cuprous iodide (665 mg, 3.5 mmol), 4,7-dimethoxy-1,10-phenanthroline (580 mg, 2.45 mmol) and cesium carbonate (2.2 g, 7.0 mmol) were added to a solution of 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one (600 mg, 3.5 mmol) and 2-bromo-4-chloronicotinaldehyde (1.1 g, 5.1 mmol) in 1,4-dioxane (30 mL) . The mixture was reacted at 90 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (400 mg, yield 37%). [M+H] + 314.0

[0832] According to the preparation steps of intermediate I-1, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0833]

[0834]

[0835] Intermediate I-2

[0836] (5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid

[0837]

[0838] Step 1: (2R,5S)-2,5-dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

[0839] Under nitrogen protection, Xant-phos (3.8 g, 0.64 mmol), Pd2(dba)3 (3.0 g, 0.32 mmol) and cesium carbonate (21.3 g, 65.3 mmol) were added to a solution of 5-bromo-2-nitropyridine (7.0 g, 32.7 mmol) and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (10.0 g, 49.0 mmol) in 1,4-dioxane (150 mL). The mixture was heated at 100 °C. ℃ After reacting for 16 hours, the mixture was cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product. [M+H] + 337.1

[0840] Step 2: (2R,5S)-2,5-dimethyl-1-(6-nitropyridin-3-yl)piperazine

[0841] Under nitrogen protection, concentrated hydrochloric acid (3 mL) was added to the methanol (10 mL) solution of (2R,5S)-2,5-dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester obtained in step 1. The reaction was stirred at room temperature for 30 minutes, concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (3.3 g, two-step yield 43%). [M+H] + 237.1

[0842] Step 3: (2S,5R)-2,5-dimethyl-1-(6-nitropyridin-3-yl)-4-(oxetane-3-yl)piperazine

[0843] Under nitrogen protection, zinc chloride (5.7 g, 42.0 mmol) and sodium cyanoborohydride (2.6 g, 42.0 mmol) were added to a solution of (2R, 5S)-2,5-dimethyl-1-(6-nitropyridin-3-yl)piperazine (3.3 g, 14.0 mmol) and oxetane-3-one (3.1 g, 42.0 mmol) in methanol (20 mL). The reaction was stirred at 50 ° C for 5 hours, concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (3.3 g, yield 80%). [M+H] + 293.1

[0844] Step 4: 5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine

[0845] At room temperature, hydrogen was introduced into a mixture of (2S,5R)-2,5-dimethyl-1-(6-nitropyridin-3-yl)-4-(oxetane-3-yl)piperazine (3.3 g, 11.3 mmol) and 10% palladium-carbon (containing 50% water, 400 mg) in methanol (50 mL), and the mixture was reacted at room temperature for 12 hours. The reaction solution was filtered, the filtrate was collected, and the target product (2.94 g, yield 99%) was obtained by vacuum concentration, which was directly used in the next step. [M+H] + 263.1

[0846] Step 5: 5-Bromo-3-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methylpyridin-2(1H)-one

[0847] Under nitrogen protection, Xant-phos (325 mg, 0.56 mmol), Pd2(dba)3 (515 mg, 0.56 mmol) and cesium carbonate (7.3 g, 22.5 mmol) were added to a solution of 5-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazin-1-yl)pyridin-2-amine (2.94 g, 11.2 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 11.2 mmol) in 1,4-dioxane (150 mL). The mixture was reacted at 100 ° C for 16 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol / dichloromethane) to obtain (4.7 g, yield 93%). [M+H] + 448.1,450.0

[0848] Step 6: (5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid

[0849] Under nitrogen protection, Xphos (500 mg, 1.05 mmol), Pd2(dba)3 (480 mg, 0.52 mmol) and potassium acetate (3.0 g, 31.4 mmol) were added to a solution of 5-bromo-3-((5-((2S,5R)-2,5-dimethyl-4-(oxetane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methylpyridin-2(1H)-one (4.7 g, 10.5 mmol) and biboronic acid pinacol ester (13.3 g, 52.4 mmol) in 1,4-dioxane (200 mL) under nitrogen protection. The mixture was reacted at 60°C for 16 hours and then cooled to room temperature. The reaction solution was filtered, the filtrate was collected and concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target compound (2.3 g, yield 53%). [M+H] + 414.2

[0850] According to the preparation steps of intermediate I-2, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0851]

[0852]

[0853]

[0854]

[0855]

[0856] Intermediate I-3

[0857] 5-Bromo-3-((5-ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methylpyridin-2(1H)-one

[0858] Step 1: N-(2-methoxyethyl)-6-nitropyridin-3-amine

[0859] Triethylamine (21.2 g, 210 mmol) was added to a DMSO (30 mL) solution of 5-fluoro-2-nitropyridine (4.26 g, 30 mmol) and 2-methoxyethylamine (2.48 g, 33 mmol). The mixture was reacted at 100 °C for 4 hours and then cooled to room temperature. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were collected and combined, concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / dichloromethane) to obtain the target product (5.92 g, yield 100%). [M+H] + 198.1

[0860] Step 2: N-ethyl-N-(2-methoxyethyl)-6-nitropyridin-3-amine

[0861] At 0-5°C, under nitrogen protection, add 60% sodium hydride (mineral oil dispersion) (240 mg, 6.0 mmol) to a DMF (10 mL) solution of N-(2-methoxyethyl)-6-nitropyridine-3-amine (986 mg, 5.0 mmol), and stir at this temperature for 1 hour. Add bromoethane to the mixture, react at 60°C for 2 hours, and cool to room temperature. Concentrate the reaction solution under vacuum, dissolve the residue in dichloromethane (100 mL), and wash with water (50 mL). Collect the organic phase, concentrate under vacuum to obtain the target product (1.13 g, yield 100%), which is directly used in the next step. [M+H] + 226.1

[0862] Step 3: N 5 -ethyl-N 5 -(2-Methoxyethyl)pyridine-2,5-diamine

[0863] At room temperature, hydrogen was introduced into a mixture of N-ethyl-N-(2-methoxyethyl)-6-nitropyridine-3-amine (1.13 g, 5.0 mmol) and 10% palladium-carbon (containing 50% water, 200 mg) in methanol (20 mL), and the mixture was reacted at room temperature for 16 hours. The reaction solution was filtered, the filtrate was collected, and the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (875 mg, yield 90%). [M+H] + 196.1

[0864] Step 4: 5-Bromo-3-((5-ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methylpyridin-2(1H)-one

[0865] Under nitrogen protection, 5 -ethyl-N 5 Xant-phos (58 mg, 0.1 mmol), Pd2(dba)3 (92 mg, 0.1 mmol) and cesium carbonate (652 mg, 2.0 mmol) were added to a solution of -(2-methoxyethyl)pyridine-2,5-diamine (195 mg, 1.0 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (267 mg, 1.0 mmol) in 1,4-dioxane (5 mL). The mixture was reacted at 100°C for 16 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure in vacuo, and the residue was purified by silica gel column chromatography (methanol / dichloromethane) to obtain the target product (257 mg, yield 67%). [M+H] + 381.1,383.1

[0866] According to the preparation steps of intermediate I-3, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875] Intermediate I-4

[0876] (3-(Acetoxymethyl)-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)boronic acid

[0877]

[0878] Step 1: 2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0879] At 0-5°C, under nitrogen protection, sodium borohydride (0.13 g, 3.5 mmol) was added to a solution of 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (1.71 g, 5.0 mmol) (Intermediate I-55) in methanol (5 mL) and dichloromethane (15 mL), and the mixture was reacted at this temperature for 10 minutes. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were collected and combined, and concentrated under vacuum to obtain the target product (1.72 g, yield 100%), which was directly used in the next step. [M+H] + 344.1

[0880] Step 2: 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yl)methyl acetate

[0881] At 0-5°C, under nitrogen protection, acetyl chloride (1.18 g, 15 mmol) was added to a solution of 2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (1.72 g, 5.0 mmol) and triethylamine (2.53 g, 25 mmol) in dichloromethane (30 mL), and the mixture was reacted at this temperature for 1 hour. Water (20 mL) and dichloromethane (30 mL) were added to the reaction solution, the organic phases were collected and combined, and the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.65 g, yield 86%). [M+H] + 386.1

[0882] Step 3: (3-(Acetoxymethyl)-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)boronic acid

[0883] Under nitrogen protection, Xphos (333 mg, 0.7 mmol), Pd(dppf)Cl2 CH2Cl2 (570 mg, 0.7 mmol) and potassium acetate (2.3 g, 23.3 mmol) were added to a solution of 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yl)methyl acetate (3.0 g, 7.79 mmol) and biboronic acid pinacol ester (5.9 g, 23.3 mmol) in 1,4-dioxane (120 mL). The mixture was reacted at 90°C for 16 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (2.9 g, yield 94%). [M+H] + 396.1

[0884] According to the preparation steps of intermediate I-4, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0885]

[0886]

[0887] Intermediate I-5

[0888] 5-Bromo-3-((1-ethyl-1H-1,2,3-triazol-4-yl)amino)-1-methylpyrazin-2(1H)-one

[0889]

[0890] Under nitrogen protection, 3,5-dibromo-1-methylpyrazine-2(1H)-one (5.0 g, 18.7 mmol) and 1-ethyl-1H-1,2,3-triazole-4-amine (2.1 g, 18.7 mmol) were dissolved in N-methylpyrrolidone (7 mL). The mixture was reacted at 120 ° C for 3 hours and cooled to room temperature. Filtered, the filter cake was washed with methanol (5 mL) to obtain the target product (3.9 g, yield 50%). [M+H] + 299.0,301.0

[0891] According to the preparation steps of intermediate I-5, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0892]

[0893] Intermediate I-13

[0894] (S)-5-Bromo-1,6-dimethyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridin-2(1H)-one

[0895]

[0896] Step 1: 3,5-Dibromo-6-methylpyridin-2(1H)-one

[0897] Under nitrogen protection, NBS (3.1 g, 17.4 mmol) was added to a DMF (30 mL) solution of 6-methylpyridin-2(1H)-one (949 mg, 8.7 mmol). The mixture was reacted at room temperature for 4 hours. The reaction solution was poured into water (50 mL), the precipitated solid was collected, and then washed with methanol to obtain the target product, which was directly used in the next step.

[0898] Step 2: 3,5-Dibromo-1,6-dimethylpyridin-2(1H)-one

[0899] Under nitrogen protection, iodomethane (1.3 g, 8.7 mmol) and cesium carbonate (1.6 g, 11.3 mmol) were added to a DMF (30 mL) solution of 3,5-dibromo-6-methylpyridin-2(1H)-one (2.3 g, 8.7 mmol). The mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water (50 mL), the precipitated solid was collected, and then the solid was washed with methanol to obtain the target product (2.2 g, two-step yield 92%). [M+H] + 281.8

[0900] Step 3: (S)-5-bromo-1,6-dimethyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridin-2(1H)-one

[0901] Intermediate I-13 was prepared using 3,5-dibromo-1,6-dimethylpyridin-2(1H)-one and corresponding reagents according to the corresponding steps of intermediate I-2. [M+H] + 448.1,450.1

[0902] Intermediate I-16

[0903] (S)-6-Chloro-2-ethyl-4-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridazin-3(2H)-one

[0904] Step 1: 4-Bromo-6-chloro-2-ethylpyridazin-3(2H)-one

[0905] At 0-5°C, under nitrogen protection, add 60% sodium hydride (mineral oil dispersion) (0.46 g, 11.5 mmol) to a DMF (20 mL) solution of 4-bromo-6-chloropyridazine-3 (2H) -one (1.0 g, 4.8 mmol). The mixture was reacted at 0-5°C for 30 minutes, then iodoethane (1.5 g, 9.6 mmol) was added and the reaction was continued at room temperature for 5 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were collected and combined, and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (0.91 g, yield 80%). [M+H] + 238.9

[0906] Step 2: (S)-6-Chloro-2-ethyl-4-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridazin-3(2H)-one

[0907] Intermediate I-16 was prepared using 4-bromo-6-chloro-2-ethylpyridazin-3(2H)-one and corresponding reagents according to the corresponding steps of intermediate I-2. [M+H] + 405.1

[0908] Intermediate I-31

[0909] 5-Bromo-1-methyl-3-((1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)amino)pyridin-2(1H)-one

[0910] Step 1: 4-Nitro-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole

[0911] At 0-5°C, under nitrogen protection, DIAD (13.9 g, 43.8 mmol) was added to a solution of 4-nitro-1H-1,2,3-triazole (4.0 g, 35.1 mmol), 2-trifluoroethanol (5.12 mL, 43.8 mmol) and triphenylphosphine (18.4 g, 43.8 mmol) in tetrahydrofuran (180 ml). The mixture was reacted at 60°C for 16 hours and then cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (4.61 g, yield 68%). [M+H] + 197.0

[0912] Step 2: 5-Bromo-1-methyl-3-((1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)amino)pyridin-2(1H)-one

[0913] Use 4-nitro-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole and corresponding reagents, and follow the corresponding steps of intermediate I-3 to prepare intermediate I-31. [M+H] + 352.0,353.9

[0914] According to the preparation steps of intermediates I-31, I-3 and I-5, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0915]

[0916]

[0917] Intermediate I-37

[0918] 5-Bromo-1-methyl-3-((1'-(oxetane-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-6-yl)amino)pyridin-2(1H)-one

[0919] Step 1: tert-Butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)carboxylate

[0920] Under nitrogen protection, Pd(dppf)Cl2 CH2Cl2 (612 mg, 0.75 mmol) and sodium carbonate (3.18 g, 30 mmol) were added to a solution of 1-nitro-tert-butyl-4,5-cyclohexene-4-boronate (4.41 g, 15 mmol) and 5-fluoro-2-nitropyridine (3.03 g, 15 mmol) in 1,4-dioxane (20 mL) and water (2 mL) . The mixture was reacted at 100°C for 3 hours and then cooled to room temperature, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (4.58 g, yield 100%). [M+H] + 306.1

[0921] Step 2: 5-Bromo-1-methyl-3-((1'-(oxetan-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridinyl]-6-yl)amino)pyridin-2(1H)-one

[0922] Intermediate I-37 was prepared using 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)carboxylic acid tert-butyl ester and corresponding reagents according to the corresponding steps of intermediate I-2. [M+H] + 417.0,419.0

[0923] According to the preparation steps of intermediate I-37, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0924]

[0925] Intermediate I-43

[0926] (S)-5-Bromo-1-methyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)amino)pyridin-2(1H)-one

[0927] Step 1: (S)-tert-butyl 3-methyl-4-(5-nitropyrazin-2-yl)piperazine-1-carboxylate

[0928] Potassium carbonate (1.38 g, 10 mmol) was added to a DMF (10 mL) solution of 2-bromo-5-nitropyrazine (1.22 g, 6.0 mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.00 g, 5.0 mmol). The mixture was reacted at 80°C for 4 hours and then cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.50 g, yield 93%). [M+H-56] + 268.1

[0929] Step 2: (S)-5-Bromo-1-methyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)amino)pyridin-2(1H)-one

[0930] Use (S)-3-methyl-4-(5-nitropyrazine-2-yl)piperazine-1-carboxylic acid tert-butyl ester and corresponding reagents, and follow the corresponding steps of intermediate I-2 to prepare intermediate I-43. [M+H] + 435.1,437.1

[0931] Intermediate I-44

[0932] (S)-5-Bromo-1-methyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)amino)pyridin-2(1H)-one

[0933] Step 1: 5-Bromo-N,N-di(4-methoxybenzyl)pyrimidin-2-amine

[0934] At 0-5°C, under nitrogen protection, add 60% sodium hydride (mineral oil dispersion) (1.72g, 43mmol) to a solution of 5-bromopyrimidin-2-amine (3.48g, 20mmol) in tetrahydrofuran (60mL). The mixture was reacted at 0-5°C for 30 minutes, then p-methoxybenzyl chloride (7.83g, 50mmol) was added and the reaction was continued at 75°C for 8 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were collected and combined, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.07g, yield 25%). [M+H] + 414.1,416.1

[0935] Step 2: (S)-tert-butyl 4-(2-(bis(4-methoxybenzyl)amino)pyrimidin-5-yl)-3-methylpiperazine-1-carboxylate

[0936] Under nitrogen protection, BINAP (311 mg, 0.50 mmol), Pd2(dba)3 (229 mg, 0.25 mmol) and sodium tert-butoxide (960 mg, 10 mmol) were added to a toluene (30 mL) solution of 5-bromo-N,N-di(4-methoxybenzyl)pyrimidin-2-amine (2.07 g, 5.0 mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (10.0 g, 49.0 mmol). The mixture was reacted at 80°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.60 g, yield 30%). [M+H] + 534.3

[0937] Step 3: (S)-5-(2-methylpiperazin-1-yl)pyrimidin-2-amine

[0938] Under nitrogen protection, a solution of (S)-tert-butyl 4-(2-(di(4-methoxybenzyl)amino)pyrimidin-5-yl)-3-methylpiperazine-1-carboxylate (1.60 g, 3.0 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 30 minutes and concentrated under vacuum to obtain the target product, which was directly used in the next step. [M+H] + 194.1

[0939] Step 4: (S)-tert-Butyl 4-(2-aminopyrimidin-5-yl)-3-methylpiperazine-1-carboxylate

[0940] Triethylamine (455 mg, 4.5 mmol) was added to a solution of (S)-5-(2-methylpiperazin-1-yl)pyrimidin-2-amine and di-tert-butyl dicarbonate (720 mg, 3.3 mmol) obtained in the previous step in dichloromethane (10 mL). The mixture was reacted at room temperature for 1 hour. The residue was concentrated under vacuum and purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (880 mg, two-step yield 100%). [M+H] + 294.1

[0941] Step 5: (S)-5-Bromo-1-methyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)amino)pyridin-2(1H)-one

[0942] Use (S)-4-(2-aminopyrimidin-5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and corresponding reagents, and follow the corresponding steps of intermediate I-2 to prepare intermediate I-44. [M+H] + 435.0,437.0

[0943] Intermediate I-45

[0944] 5-Bromo-1-methyl-3-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)amino)pyridin-2(1H)-one

[0945] Step 1: 6-Nitro-N-(tetrahydro-2H-pyran-3-yl)pyridin-3-amine

[0946] Under nitrogen protection, BINAP (0.37 g, 0.60 mmol), Pd2(dba)3 (0.55 g, 0.60 mmol) and cesium carbonate (3.91 g, 12 mmol) were added to a solution of tetrahydro-2H-pyran-3-amine (0.61 g, 6.0 mmol) and 5-bromo-2-nitropyridine (1.46 g, 7.2 mmol) in 1,4-dioxane (50 mL). The mixture was reacted at 100 ° C for 16 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (0.72 g, yield 54%). [M+H] + 224.1

[0947] Step 2: 5-Bromo-1-methyl-3-((5-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)amino)pyridin-2(1H)-one

[0948] Use 6-nitro-N-(tetrahydro-2H-pyran-3-yl)pyridin-3-amine and corresponding reagents, and follow the corresponding steps of intermediate I-3 to prepare intermediate I-45. [M+H] + 379.0,381.0

[0949] According to the preparation steps of intermediate I-45, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0950]

[0951] Intermediate I-47

[0952] 5-Bromo-1-methyl-3-((5-(morpholine-4-carbonyl)pyridin-2-yl)amino)pyridin-2(1H)-one

[0953] Step 1: (6-aminopyridin-3-yl)(morpholino)methanone

[0954] Under nitrogen protection, a solution of 6-aminonicotinic acid (1.38 g, 10 mmol) and CDI (1.95 g, 12 mmol) in DMF (12 mL) was reacted at 70 ° C for 1 hour, and then stirred at room temperature for 1 hour. Morpholine (1.74 g, 20 mmol) was added to the mixture and reacted at room temperature for 16 hours. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (1.05 g, yield 51%). [M+H] + 208.1

[0955] Step 2: 5-Bromo-1-methyl-3-((5-(morpholine-4-carbonyl)pyridin-2-yl)amino)pyridin-2(1H)-one

[0956] Intermediate I-47 was prepared using (6-aminopyridin-3-yl)(morpholino)methanone and corresponding reagents according to the corresponding steps of intermediate I-3. [M+H] + 393.0,395.0

[0957] According to the preparation steps of intermediate I-47, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0958]

[0959] Intermediate I-52

[0960] 4-Chloro-2-(6-fluoro-1-oxopyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0961]

[0962] Step 1: Ethyl 1-(2,2-diethoxyethyl)-7-fluoro-1H-indole-2-carboxylate

[0963] 2-Bromo-1,1-diethoxyethane (4.0 g, 20 mmol) and cesium carbonate (8.2 g, 25 mmol) were added to a solution of ethyl 7-fluoro-1H-indole-2-carboxylate (2.07 g, 10 mmol) in DMF (15 mL). The mixture was reacted at 110 ° C for 16 hours, cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic phases were collected and combined, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.5 g, yield 77%). [M+H-EtOH] + 278.1

[0964] Step 2: 6-Fluoropyrazino[1,2-a]indol-1(2H)-one

[0965] To a solution of 1-(2,2-diethoxyethyl)-7-fluoro-1H-indole-2-carboxylic acid ethyl ester (2.5 g, 7.7 mmol) in acetic acid (50 mL) was added ammonium acetate (12 g, 154 mmol). The mixture was reacted at 110°C for 16 hours and then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.5 g, yield 77%). [M+H] + 203.0

[0966] Step 3: 4-Chloro-2-(6-fluoro-1-oxopyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0967] Intermediate I-52 was prepared using 6-fluoropyrazino[1,2-a]indol-1(2H)-one and corresponding reagents according to the corresponding steps of intermediate I-1. [M+H] + 342.0

[0968] According to the preparation steps of intermediates I-52 and I-1, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0969]

[0970] Intermediate I-58

[0971] 4-Chloro-2-(7,7-difluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0972] Step 1: 7,7-difluoro-8,9-dihydropyrazino[1,2-a]indole-1,6(2H,7H)-dione

[0973] Using 6,6-fluoro-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester, the target compound was prepared according to the corresponding steps of intermediate I-1. [M+H] + 239.0

[0974] Step 2: 7,7-difluoro-6-hydroxy-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one

[0975] At 0-5°C, under nitrogen protection, sodium borohydride (239 mg, 6.3 mmol) was added to a solution of 7,7-difluoro-8,9-dihydropyrazino[1,2-a]indole-1,6(2H,7H)-dione (500 mg, 2.1 mmol) in methanol (10 mL), and the mixture was reacted at this temperature for 10 minutes. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phases were collected and combined, and concentrated under vacuum to obtain the target product, which was directly used in the next step.

[0976] Step 3: 7,7-difluoro-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one

[0977] Under nitrogen protection, triethylsilane (771 mg, 6.3 mmol) was added to the trifluoroacetic acid (5 mL) solution of 7,7-difluoro-6-hydroxy-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one obtained in the previous step. The mixture was reacted at room temperature for 1 hour, concentrated under vacuum, and saturated sodium bicarbonate aqueous solution (10 mL) was added to the residue, and extracted with dichloromethane (10 mL x 2). The organic phases were collected and combined, concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (120 mg, two-step yield 26%). [M+H] + 225.0

[0978] Step 4: 4-Chloro-2-(7,7-difluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0979] Use 7,7-difluoro-6,7,8,9-tetrahydropyrazino[1,2-a]indol-1(2H)-one and corresponding reagents to prepare intermediate I-58 according to the corresponding steps of intermediate I-1. [M+H] + 364.0

[0980] According to the preparation steps of intermediate I-58, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[0981]

[0982] Intermediate I-61

[0983] 4-Chloro-2-(8,10-difluoro-1-oxopyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0984] Step 1: Ethyl 3,5-difluoro-1H-indole-2-carboxylate

[0985] At 0-5°C, under nitrogen protection, add Selectfluor (7.08g, 20mmol) to a solution of 5-fluoro-1H-indole-2-carboxylic acid ethyl ester (4.14g, 20mmol) in acetonitrile (100mL), and react at this temperature for 16 hours. Add saturated aqueous ammonium chloride solution (20mL) and water (100mL) to the reaction solution, and extract with ethyl acetate (50mL x2). Collect and combine the organic phases, concentrate under vacuum, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the target product (2.4g, yield 53%). [M+H] + 226.0.

[0986] Step 2: 4-Chloro-2-(8,10-difluoro-1-oxopyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[0987] Using 3,5-difluoro-1H-indole-2-carboxylic acid ethyl ester and corresponding reagents, the intermediate I-61 was prepared according to the corresponding steps of the intermediate I-52. [M+H] + 360.0

[0988] Intermediate I-62

[0989] Acetate (2-(9-bromo-7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-chloropyridin-3-yl)methyl ester

[0990]

[0991] To a solution of 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yl)methyl acetate (800 mg, 2.07 mmol) in dichloromethane (30 mL) at 0°C was added NBS (367 mg, 2.07 mmol). The mixture was reacted at room temperature for 16 hours, quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the target product (800 mg, yield 83%). [M+H] + 464.0,466.0

[0992] Intermediate I-63

[0993] 4-Chloro-2-(7,7-dimethyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]pyrrolo[2,1-f][1,2,4]triazin-3-yl)nicotinaldehyde

[0994]

[0995] Step 1: 1-Amino-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester

[0996] At 0-5°C, under nitrogen protection, add 60% sodium hydride (mineral oil dispersion) (1.06 g, 26.5 mmol) to a DMF (30 mL) solution of 5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester (5.0 g, 24.1 mmol). The mixture was reacted at 0-5°C for 30 minutes, and then O-(2,4-dinitrophenyl)hydroxylamine (5.3 g, 26.5 mmol) was added to the reaction solution and reacted at room temperature for 3 hours. The product was concentrated under vacuum and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (4.3 g, yield 75%). [M+H] + 223.0

[0997] Step 2: 7,7-Dimethyl-7,8-dihydro-3H-cyclopenta[4,5]pyrrolo[2,1-f][1,2,4]triazine-4(6H)-one

[0998] Under nitrogen protection, add ammonium acetate (7.4 g, 96.5 mmol) to a mixture of 1-amino-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester (4.3 g, 19.3 mmol) and formamide (30 mL). The mixture is reacted at 140 ° C for 16 hours and then cooled to room temperature. Filter, collect and wash the filter cake with methanol to obtain the target product (3.1 g, yield 80%). [M+H] + 204.0

[0999] Step 3: 4-chloro-2-(7,7-dimethyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]pyrrolo[2,1-f][1,2,4]triazin-3-yl)nicotinaldehyde

[1000] Use 7,7-dimethyl-7,8-dihydro-3H-cyclopenta[4,5]pyrrolo[2,1-f][1,2,4]triazine-4(6H)-one and corresponding reagents to prepare intermediate I-63 according to the corresponding steps of intermediate I-1. [M+H] + 343.1

[1001] According to the preparation steps of intermediate I-63, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[1002]

[1003]

[1004] Intermediate I-68

[1005] (8-((tert-Butyloxycarbonyl)(1-ethyl-1H-1,2,3-triazol-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)boronic acid

[1006]

[1007] Intermediate I-68 was prepared using intermediate I-21 and corresponding reagents according to step 1 of intermediate I-74 and step 6 of I-2. [M+H] + 374.1

[1008] According to the preparation steps of intermediate I-68, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[1009]

[1010] Intermediate I-74

[1011] 4-Chloro-2-(7-methyl-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[1012] Step 1: 7-Oxo-4,5,6,7-tetrahydro-1H-indole-1,2-dicarboxylic acid 1-(tert-butyl) 2-ethyl ester

[1013] To a solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (2.07 g, 10 mmol) and di-tert-butyl dicarbonate (7.51 g, 30 mmol) in tetrahydrofuran (30 mL), add 4-dimethylaminopyridine (0.12 g, 1.0 mmol). The mixture was reacted at room temperature for 16 hours. The residue was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.07 g, yield 100%). [M+Na] + 330.3

[1014] Step 2: Ethyl 6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

[1015] At -78°C, under nitrogen protection, 1M HMDSLi / tetrahydrofuran solution (24mL, 24mmol) was added dropwise to a solution of 7-oxo-4,5,6,7-tetrahydro-1H-indole-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (3.07g, 10mmol) in tetrahydrofuran (50mL), and the mixture was naturally warmed to 0°C and continued to react for 30 minutes. At -78°C, iodomethane (3.41g, 24mmol) was added dropwise to the reaction solution, and the mixture was naturally warmed to room temperature and continued to react for 4 hours. The reaction solution was cooled to 0°C, quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (50mL x 2). The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo. Under nitrogen protection, the resulting residue was stirred in trifluoroacetic acid (10 mL) at room temperature for 30 minutes, concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (1.19 g, yield 54%). [M+H] + 221.1

[1016] Step 3: Ethyl 6-methyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

[1017] Under nitrogen protection, triethylsilane (2.5 mL) was added to a solution of 6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester (1.19 g, 5.38 mmol) in trifluoroacetic acid (10 mL). The mixture was reacted at room temperature for 16 hours, concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (980 mg, yield 88%). [M+H] + 208.1

[1018] Step 4: 4-Chloro-2-(7-methyl-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[1019] Use 6-methyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester and corresponding reagents, and follow the corresponding steps of intermediate I-1 to prepare intermediate I-74. [M+H] + 342.0

[1020] Intermediate I-75

[1021] 4-Chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-2-yl)nicotinaldehyde

[1022]

[1023] Step 1: 5,5-Dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carbohydrazide

[1024] A solution of 5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid ethyl ester (2.49 g, 12 mmol) and hydrazine hydrate aqueous solution (20 mL, 36 mmol) in ethanol (8 mL) was reacted at 150°C for 2 hours in a microwave reactor and then cooled to room temperature. Filter, wash with water, collect the filter cake, and dry under vacuum to obtain the target product (2.09 g, yield 90%). [M+H] + 194.1

[1025] Step 2: 7,7-Dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazine-1(6H)-one

[1026] Under nitrogen protection, 5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carbohydrazide (2.09 g, 10.5 mmol) and triethyl orthoformate (3.11 g, 21.0 mmol) in DMF (8 mL) were reacted at 160°C for 16 hours. Cooled to room temperature, filtered, washed with methanol and the filter cake was collected, and dried under vacuum to obtain the target product (1.65 g, yield 77%). [M+H] + 204.1

[1027] Step 3: 4-chloro-2-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-2-yl)nicotinaldehyde

[1028] Use 7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazine-1(6H)-one and corresponding reagents to prepare intermediate I-75 according to the corresponding steps of intermediate I-1. [M+H] + 343.1

[1029] According to the preparation steps of intermediate I-75, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[1030]

[1031]

[1032] Intermediate I-83

[1033] 2-(4-Chloro-3-(fluoromethyl)pyridin-2-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1034]

[1035] Step 1: (2-Bromo-4-chloropyridin-3-yl)methanol

[1036] Sodium borohydride (325 mg, 8.6 mmol) was added to a solution of 2-bromo-4-chloronicotinaldehyde (2.7 g, 12.2 mmol) in dichloromethane (30 mL) and methanol (10 mL) at 0-5°C, and stirred at this temperature for 30 minutes. Water was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (2.5 g, yield 92%).

[1037] Step 2: (2-bromo-4-chloropyridin-3-yl)methyl methanesulfonate

[1038] At 0-5°C, add methanesulfonyl chloride (573 mg, 5.0 mmol) to a solution of (2-bromo-4-chloropyridin-3-yl)methanol (1.0 g, 4.5 mmol) in dichloromethane (30 mL), and stir at this temperature for 30 minutes. Add water to the reaction solution to quench the reaction, extract with dichloromethane, collect the organic phase, and dry it over anhydrous sodium sulfate. Filter and collect the filtrate, and concentrate under vacuum to obtain the target product (1.35 g, yield 100%), which is directly used in the next step. [M+H] + 299.9,301.9

[1039] Step 3: 2-Bromo-4-chloro-3-(fluoromethyl)pyridine

[1040] To a solution of (2-bromo-4-chloropyridin-3-yl)methyl methanesulfonate (1.35 g, 5.0 mmol) in dry tetrahydrofuran (20 mL), add 1 M tetrabutylammonium fluoride / tetrahydrofuran (5.0 mL, 5.0 mmol) and stir at 65 °C for 2 hours. Add water to the reaction solution to quench the reaction, extract with ethyl acetate, collect the organic phase, and concentrate under vacuum. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (700 mg, yield 62%). [M+H] + 223.9,225.9

[1041] According to the preparation step 8 of intermediate I-1, using the corresponding raw materials and reagents, 2-(4-chloro-3-(fluoromethyl)pyridin-2-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one was prepared. [M+H] + 346.1

[1042] Intermediate I-91

[1043] 4-Chloro-2-(10-fluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

[1044] Step 1: Ethyl 3-fluoro-1H-indole-2-carboxylate

[1045] 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) salt (65.5 g, 1185 mmol) was added to a solution of 1H-indole-2-carboxylic acid ethyl ester (35.0 g, 185 mmol) in acetonitrile (1.75 L), and stirred at room temperature for 45 minutes. Saturated brine was added to quench the reaction, the organic phase was collected, and concentrated under reduced pressure in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (18.0 g, yield 47%).

[1046] Step 2: Ethyl 3-fluoro-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

[1047] Platinum dioxide (1.57 g, 1185 mmol) was added to a solution of ethyl 3-fluoro-1H-indole-2-carboxylate (10.5 g, 50.7 mmol) in acetic acid (210 mL). Hydrogen was introduced into the reaction solution under stirring at room temperature and reacted for 8 hours. The filtrate was filtered and collected, and concentrated under vacuum. The residue was diluted with water and neutralized with ammonia to pH = 8. The organic phase was extracted with ethyl acetate, and concentrated under vacuum to obtain the target product (10.5 g, yield 98%). [M+H] + 212.0

[1048] According to the preparation steps 5-8 of intermediate I-1, corresponding raw materials and reagents were used to prepare 4-chloro-2-(10-fluoro-1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde. [M+H] + 346.0

[1049] Intermediate I-92

[1050] (RS)-2-(4-chloro-3-carboxaldehydepyridin-2-yl)-7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-6-yl acetate

[1051]

[1052] Lead acetate (2.0 g, 4.5 mmol) was added to a solution of intermediate I-55 (1.0 g, 3.0 mmol) in 1,4-dioxane (15 mL), and the reaction was stirred at room temperature for 3 hours. The residue was diluted with water and neutralized with ammonia to pH = 8. The mixture was extracted with ethyl acetate, the organic phase was collected, and the residue was concentrated under reduced pressure in vacuo. The residue was purified by silica gel column chromatography (methanol / water) to obtain the target product (600 mg, yield 50%). [M+H] + 400.0

[1053] Intermediate I-99

[1054] (5-Bromo-2'-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-3'-yl)methyl acetate

[1055]

[1056] Under nitrogen protection, 3-bromo-5-iodo-1-methylpyridin-2(1H)-one (626 mg, 2.0 mmol), intermediate I-4 (790 mg, 2.0 mmol), Pd(dppf)Cl2 CH2Cl2 (162 mg, 0.20 mmol), Xphos (94 mg, 0.20 mmol) and potassium phosphate (848 mg, 4.0 mmol) in acetonitrile (40 mL) and water (2 mL) were reacted at 30°C for 3 hours. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product. [M+H] + 537.1,539.1

[1057] Intermediate I-107

[1058] N-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)propanamide

[1059]

[1060] Under nitrogen protection, triethylamine (455 mg, 4.5 mmol) was added dropwise to a solution of 3-amino-5-bromo-1-methylpyridin-2(1H)-one (609 mg, 3.0 mmol) and propionyl chloride (416 mg, 4.5 mmol) in dichloromethane (20 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (methanol / dichloromethane) to obtain the target product. [M+H] + 259.0,261.0

[1061] According to the preparation steps of intermediate I-107, the intermediates in the following table were prepared using corresponding raw materials and reagents:

[1062]

[1063] Compound 1

[1064] 2-(5-((5-(ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1065] Step 1: (2'-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-5-((5-(ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-3'-yl)methyl acetate

[1066] Under nitrogen protection, Xphos (31 mg, 0.066 mmol), Pd (dppf) Cl2 CH2Cl2 (27 mg, 0.033 mmol) and potassium phosphate trihydrate (264 mg, 0.99 mmol) were added to a solution of intermediate I-3 (126 mg, 0.33 mmol) and intermediate I-4 (134 mg, 0.33 mmol) in 1,4-dioxane (5.0 mL) and water (0.5 mL) . The mixture was reacted at 100 ° C for 4 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol / water) to obtain the target product. [M+H] + 652.3

[1067] Step 2: 2-(5-((5-(ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1068] Potassium carbonate (137 mg, 0.99 mmol) was added to a methanol (5 mL) solution of (2'-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-5-((5-(ethyl(2-methoxyethyl)amino)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-yl)methyl acetic acid obtained in step 1, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure in vacuo, and the residue was purified by thin layer chromatography (methanol / dichloromethane=1 / 20) to obtain the target product (100 mg, two-step yield 50%). [M+H] + 610.3. 1 H NMR (400MHz, CD3OD): δ8.57-8.51(m,1H),8.42-8.37(m,1H),7.77-7.74(m,1H),7.60-7.57(m,1H) ,7.48-7.45(m,1H),7.23-7.19(m,2H),7.01-6.97(m,1H),6.95-6.91(m,1H),6.80-6.76(m,1H),4 .61-4.57(m,1H),4.50-4.45(m,1H),3.69(s,3H),3.53-3.50(m,2H),3.44-3.40(m,2H),3.39-3.3 4(m,2H),3.32(s,3H),2.78-2.69(m,2H),2.66-2.57(m,2H),1.30-1.27(m,6H),1.13-1.08(m,3H).

[1069] According to the preparation steps of compound 1, the compounds in the following table were prepared using the corresponding intermediates and reagents:

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105] Compound 2

[1106] 2-(5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1107]

[1108] Step 1: 5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-2'-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1,6-dihydro-[3,4'-bipyridine]-3'-carbaldehyde

[1109] To a solution of (5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid (171 mg, 0.41 mmol) and 4-chloro-2-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (100 mg, 0.32 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Xphos (20 mg, 0.03 mmol), Pd(dppf)Cl2 CH2Cl2 (25 mg, 0.03 mmol) and cesium carbonate (260 mg, 0.8 mmol) under nitrogen. The mixture was reacted at 90°C for 4 hours and then cooled to room temperature. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL x 2). The organic phases were collected and combined, and concentrated under vacuum to obtain the target product (180 mg, yield 68%), which was directly used in the next step. [M+H] + 647.3

[1110] Step 2: 2-(5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1111] To a solution of 5-((5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-1-methyl-6-oxo-2'-(1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1,6-dihydro-[3,4'-bipyridine]-3'-carbaldehyde (180 mg, 0.28 mmol) in methanol (4 mL) and dichloromethane (10 mL) was added sodium borohydride (16 mg, 0.42 mmol) at 0-5°C under nitrogen protection, and the mixture was reacted at room temperature for 15 minutes. Water (0.5 mL) was added to the reaction solution to quench the reaction, and the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol / water) and thin layer chromatography (methanol / dichloromethane = 1 / 20) to obtain the target product (80 mg, yield 44%). [M+H] + 649.3. 1 H NMR (400MHz, CD3OD): δ8.73(d,J=2.2Hz,1H),8.54(d,J=5.1Hz,1H),8.00(d,J=2.6Hz,1H), 7.59-7.46(m,3H),7.24(d,J=5.9Hz,1H),7.03(d,J=8.8Hz,1H),6.94(s,1H),6.79(d,J=5. 9Hz,1H),4.77-4.55(m,5H),4.49-4.47(m,1H),3.81-3.64(m,4H),3.20-3.18(m,1H),2.91 -2.87(m,3H),2.77-2.73(m,4H),2.62-2.42(m,3H),1.94-1.92(m,1H),0.89-0.86(m,6H).

[1112] According to the preparation steps of compound 2, the compounds in the following table were prepared using corresponding intermediates and reagents:

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134] Compound 68

[1135] 2-(5-((5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1136]

[1137] Compound 68a and corresponding reagents were used to prepare compound 68 according to step 2 of intermediate I-4 and step 2 of compound 2. [M+H] + 595.3

[1138] 1 H NMR (400MHz, CD3OD): δ8.55-8.50(m,1H),8.07-8.01(m,1H),7.58-7.54(m,1H),7.43(s ,1H),7.24-7.19(m,1H),6.93(s,1H),6.81-6.74(m,1H),5.98-5.91(m,1H),4.77-4.70 (m,2H),4.62-4.52(m,1H),4.51-4.40(m,1H),4.10-4.07(m,1H),4.06-3.93(m,3H),3. 68(s,3H),2.78-2.70(m,2H),2.64-2.59(m,2H),2.21-2.16(m,3H),1.30-1.27(m,6H).

[1139] Compound 69

[1140] 2-(3'-(Hydroxymethyl)-1-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1141]

[1142] Compound 69 was prepared using compound 68a and corresponding reagents according to step 3 of intermediate I-2 and step 2 of compound 2. [M+H] + 576.2

[1143] 1H NMR (400MHz, CD3OD): δ8.57-8.50(m,1H),8.04-7.96(m,1H),7.59-7.55(m,1H),7.46 -7.41(m,1H),7.24-7.19(m,1H),6.93(s,1H),6.81-6.73(m,1H),5.86(s,1H),4.60-4 .53(m,1H),4.50-4.41(m,1H),4.09-3.97(m,2H),3.68(s,3H),3.64-3.58(m,2H),2.9 8-2.88(m,2H),2.78-2.69(m,2H),2.66-2.58(m,2H),2.46(s,3H),1.30-1.27(m,6H).

[1144] Compound 70

[1145] 2-(3'-(Hydroxymethyl)-5-((5-(2-methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1146]

[1147] Compound 70 was prepared using compound 68a and corresponding reagents according to step 2 of intermediate I-10 and compound 2. [M+H] + 611.3

[1148] 1H NMR (400MHz, CD3OD): δ8.51(d,J=5.1Hz,1H),7.96(d,J=2.2Hz,1H),7.54(d,J=5.1Hz,1H),7.41(d,J=2 .2Hz,1H),7.19(d,J=5.9Hz,1H),6.92(s,1H),6.76(d,J=5.9Hz,1H),5.84(s,1H),4.55(d,J=12.0Hz,1 H),4.44(d,J=12.0Hz,1H),4.03-3.98(m,2H),3.71-3.68(m,2H),3.66(s,3H),3.59-3.55(m,2H),3.33 (s,3H),3.03-2.97(m,2H),2.78-2.73(m,2H),2.73-2.70(m,2H),2.62-2.58(m,2H),1.29-1.26(m,6H).

[1149] Compound 96

[1150] (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1151]

[1152] Under nitrogen protection, a solution of intermediate I-168 (108 mg, 0.37 mmol), intermediate I-99 (200 mg, 0.37 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), Xant-phos (23 mg, 0.04 mmol) and cesium carbonate (241 mg, 0.74 mmol) in 1,4-dioxane (20 mL) was reacted at 100 °C for 12 hours.

[1153] The reaction solution was concentrated under vacuum, potassium carbonate (276 mg, 5.0 mmol) and methanol (10 mL) were added, and stirred at room temperature for 15 minutes. The residue was concentrated under vacuum, and purified by silica gel column chromatography (methanol / water) to give a yellow solid (120 mg, two-step yield 42%). [M+H] + 707.4.

[1154] Concentrated hydrochloric acid was added to a solution of the yellow solid in methanol (2 mL), and the mixture was stirred at room temperature for 30 minutes. The residue was concentrated under vacuum, and purified by silica gel column chromatography (methanol / dichloromethane) to give compound 96 (50 mg, yield 49%). [M+H] + 607.3

[1155] 1 H NMR (400MHz, CD3OD) δ8.67(d,J=1.8Hz,1H),8.53(d,J=5.1Hz,1H),7.94(d,J=2.6Hz, 1H),7.56-7.52(m,2H),7.44-7.42(m,1H),7.20(d,J=5.9Hz,1H),7.01(d,J=8.9Hz,1 H),6.92(s,1H),6.77(d,J=5.9Hz,1H),4.55-4.41(m,2H),3.68(s,3H),3.38-3.32(m ,1H),3.07-2.86(m,5H),2.77-2.55(m,5H),1.29-1.27(m,6H),0.90(d,J=6.3Hz,3H).

[1156] According to the preparation steps of compound 96, intermediate I-99 and corresponding amine intermediates and reagents were used to prepare the compounds in the following table:

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163] Compound 98

[1164] 2-(5-amino-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1165]

[1166] Under nitrogen protection, intermediate I-148 (220 mg, 0.60 mmol), intermediate I-4 (237 mg, 0.60 mmol), Pd(dppf)Cl2 CH2Cl2 (49 mg, 0.06 mmol), Xphos (57 mg, 0.12 mmol) and potassium phosphate trihydrate (479 mg, 1.80 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were reacted at 100 ° C for 4 hours. The mixture was concentrated under vacuum and the obtained residue was purified by silica gel column chromatography (methanol / water) to obtain a yellow solid (268 mg, yield 70%). [M+H] + 638.3.

[1167] Trifluoroacetic acid (2 mL) was added to a solution of the yellow solid in methanol (5 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and potassium carbonate (174 mg, 1.26 mmol) and methanol (5 mL) were added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under vacuum, and purified by silica gel column chromatography (methanol / water) to give compound 98 (48 mg, yield 26%).

[1168] [M+H] + 432.2

[1169] 1 H NMR (400MHz, CD3OD) δ8.55-8.48(m,1H),7.52-7.48(m,1H),7.36-7.30(m,1H),7.24-7.20(m,1H),6.95-6.91(m,1H),6.91-6.86(m, 1H),6.78-6.72(m,1H),4.55-4.49(m,1H),4.47-4.41(m,1H),3.64(s,3H),2.79-2.68(m,2H),2.66-2.56(m,2H),1.30-1.27(m,6H).

[1170] Compounds 119 and 120

[1171] 2-(3'-(Hydroxymethyl)-5-((5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-1(6H)-one optically pure enantiomer

[1172]

[1173] (RS)-2-(3'-(hydroxymethyl)-5-((5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-1(6H)-one (Compound 110, 110 mg) was separated by chiral HPLC to give a pair of optically pure enantiomers, (R)-2-(3'-(hydroxymethyl)-5-((5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-1(6H)-one -yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-1(6H)-one and (S)-2-(3'-(hydroxymethyl)-5-((5-(2-methoxyethyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-d][1,2,4]triazin-1(6H)-one. Chiral HPLC separation conditions: column: AD-H (0.46 cm ID x 15 cm L); mobile phase: CO2 / ethanol = 60:40; flow rate: 2.5 mL; detector wavelength: UV 254 nm).

[1174] Under the above conditions, the compound obtained after removing the solvent from the first eluate was named compound 119 (40 mg, yield 36%), ee% = 100%, MS (m / z): 626.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.57-8.51(m,1H),8.43-8.38(m,1H),7.97-7.91(m,1H),7.60-7.5 7(m,1H),7.41-7.38(m,1H),7.07-7.01(m,1H),5.93-5.89(m,1H),4.60-4.51(m,2H),4. 04-3.91(m,2H),3.83-3.76(m,1H),3.68(s,3H),3.60-3.53(m,2H),3.40-3.35(m,1H),2 .99-2.87(m,2H),2.86-2.81(m,2H),2.73-2.62(m,3H),1.43-1.39(m,3H),1.31(s,6H).

[1175] Under the above conditions, the compound obtained after removing the solvent from the second eluate was named Compound 120 (42 mg, yield 38%), ee% = 99.68%, MS (m / z): 626.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.56-8.52(m,1H),8.42-8.38(m,1H),7.95-7.92(m,1H),7.60-7.5 7(m,1H),7.41-7.38(m,1H),7.06-7.02(m,1H),5.93-5.89(m,1H),4.60-4.49(m,2H),4. 03-3.93(m,2H),3.82-3.76(m,1H),3.68(s,3H),3.59-3.52(m,2H),3.40-3.34(m,1H),2 .99-2.87(m,2H),2.86-2.81(s,2H),2.73-2.62(m,3H),1.43-1.39(m,3H),1.30(s,6H).

[1176]

[1177]

[1178] The optically pure enantiomers / diastereomers in the above table were obtained by chiral HPLC separation. The separation conditions were: flow rate of 2.5 mL, detector wavelength: UV 254 nm, the chiral column used, the mobile phase and the ee (de) values ​​of the obtained compounds are shown in the following table (wherein, in each pair of enantiomeric compounds, the compound with the first number is the compound obtained by removing the solvent from the first eluate obtained from the chiral column, and the compound with the second number is the compound obtained by removing the solvent from the second eluate obtained from the chiral column):

[1179]

[1180]

[1181] Compound 135

[1182] 2-((2'-(7,7-dimethyl-1-oxo-1,6,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-2-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-5-yl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile

[1183]

[1184] Concentrated hydrochloric acid (2 mL) was added to a solution of compound 135a (250 mg, 0.36 mmol) in methanol (5 mL), and stirred at 50 ° C for 30 minutes. The reaction solution was concentrated under vacuum, acetonitrile (20 mL), potassium carbonate (150 mg, 1.08 mmol) and cyanogen bromide (45 mg, 0.43 mmol) were added, and stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was collected, and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol / water) to give compound 135 (60 mg, yield 29%). [M+H] + 578.3

[1185] 1H NMR (400MHz, CD3OD) δ8.49(d,J=5.1Hz,1H),8.05(d,J=1.8Hz,1H),7.51(d,J=7.2Hz,1H),7.41(d,J=1.8Hz,1H),7.18(d,J=5.9Hz,1H),6.90( s,1H),6.75(d,J=5.9Hz,1H),5.89(s,1H),4.57-4.37(m,4H),4.10(t, J=5.3Hz,2H),3.77-3.58(m,5H),2.78-2.53(m,4H),1.28-1.24(m,6H).

[1186] According to the preparation steps of compound 135, the compounds in the following table were prepared using the corresponding intermediates and reagents:

[1187]

[1188]

[1189] Compound 223

[1190] (S)-2-(3'-(methoxymethyl)-1-methyl-5-(methyl(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridinyl]-2'-yl)-7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[1191]

[1192] At 0-5°C, add 60% NaH (38 mg, 0.95 mmol) to a DMF (10 mL) solution of compound 19 (100 mg, 0.15 mmol) and stir at this temperature for 30 minutes. Add iodomethane (123 mg, 0.87 mmol) and react at room temperature for 30 minutes. Pour the reaction solution into water, extract with ethyl acetate, collect the organic phase, concentrate under vacuum, and purify the residue by silica gel column chromatography (methanol / water) to obtain compound 223 (18 mg, yield 7%). [M+H] + 691.2.

[1193] 1H NMR (400MHz, CD3OD) δ8.61-8.54(m,1H),7.96-7.89(m,1H),7.85-7.79(m,1H),7.78-7.71(m,1H),7.62-7.56(m,1H), 7.47-7.39(m,1H),7.24-7.17(m,1H),6.91(s,1H),6.77-6.66(m,2H),4.72-4.67(m,2H),4.64-4.58(m,3H),4.42-4. 35(m,1H),4.27-4.19(m,1H),3.68(s,3H),3.54-3.47(m,1H),3.34(s,3H),3.14(s,3H),3.07-2.96(m,2H),2.78-2.7 1(m,2H),2.67-2.59(m,3H),2.59-2.51(m,1H),2.43-2.34(m,1H),2.14-2.05(m,1H),1.29(s,6H),0.93-0.90(m,3H).

[1194] Compound 228

[1195]

[1196] At 0-5°C, add 60% NaH (38 mg, 0.95 mmol) to a DMF (10 mL) solution of compound 19 (200 mg, 0.30 mmol) and stir at this temperature for 30 minutes. Add iodomethane (111 mg, 0.78 mmol) and react at room temperature for 30 minutes. Pour the reaction solution into water, extract with ethyl acetate, collect the organic phase, concentrate under vacuum, and purify the residue by silica gel column chromatography (methanol / water) to obtain compound 228 (45 mg, yield 9%). [M+H] + 677.3.

[1197] 1H NMR(400MHz,CD3OD)δ8.74-8.68(m,1H),8.55-8.49(m,1H),7.98-7.89(m,1H),7.57-7.51(m,1H),7.43-7.39(m,1H),7 .37-7.32(m,1H),7.22-7.14(m,1H),7.01-6.95(m,1H),6.91(s,1H),6.79-6.71(m,1H),4.70-4.65(m,2H),4.63-4.55( m,2H),4.42-4.34(m,1H),4.28-4.21(m,1H),3.68(s,3H),3.51-3.44(m,2H),3.11(s,3H),3.09-2.98(m,2H),2.76-2. 69(m,2H),2.63-2.58(m,2H),2.56-2.50(m,1H),2.49-2.38(m,2H),2.23-2.15(m,1H),1.27(s,6H),0.97-0.91(m,3H).

[1198] Example 2 Biochemical BTK Determination

[1199] 1. Reagents and Materials

[1200] BTK recombinant protein: Invitrogen, catalog number PV3363;

[1201] Kinase assay kit-tyrosine 1 peptide: Invitrogen, cat. no. PV3190;

[1202] 384-well low-flange black flat-bottom polystyrene NBS microplate, no cover, non-sterile: Corning, Cat. No. 3575;

[1203] 96-well polystyrene conical bottom MicroWell TM Plates, with lid closure: Thermo Scientific TM Nunc TM , item number 277143;

[1204] Envision multi-mode plate reader: PerkinElmer;

[1205] Shaking plate instrument: Eppendorf;

[1206] TS-2102 shaking incubator: TENSUC;

[1207] 2. Methods

[1208] The biochemical test is an experimental method established by using fluorescence resonance energy transfer (FRET) technology, a dual enzyme format, and different sensitivities to phosphorylated and non-phosphorylated short peptide protein cleavage. Two fluorescent groups are labeled at both ends of the short peptide substrate to form a FRET pairing combination. In the primary reaction process (enzyme reaction), the enzyme transfers the γ-phosphate group on ATP to a serine or threonine residue of the short peptide substrate. In the second step reaction (color reaction), a site-specific protease (color reagent) recognizes and cuts the non-phosphorylated short peptide. Phosphorylated short peptides can inhibit this cleavage. Cutting the short peptide can disrupt the donor (such as coumarin) and acceptor fluorescent groups (fluorescein) on the short peptide, while the phosphorylated short peptide can maintain FRET. The ratio calculation method is as follows: calculate the ratio of the respective emission signals generated by the donor fluorescent group after excitation at 400nm and emission to the acceptor. Emission signal ratio = coumarin emission light (445nm) / fluorescein emission light (520nm). If the FRET peptide is phosphorylated (such as no kinase inhibitor), the emission ratio will remain at a low level; if the FRET peptide is non-phosphorylated (such as kinase inhibition), the emission ratio will be higher. This is used to distinguish the inhibitory effects of different compound inhibitors on BTK kinase activity.

[1209] according to Kinase Assay Kit - Tyrosine 1 Peptide Instructions for Experimental Operations. Reagent Preparation: 1.33× Kinase Buffer, dilute 5× Kinase Buffer with water to 1.33× Kinase Buffer; Enzyme Solution, dissolve the kinase in 1.33× Kinase Buffer, the final working concentration is 3.32nM; Short Peptide Solution, dissolve the short peptide stock solution (1mM dissolved in DMSO) in 1.33× Kinase Buffer, the final working concentration is 2μM; Z′-LYTE Tyr01 phosphorylated short peptide solution, dissolve 0.6μl stock solution (1mM dissolved in DMSO) in 149.4μl 1.33× kinase buffer; ATP solution, dissolve ATP stock solution (10mM aqueous solution) in 1.33× kinase buffer, and the final working concentration is 32μM; colorimetric solution, dissolve colorimetric solution B in colorimetric buffer, and the final working concentration is 1× colorimetric solution; 4× compound configuration, dilute the compound in 3-fold gradient concentration, and finally obtain a 4% DMSO aqueous solution containing different concentrations of the compound, and the final working concentrations are 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37nM, a total of 8 concentration points.

[1210] Specific experimental steps: This experiment has three control groups, each with 8 replicates, namely C1 100% inhibition group (without ATP), C2 0% inhibition group (with ATP), and C3 100% phosphorylation group. Add 2.5μl of gradient dilution compound to each well of the 384-well plate, double replicate, and add 4% DMSO solution to C1, C2, and C3 wells. Afterwards, remove the C3 well, add 2.5μl BTK enzyme solution to each remaining well, and let stand at 4°C for 30 minutes. Afterwards, remove the C3 well, add 2.5μl short peptide solution to each well, and add 5μl phosphorylated short peptide solution to each well of C3. Add 2.5μl 1.33× kinase buffer to each well of C1 and C3, and add 2.5μl ATP solution to each remaining well. Centrifuge briefly, shake the plate at 1000rpm for 30 seconds, and centrifuge briefly. Place the 384 plate in a shaking incubator away from light and incubate at room temperature for 1 hour. After the enzyme reaction is completed, add 5 μl of color development solution to each well, centrifuge briefly, shake the plate at 1000 rpm for 30 seconds, and centrifuge briefly. Place the 384 plate in a shaking incubator away from light and incubate at room temperature for 1 hour to complete the color development reaction.

[1211] 3. Detection

[1212] After color development, the 384-well plate was taken out and read using the Envision multi-mode plate reader with an emission wavelength of 405 nm and an excitation wavelength of 460 nm / 535 nm to detect the light signal. The 460 nm reading / 535 nm reading of each well was used as the signal value of each well.

[1213] 4. Calculation

[1214] The average signal value of C3 was taken as 100% phosphorylation, the average signal value of C1 was taken as 0% phosphorylation, and the average signal value of C2 was taken as the phosphorylation rate of the short peptide in the presence of BTK kinase. The inhibition rate (%) of each concentration of the compound was calculated according to the signal value of each well, and the IC was obtained by using the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited). 50 value.

[1215] The phosphorylation rate was calculated as follows:

[1216] Phosphorylation rate (%) = 100-100 × [(emission signal ratio × F 100％ )-C 100％ ] / {(C 0％ -C 100％ )+[transmitted signal ratio×(F 100％ -F 0％ )]}

[1217] Wherein, emission signal ratio = coumarin emission signal (460nm) / fluorescein emission signal (535nm); C 100％= average coumarin emission signal of C3; C 0％ = average value of coumarin emission signal of C1; F 100％ = average fluorescence emission signal of C3; F 0％ = Average value of fluorescein emission signal of C1.

[1218] The inhibition rate was calculated as follows:

[1219] Inhibition rate (%) = 100 × (C2 phosphorylation rate - detection well phosphorylation rate) / C2 phosphorylation rate

[1220] 5. Test results

[1221]

[1222]

[1223] Example 3

[1224] Determination of phosphorylated BTK in Ramos cells

[1225] 1. Reagents and Materials

[1226] Ramos cells: Ramos cells were purchased from the ATCC cell bank of the American Standard Biological Collection Center and cultured in a cell culture incubator at 5% CO2 and 37°C using PRMI1640 medium containing L-glutamine, 1.5 g / L sodium bicarbonate, 2.383 g / L HEPES solution, 0.11 g / L sodium pyruvate and 4.5 g / L glucose, plus 10% fetal bovine serum (FBS);

[1227] PRMI 1640 medium: GIBCO, catalog number A10491-01;

[1228] Fetal bovine serum (FBS): GIBCO, catalog number 100100-147;

[1229] Hank's balanced salt solution (HBSS): GIBCO, catalog number 14025-092;

[1230] Immunoglobulin M (IgM): Jackson Immuno, catalog number 109-006-129;

[1231] 3% hydrogen peroxide (3% H2O2): Sigma, product number 88597-100ML-F;

[1232] BTK phospho-Y223 HTRF kit: Cisbio, catalog number 63ADK017PEH;

[1233] Microplate reader: Envision, Perkin Elmer;

[1234] 384-well plate CulturPlateTM384: Perkin Elmer, catalog number 6007680

[1235] 96-well plate: Corning, catalog number 3799.

[1236] 2. Methods

[1237] Ramos cells were starved for 2 hours with 1% FBS in PRMI 1640 medium. The starved Ramos cells were diluted to 5.0 x 10 6 cells / ml, seeded into 96-well plates at 20 μL / well, i.e. 1.0 x 10 5 The cells were cultured in a cell culture incubator at 37°C and 5% CO2. After 1 hour of incubation, the test compound was diluted 4-fold with Hank's balanced salt solution to the corresponding concentration, and then 5 μL / well of the diluted test compound of different concentrations (the final concentration of the test compound was 3.0, 0.75, 0.188, 0.047, 0.012, 0.0029, 0.0007 and 0.00018 μM, the final concentration of DMSO was 0.3%, double wells) or 5 μL / well of the control solution (1.5% DMSO, 8 replicates) was added to the 20 μL / well cell culture system, and incubated together for one hour, and then 5 μL / well of a mixture of human immunoglobulin M (final concentration of 10 μg / mL) and hydrogen peroxide (final concentration of 3.3 mM) diluted with Hank's balanced salt solution was added to the test compound treatment wells and anti-human immunoglobulin M control treatment wells, 5 μL / well of Hank's balanced salt solution was added to the negative control treatment wells, and at 5% Incubate in a CO2, 37°C cell culture incubator for 10 minutes.

[1238] Add 10 μL / well cell lysis buffer to each well of the 96-well plate, mix well and lyse at room temperature for 30 minutes, pipette 16 μL / well lysis buffer into a new 384-well plate, then add 4 μL / well phosphorylated BTK antibody, centrifuge (1000 rpm) for 1 minute, shake for 1 minute, centrifuge (1000 rpm) for 1 minute, and finally put into a constant temperature incubator for overnight incubation. Detect on the next day.

[1239] 3. Detection

[1240] Take out the 384-well plate that has been incubated overnight in the thermostatic incubator and use the Envision microplate reader to detect the light signal at an emission wavelength of 320nm and an excitation wavelength of 665nm / 615nm. Multiply (the reading value of each well at 665nm / 615nm) by 10 4as the signal value for each well.

[1241] 4. Calculation

[1242] The average signal value of the wells with human immunoglobulin M (final concentration of 10 μg / mL) and hydrogen peroxide (final concentration of 3.3 mM) added but without the test compound was taken as the high value, and the average signal value of the wells without human immunoglobulin M stimulation and without the test compound was taken as the low value. The inhibition rate (%) of each concentration of the compound was calculated based on the signal value of each well, and then the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) was used to calculate and obtain the IC 50 value.

[1243] The inhibition rate was calculated as follows:

[1244] Inhibition rate (%) = 100% - {(test compound treated well - negative control treated well) / (anti-human immunoglobulin M control treated well - negative control treated well)} × 100%, where,

[1245] Wells treated with test compounds: indicate the signal values ​​of Ramos cells treated with anti-human immunoglobulin M, hydrogen peroxide and test compounds.

[1246] Wells treated with anti-human immunoglobulin M control: indicate the signal value of Ramos cells treated with anti-human immunoglobulin M and hydrogen peroxide but without the test compound.

[1247] Negative control treatment wells: represent the signal value of Ramos cells without test compound and without immunoglobulin stimulation.

[1248] 5. Test results

[1249]

[1250]

[1251] Example 4 Determination of B cell activity in rat whole blood

[1252] 1. Reagents and Materials

[1253] Peripheral whole blood of female Wistar rats;

[1254] Phosphate buffered saline (PBS): GIBCO, catalog number C20012500BT;

[1255] PE anti rat B220: eBioscience, catalog number 12-0460-82;

[1256] FITC anti rat CD86 antibody: eBioscience, catalog number 11-0860-82;

[1257] 10× lysis buffer: BD Biosciences, catalog number 555899;

[1258] IC fixation buffer: Invitrogen, catalog number 00-8222-49;

[1259] 96-well U-bottom plate: Nunc, catalog number 163320;

[1260] 96-well V-bottom plate: Nunc, catalog number 49952;

[1261] Dimethyl sulfoxide (DMSO): Sigma-Aldrich, product number 34869-4L;

[1262] Mouse anti-rat IgD: Bio-rad, catalog number MCA190;

[1263] Flow cytometer: BD FACS Canto II, BD.

[1264] 2. Methods

[1265] When the compound activity is measured, the peripheral whole blood collected from rats is added to a 96-well plate at 80 μL / well and cultured in a cell culture incubator at 5% CO2 and 37°C. Half an hour later, the test compound is diluted with PBS and diluted to the corresponding concentration in a 3-fold gradient, and then the test compound of different concentrations after dilution is added to the rat whole blood culture system at 10 μL / well (the final concentration of the test compound is 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014 and 0.0005 μM, the final concentration of DMSO is 0.3%, double wells) or 10 μL / well control solution (0.3% DMSO, 6 replicates) is added to the corresponding wells and cultured in a cell culture incubator for one hour. Then, add 10 μL / well of anti-rat immunoglobulin D diluted with PBS (final concentration of 10 μg / mL) to the test compound-treated wells and anti-rat immunoglobulin D control-treated wells, or 10 μL / well PBS to the negative control-treated wells, mix well, and continue to culture in a cell culture incubator at 5% CO2 and 37°C for 18 hours.

[1266] On the next day, the 96-well plate was taken out, and a flow cytometry antibody mixture diluted with PBS was added to each well (the final concentration of anti-rat B220PE antibody was 1 μg / mL and the final concentration of anti-rat CD86 FITC antibody was 1 μg / mL). After incubation in the dark for 30 minutes, 50 μL of blood was drawn from each well and added to the newly prepared 500 μL lysis buffer to lyse the red blood cells, shaken for 20 minutes, centrifuged to remove the supernatant, and then washed, fixed, and detected on a flow cytometer.

[1267] 3. Detection

[1268] The activation of B cells in the samples was determined by flow cytometry.

[1269] 4. Calculation

[1270] The average value of the activated B cell ratio in the wells with anti-rat immunoglobulin D but without the test compound was used as the anti-rat immunoglobulin D control treatment wells, and the average value of the activated B cell ratio in the wells without immunoglobulin D stimulation and without the test compound was used as the negative control treatment wells. The inhibition rate (%) of each concentration was calculated based on the B cell activation ratio in each well, and then the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) was used to calculate and obtain the IC 50 value.

[1271] The inhibition rate was calculated as follows:

[1272] Inhibition rate (%) = 100% - {(test compound treated well - negative control treated well) / (anti-rat immunoglobulin D control treated well - negative control treated well)} × 100%, where,

[1273] Wells treated with the test compound: indicate the activation ratio of B cells in rat whole blood treated with anti-rat immunoglobulin D and the test compound.

[1274] Wells treated with anti-rat immunoglobulin D control: indicate the activation ratio of B cells in rat whole blood treated with anti-rat immunoglobulin D but without the test compound.

[1275] Negative control treatment wells: represent the activation ratio of B cells in rat whole blood without test compound and without immunoglobulin stimulation.

[1276] The above test shows that the compound of the present invention has a strong ability to inhibit the activation of B cells in rat whole blood.

[1277]

[1278]

[1279] Example 5 Liver microsome stability test

[1280] 1. Experimental materials:

[1281] Male CD-1 mouse mixed liver microsomes and male SD rat mixed liver microsomes were purchased from Bioreclamation IVT, USA.

[1282] Phenacetin, glucose-6-phosphate dehydrogenase (G-6-PDH) and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Sigma-Aldrich, USA. Glucose-6-phosphate (G-6-P) was purchased from Shanghai Libo Chemical Technology Co., Ltd.

[1283] 2. Solution preparation:

[1284] 10 mM stock solution of the test compound: Weigh a certain amount of the test compound, dissolve it in an appropriate volume of DMSO, and prepare a stock solution with a concentration of 10 mM for later use.

[1285] Reaction termination solution: Dissolve an appropriate amount of the internal standard compound phenacetin in acetonitrile to prepare a reaction termination solution with a concentration of 1000 ng / mL and keep it at room temperature for use.

[1286] 3. Experimental methods:

[1287] The stock solution of the compound to be tested is diluted to 0.1mM (the concentration of the compound in the final reaction system is 1μM) with an organic solvent (usually a mixture of acetonitrile, methanol and water in different proportions, depending on the solubility of the compound. If necessary, 1N hydrochloric acid or 1N sodium hydroxide will be added to assist dissolution) and the concentration ratio of the organic solvent in the incubation system does not exceed 1% (the proportion of DMSO is required to be no more than 0.1%). An appropriate amount of 100mM NADP, 500mM G-6-P and 100Unit / mL G-6-PDH are mixed and diluted with ultrapure water (the final system contains 1mM NADP, 5mM G-6-P and 1Unit / mL G-6-PDH). After preparation, it is pre-incubated in a 37°C water bath for 10 minutes and then placed on ice for use as a NADPH regeneration solution. 20mg / mL liver microsome solution was mixed with 200mM phosphate buffer and diluted with ultrapure water to obtain a liver microsome solution containing 2.5mg / mL liver microsome (the final concentration in the reaction system was 0.5mg / mL) and 50mM phosphate buffer. The diluted liver microsome solution was mixed with 0.1mM compound solution, and an appropriate volume of 100mM EDTA, 300mM MgCl2 solution, 200mM phosphate buffer (the final system was 3mM MgCl2, 1mM EDTA and 50mM phosphate buffer) and water were added. Finally, NADPH regeneration solution was added, and then placed in a 37℃ water bath to start the reaction. The reaction time was 30 minutes, and the reaction was terminated by adding glacial acetonitrile reaction stop solution containing internal standard. The 0-minute sample was not incubated in a 37℃ water bath. In addition, unlike the 30-minute sample, the glacial acetonitrile reaction stop solution containing internal standard was added first, and then the NADPH regeneration solution was added. The sample to which the internal standard solution was added was vortexed and mixed, and then centrifuged at 4400 rpm for 10 minutes. The supernatant was diluted ten times with 50% methanol and analyzed by LC-MS / MS.

[1288] 4. Analytical methods:

[1289] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis was used to determine the concentration of the compound in the sample. The peak area ratio of the compound and the internal standard was used as an indicator to calculate the percentage of the remaining compound after 30 minutes of incubation compared with the 0-minute sample to evaluate the metabolic stability of the compound.

[1290] Instruments: API4500, API4000 or LTQ mass spectrometer; liquid phase is UHPLC system (Shimadzu LC-30AD, model Nexra X2) including liquid delivery unit, column oven, detector and autosampler; or Agilent 1200 dual pump series HPLC and CTC autosampler.

[1291] Column: Waters XSELECT Hss T3 C18 (2.5μm, 2.1×50mm) or CAPCELLPAK MG (5μm, 2.0×50mm)

[1292] Mobile Phase:

[1293] A: Water containing 0.1% FA (formic acid) (with or without 0.1% ACN (acetonitrile))

[1294] B: Acetonitrile containing 0.1% FA (formic acid).

[1295] According to the above tests, the stability of the liver microsomes of mice and rats of compounds 2, 9, 19, 22, 34, 44, 56, 58, 63, 64, 74, 75, 78, and 79 of the present invention is better than that of the reference compound GDC-0853.

[1296]

[1297] *RLM, rat liver microsomes.

[1298] **MLM, mouse liver microsomes, mouse liver microsomes.

[1299] Example 6 Pharmacokinetics Study in Mice

[1300] 1. Experimental materials:

[1301] Solutol HS15 was purchased from BASF, Germany, ethanol (anhydrous) was purchased from Nanjing Chemical Reagent Co., Ltd., physiological saline was purchased from Huayu (Wuxi) Pharmaceutical Co., Ltd., and dimethyl sulfoxide (DMSO) and sodium carboxymethyl cellulose 800-1200 (CMC-Na) were purchased from Sinopharm Chemical Reagent Co., Ltd.

[1302] 2. Solution preparation:

[1303] Preparation of ethanol / Solutol mixed solution (1:1, v / v): Take an appropriate amount of Solutol HS15 and place it in a centrifuge tube and place it in a 37°C water bath until it dissolves. After it is placed on the operating table to room temperature, take 1 mL of Solutol into a centrifuge tube containing 1 mL of ethanol and mix thoroughly.

[1304] Preparation of intravenous preparation: Accurately weigh appropriate amounts of compound 19 powder and GDC-0853 and place them in centrifuge tubes, then add appropriate amount of dimethyl sulfoxide and vortex until completely dissolved to obtain a stock solution. Take an appropriate amount of the stock solution and place it in a blank centrifuge tube, then add an appropriate amount of the ethanol / solutol mixed solution prepared in advance, vortex, then add an appropriate amount of physiological saline and mix thoroughly until a transparent liquid.

[1305] Preparation of oral administration preparation: Accurately weigh appropriate amounts of compound 19 powder and GDC-0853 and place them in centrifuge tubes respectively, add appropriate amount of CMC-Na adjusted to pH 2.1 with hydrochloric acid, vortex and sonicate until a uniform suspension liquid is obtained.

[1306] 3. Animal Dosing and Sample Collection:

[1307] Male ICR mice were purchased from Shanghai Lingchang Biotechnology Co., Ltd. 18 mice were randomly divided into intravenous administration group and oral administration group. Mice fasted overnight before administration, fasted within 4 hours after administration but had free access to water, and were free to eat and drink 4 hours later. After anesthesia with isoflurane, blood was collected from the retroorbital venous plexus into anticoagulant centrifuge tubes, which were placed in an ice box until centrifugation to separate plasma.

[1308] 4. Sample analysis:

[1309] After pretreatment, the plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The instrument model was API5500, the analytical column was Waters XSELECT HSS T3 C18 column (50×2.1mm, 2.5μm), and the mobile phase was deionized water containing 0.1% formic acid and 0.1% acetonitrile as the aqueous phase and acetonitrile containing 0.1% formic acid as the organic phase. Determine the concentration of the compound in the sample. First, establish a standard curve, use the peak area ratio of the compound and the internal standard in the standard curve as an indicator, and use the quadratic regression equation to fit the theoretical concentration of compound 19 and the peak area ratio of compound 19 and the internal standard to obtain a regression equation. By measuring the peak area ratio of the compound and the internal standard of the sample to be tested, the sample concentration is calculated according to the standard curve. The same method is used to determine the concentration of GDC-0853 in the sample.

[1310] 5. Data Analysis:

[1311] The pharmacokinetic parameters of compound 19 and GDC-0853 in mice were calculated using the average drug concentration in plasma at each time point using the Thermo Kinetica software with a non-compartmental model.

[1312] According to the above test, compound 19 of the present invention has a higher plasma exposure (AUC 0-∞ ), which is about 1.7 times that of the reference GDC-0853. The maximum plasma drug concentration (C max ) mean values ​​were similar (compound 19 was 3807 ng / mL, GDC-0853 was 4063 ng / mL), but had a longer elimination half-life (T 1 / 2) (Compound 19 elimination half-life is 2.7h, GDC-0853 is 1.5h). After oral administration, the plasma drug concentration of compound 19 detected at 8h was about 3.9 times that of GDC-0853 (compound 19 was 555ng / mL, GDC-0853 was 143ng / mL). The plasma drug concentration of compound 19 was still detectable at 24h (average concentration 8.5ng / mL), while the plasma drug concentration of GDC-0853 at 24h was already below the detection limit (2.4ng / mL). The test results are shown in the following table:

[1313] Compound 19 GDC-0853 Dosage (mg / kg) 10 10 <![CDATA[AUC 0-∞ (ng / mL*h)]]> 17806 10268 <![CDATA[T 1 / 2 (h)]]> 2.7 1.5 <![CDATA[C max (ng / mL)]]> 3807 4063 <![CDATA[C 8h (ng / mL)]]> 555 143 <![CDATA[C 24h (ng / mL)]]> 8.5 <2.4

[1314] Example 7 Evaluation of the in vivo efficacy of the compounds of the present invention on subcutaneous transplanted TMD8 cells

[1315] Objective: To study the antitumor activity of compound 19 of the present invention in a TMD8 mouse subcutaneous transplant tumor model.

[1316] Methods: Human diffuse large cell lymphoma TMD8 cells (authorized by Tokyo Medical and Dental University) were cultured in RPMI1640 medium containing 10% fetal bovine serum. Tumor cells were suspended in RPMI1640 and mixed with Matrigel (purchased from Corning, USA) at a ratio of 1:1. 7 The cells were implanted subcutaneously into the right flank of male Balb / c nude mice (Shanghai Lingchang Biotechnology Co., Ltd.) treated with cyclophosphamide (200 mg / kg, intraperitoneal injection 24 h before inoculation). When the average tumor volume reached about 400 mm 3 At 14:00, mice were randomly divided into the following 5 groups according to tumor volume: vehicle control group, positive reference ibrutinib (Ibrutinib, Shanghai Tianxi Chemical Co., Ltd.) at a dose of 50 mg / kg, reference GDC-0853 at a dose of 10 mg / kg, compound 19 at a dose of 10 mg / kg, and compound 19 at a dose of 30 mg / kg. There were 8 animals in each group. The solvent for ibrutinib was 0.5% sodium methylcellulose solution, and the solvent for GDC-0853 and compound 19 was 0.5% hydroxypropyl methylcellulose solution (pH = 3). All drugs were administered orally by gavage once a day, and the vehicle control group was gavaged with 0.5% hydroxypropyl methylcellulose solution (pH = 3).

[1317] Tumor volume was measured regularly (tumor volume = 0.5 × long diameter × short diameter). 2 ) and mouse body weight. Statistical analysis was performed on the changes in tumor volume and body weight. P < 0.05 was considered statistically significant, and p < 0.01 was considered statistically extremely significant. The antitumor activity was evaluated by tumor growth inhibition rate.

[1318] Tumor growth inhibition rate (TGI%) = 100% × (1-(TV Dt( Treatment Group ) -TV D0( Treatment Group ) ) / (TV Dt( Control group ) -TV D0( Control group ) ))

[1319] Relative body weight (RBW%) = BW Dt / BW D0 ×100%

[1320] Among them, TV D0 TV represents the tumor volume measured for the first time in each group, that is, the tumor volume before drug administration. Dt Indicates the tumor volume measured on the subsequent day; BW D0 Indicates the weight of the animals obtained when they were first weighed in each group, i.e., the weight of the animals before administration; BW Dt Indicates the weight of the animal when weighed on the subsequent day.

[1321] Results: The experimental results are shown in Table 1 and Figure 1 shown.

[1322] 21 days after administration, compared with the vehicle control group, the inhibition rate of tumor growth by ibrutinib at a dose of 50 mg / kg was 42.4%; the inhibition rate of GDC-0853-10 mg / kg was -12.8%; the compound 19 of the present invention showed a dose-dependent anti-tumor effect, and its tumor growth inhibition rates of 10 mg / kg and 30 mg / kg were 76.5% and 114%, respectively, which were statistically significantly different from the vehicle control group. And the tumors of 8 mice in the high-dose 30 mg / kg administration group of compound 19 disappeared completely. In addition, the changes in tumor volume in the two dose groups of compound 19 were statistically significant or extremely significant compared with the two reference substances, indicating that at the tested dose, the anti-tumor effect of compound 19 of the present invention was significantly better than that of the reference substance. In this experiment, the body weight of mice in all administration groups did not decrease significantly compared with before administration, indicating that the animals were well tolerated at the tested dose.

[1323] The above results demonstrate that compound 19 of the present invention exhibits a dose-dependent anti-tumor growth effect in the TMD8 subcutaneous transplant tumor model, and once-daily administration of 30 mg / kg can cause complete disappearance of the tumor.

[1324] Table 1 Effects of each group on the growth of TMD8 subcutaneous transplanted tumors

[1325]

[1326]

[1327] Compared with the vehicle group: **p<0.01; compared with the ibrutinib treatment group: #p<0.05, ##p<0.01; compared with the GDC-0853 treatment group: $$p<0.01.

[1328] Example 8 Evaluation of the efficacy of BTK target inhibition in vivo

[1329] Objective: To study the inhibitory effect of the compounds of the present invention on B cell activation in vivo by inducing activation of B cells in mouse whole blood with anti-IgD antibodies, thereby determining the BTK target inhibitory effect of the compounds of the present invention in vivo.

[1330] Methods: C57BL / 6 mice (female, 18-20 g, purchased from Shanghai Lingchang Biotechnology Co., Ltd.) were grouped according to Table 2.

[1331] Table 2 In vivo drug administration grouping information

[1332]

[1333] After administration, the animals in each group were placed in CO2 anesthesia at the set time, blood was collected from the inner canthus of the orbit, and heparin was used for anticoagulation; 90 μL of whole blood from each group of mice was added to a 96-well culture plate, and anti-mouse IgD antibody (BIO-RAD, catalog number MCA4693) was added to each well to a final concentration of 0.01 μg / μL (each drug treatment group and anti-IgD antibody induced vehicle group, respectively); 90 μL of whole blood from mice in the vehicle group was added to the 96-well culture plate, and PBS (phosphate buffered saline, GIBCO, catalog number C20012500BT) was added to each well to a final concentration of 0.01 μg / μL (i.e., the vehicle control group); the groups were mixed evenly and incubated in a 37°C / 5% CO2 incubator for 4 hours. Blood from mice in the drug treatment group was centrifuged to separate plasma for blood drug concentration analysis.

[1334] Fluorescently labeled antibodies Anti-CD19-APC (BD Biosciences, Catalog No. 550992) and Anti-CD69-PE (BD Biosciences, Catalog No. 553237) were added to the cultured whole blood, mixed evenly, and incubated at room temperature in the dark for 30 minutes; 50 μL of sample was transferred to a 96-well deep V-shaped culture plate containing 380 μL of freshly prepared lysis buffer (BD Biosciences, Catalog No. 555899), shaken, and placed at room temperature in the dark for 15 minutes to remove red blood cells; 400 μL of flow buffer (2% FBS / PBS, FBS: fetal bovine serum, GIBCO, Catalog No. 100100-147; PBS: GIBCO, Catalog No. C20012500BT) was added, and centrifuged at 1200 rpm and 4°C for 8 minutes; the supernatant was removed, and the cell pellet was washed twice with flow buffer and centrifuged; the cells were resuspended with 400 μL of flow buffer and analyzed by BDFACS. LSRFortessa flow cytometer was used to detect the expression of CD69+ in CD19+ positive cells (B cells) and analyze the data.

[1335] Calculation of B cell activation rate:

[1336] B cell activation rate = CD69 + CD19 + Percentage of double positive B cells / CD19 + Percentage of single positive B cells

[1337] Calculation of inhibition rate:

[1338] Inhibition rate = (B cell activation rate percentage of anti-IgD antibody-induced vehicle group-B cell activation rate percentage of drug-treated group) / (B cell activation rate percentage of anti-IgD antibody-induced vehicle group-B cell activation rate percentage of vehicle control group) × 100%

[1339] Data are expressed as mean ± standard error. The p value was calculated by one-way analysis of variance and Dunnett's test for the comparison between each drug treatment group and the anti-IgD antibody-induced vehicle group using Graphpad Prism, and the p value was calculated by unpaired t test for the comparison between the two drug treatment groups.

[1340] Results: The experimental results are as follows Figure 2 As shown in Table 3.

[1341] In this experiment, 16 hours after administration, the inhibition rate of B cell activation by GDC-0853 20 mg / kg was 9%. The inhibition rate of B cell activation by compound 232 of the present invention at a dose of 20 mg / kg was 89%, which was statistically significantly different from the anti-IgD antibody-induced vehicle group.

[1342] Table 3 Effect of in vivo administration on B cell activation in whole blood of mice induced by anti-IgD antibody

[1343]

[1344] #### indicates p < 0.0001 compared with the vehicle control group;

[1345] *** indicates p < 0.001 compared with the anti-IgD antibody-induced vehicle group;

[1346] & indicates p<0.05 compared with the reference GDC-0853-treated group.

[1347] The in vivo BTK target inhibitory effects of compound 19 and compound 176 in PCT patent application WO2013067274 (referred to as "reference compound 176") were further determined according to the above method and grouped as shown in Table 4 below.

[1348] Table 4 In vivo drug administration grouping information

[1349]

[1350]

[1351] Results: The experimental results are as follows Figure 3 As shown in Table 5.

[1352] In this experiment, 16 hours after administration, the inhibition rate of reference compound 176 on B cell activation at a dose of 5 mg / kg was 48%; the inhibition rate of compound 19 of the present invention on B cell activation at a dose of 5 mg / kg was 80%, which was statistically significantly different from the anti-IgD antibody-induced solvent group.

[1353] Table 5 Effect of in vivo administration on B cell activation in whole blood of mice induced by anti-IgD antibody

[1354]

[1355] #### indicates p < 0.0001 compared with the vehicle control group;

[1356] ** indicates p < 0.01 compared with the anti-IgD antibody-induced vehicle group;

[1357] **** indicates p < 0.0001 compared with the anti-IgD antibody-induced vehicle group;

[1358] & indicates p<0.05 compared with the compound 19-treated group.

[1359] Example 9 Therapeutic effect of the compounds of the present invention on type II collagen-induced arthritis model in rats

[1360] Research Methods

[1361] An appropriate amount of bovine type II collagen (CII, Chondrex (Redmond, WA, USA), Cat#20021) was weighed and dissolved in 0.1 molar acetic acid (SPGC Sinopharm Chemical Reagent Co., Ltd (Shanghai, PRChina), Cat#:10000218.) to prepare a solution with a concentration of 6 mg / mL. The solution was stirred overnight at 4°C, and then an equal volume of Freund's incomplete adjuvant (Sigma-Aldrich. (St. Louis, MO, USA), Cat#:SLBW0366.) was added and fully emulsified to prepare an emulsion with a CII concentration of 3 mg / mL.

[1362] Female Lewis rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (certificate number 1100111911070522, initial body weight 110-130 g), and three rats were randomly selected as the normal group, and the remaining rats were grouped according to the following table. On the 0th day of the first immunization, rats other than the normal group were anesthetized with isoflurane (Hebei Yipin Pharmaceutical Co., Ltd., Lot: C002170601.), disinfected with 75% alcohol, and injected intradermally with 0.2 mL of emulsion at the base of their tails. On the 7th day of the second attack, 0.2 mL of emulsion was injected intradermally in the same manner as above.

[1363] Table 6 Modeling and drug administration group information

[1364]

[1365] After grouping and modeling, the normal group was not given any medication, and the rats in the other groups were given control solvent, reference substance GDC-085 34 mg / kg, and compound 19 orally once a day at different doses until the end of the experiment. Grouping and medication schedule are shown in Table 6.

[1366] Paw volume was measured starting from day 8 after immunization, and the volume of the left and right hind paws (V) was measured every day after the increase in paw volume was detected.

[1367] The paw volume of the left and right hind limb joints of each animal was measured, and the average paw volume (APV, which shows the changes in animal paw swelling) was calculated according to the following formula:

[1368] Average foot volume APV = (V left +V right ) / 2

[1369] The effect of drugs on mean paw volume was analyzed by repeated measure ANOVA with Dunnett's multiple comparison test using GraphPad, and p values ​​were calculated. ## p<0.01 indicates a statistically significant difference compared with the normal group, **p<0.01 indicates a statistically significant difference compared with the vehicle control group.

[1370] The average paw volume of each animal before administration was the baseline (or considered to have 100% inhibition of inflammation). The average paw volume change (APS) of each animal was calculated according to the following formula, where APV d1 is the average paw volume on day 1, APV dt is the average foot volume for administration on day t:

[1371] Average foot volume change (APS) dt =(APV dt –APV d1 )

[1372] The area under the curve (AUC) of the mean foot volume change is the area under the curve of the joint score change calculated by the trapezoidal method, and the calculation formula is:

[1373] AUC APS =1 / 2×(APS d1 +APS d2 )×(d2-d1)+1 / 2×(APS d2 +APS d3 )×(d3-

[1374] d2)+……+1 / 2×(APS dn +APS d(n-1) )×(d n -d n-1 )

[1375] The inhibition rate (IR) of the area under the curve AUC )Calculation formula:

[1376] Inhibition rate IR AUC % = (mean AUC of the model group APS -AUC in drug-treated group APS ) / (Average AUC of the model group APS -Average AUC of normal group APS )×100%

[1377] ED 50 The inhibition rate was calculated using the area under the curve (AUC) of the mean foot volume change using the XLfit software, and the model used was "log (inhibitor) vs. response-Variable slope":

[1378]

[1379] result

[1380] Lewis rats began to develop the disease on the 11th day after the first immunization with bovine type II collagen. As the disease progressed, the foot volume of the right hind limb gradually increased. The foot volume growth of the vehicle control group was compared with that of the normal group, and there was a statistically significant difference ( ## p<0.01). GDC-0853 significantly reduced paw volume compared with the vehicle control group (**p<0.01). Once-daily oral administration of compound 19 solution at 0.06, 0.25, 1, 4 and 16 mg / kg QD inhibited paw swelling in a dose-dependent manner, with inhibition rate under the curve (IR AUC ) were 58.8%, 91.3%, 95.9%, 93.2% and 97.5% respectively; the minimum effective dose was 0.06 mg / kg / day, ED 50 < 0.06 mg / kg / day, ED 90 =0.26mg / kg / day. The efficacy of 0.25mg / kg / day compound 19 (inhibition rate of area under the curve 91.3%) and 4mg / kg / day GDC-0853 (inhibition rate of area under the curve 87.1%) were comparable, with no statistical difference between the two. Both significantly improved foot volume swelling compared with the model group (p<0.001, paired t-test by Graphpad). There was a statistical difference between 4mg / kg / day compound 19 (inhibition rate of area under the curve 93.2%) and the same dose of GDC-0853 (inhibition rate of area under the curve 87.1%), significantly improving the improvement of foot volume swelling (p<0.001, paired t-test by Graphpad). See the results. Figure 4 .

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 C 1-6 alkyl; X3 and X4 are independently C or N; Y1 and Y2 are independently CR 10 or N; R1 and R2 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and phenyl; or R1, R2 together with the carbon atom to which they are attached form the following structure: in: R6 is independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl and C 1-6 or two R6 together with the carbon atom to which they are commonly attached form a 3-6 membered cyclic hydrocarbon group; m is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; Z is N or CR7; R7 is selected from hydrogen, deuterium, C 1-6 Alkyl, halogen and C 1-6 Haloalkyl; Or R1, R2 together with the carbon atom to which they are attached form Provided that R3 is halogen or X1 and X2 are not CH at the same time; R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl; R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, -(C 1-3 Alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 Alkyl or C 1-3 The alkyl groups are each optionally substituted with one or more deuterium or halogen; Cy Where: R 11 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more deuterium or halogen; U, V and W are each independently N or CR 12 ; R 12 is hydrogen, deuterium or a halogen; R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, -C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted with one or more groups selected from the following: 1) Halogen; 2) Oxo; 3) – CN; 4) C 1-6 alkyl; 5) C 2-6 alkenyl; 6) C 2-6 Alkynyl; 7) C 1-6 Alkoxy; 8) C 1-6 Haloalkyl; 9)-(C 1-6 Alkyl)-OH; 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl); 11) C 3-6 Cycloalkyl; 12) a 3-12 membered heterocyclic group, which is optionally substituted by one or more groups selected from the following: Deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclyl groups are each optionally substituted by one or more groups selected from the group consisting of deuterium, halogen, -NH2, -OH, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2 and -NH(C 3-6 Cycloalkyl); 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more groups selected from the following: Halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 14) phenyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N-(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by one or more groups selected from the following: deuterium, halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cyclic hydrocarbon), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH; and 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 Alkyl)-OH and -(C 1-6 alkyl)-O-(C 1-6 alkyl); R 10 For hydrogen, deuterium, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl; Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure: And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R1, R2 together with the carbon atoms to which they are attached form That is, the compound is a compound of formula (IA):

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R1, R2 together with the carbon atoms to which they are attached form X3 is N, X4 is C, Y1 is CH, Cy is And the compound is a compound of formula (II): in: X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl; Y2 is CH or N; R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl; R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens; W is N or CR 12 , R 12 is hydrogen or halogen; R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following: 1) Halogen; 2) Oxo; 3) – CN; 4) C 1-6 alkyl; 5) C 2-6 alkenyl; 6) C 2-6 Alkynyl; 7) C 1-6 Alkoxy; 8) C 1-6 Haloalkyl; 9)-(C 1-6 Alkyl)-OH; 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl); 11) C 3-6 Cycloalkyl; 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups; 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl); R6 is halogen, C 1-6 Alkyl or hydroxyl; and m is 0, 1, 2 or 3.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein R1, R2 together with the carbon atoms to which they are attached form X3 is N, X4 is C, Y1 is CH, Cy is And the compound is a compound of formula (III): in: X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl; Y2 is CH or N; R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl; R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens; U and V are each independently selected from N or CH; R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following: 1) Halogen; 2) Oxo; 3) – CN; 4) C 1-6 alkyl; 5) C 2-6 alkenyl; 6) C 2-6 Alkynyl; 7) C 1-6 Alkoxy; 8) C 1-6 Haloalkyl; 9)-(C 1-6 Alkyl)-OH; 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl); 11) C 3-6 Cycloalkyl; 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups; 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl); R6 is halogen, C 1-6 Alkyl or hydroxyl; m is 0, 1, 2 or 3; and R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl; Provided that the 3-12 membered heterocyclic group, when substituted, is not substituted by C at both the 2-position and the 6-position 1-6 Alkyl substituted piperazin-1-yl.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: Y2 is CH.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R3 is hydrogen or halogen.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R4 is C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 Alkyl)-O- (C 1-3 alkyl) or -CHO, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R3 is hydrogen, and R4 is -(C 1-3 Alkyl)-OH.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from in: R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl); n is 0, 1 or 2; R 22 and R 23 are independently selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl); R 24 Selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), or -C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group; A1, A2 and A3 are each independently CH or N; and R 13 Selected from: 1) Hydrogen; 2) C 1-6 alkyl; 3) C 1-6 Alkoxy; 4) Halogen; 5) C 3-6 Cycloalkyl; 6) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups; 7) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups; 8)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by -(C 1-6 Alkyl)-OH substituted, the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; and 9)–C(O)NR b 'R b ”, where R b ' and R b Together with the N atoms to which they are connected, they form 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution; Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure: And the Cy is When the 3-12 membered heterocyclic group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R 13 is piperazinyl, which is optionally substituted by one or more selected from C 1-6 Alkyl and 4-5 membered heterocyclic groups are substituted by substituents; Provided that, when R1, R2 and the carbon atoms to which they are attached form the following structure: And the Cy is When the piperazinyl group is substituted, the 2-position and 6-position are not simultaneously substituted by C 1-6 Alkyl substituted piperazin-1-yl.

12. A compound as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from in: R 24 , R 24 '、R 25 , R 25 '、R 27 and R 27 'are independently selected from hydrogen, oxo and C 1-6 alkyl; R 26 C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) or tetrahydrofuranyl; R 28 C 1-6 Alkoxy; R 29 is hydrogen or -(C 1-6 Alkyl)-OH; R 30 C 1-6 alkyl; A1, A2 and A3 are each independently CH or N.

13. A compound as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is in: A1, A2 and A3 are each independently CH or N, and R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

15. A compound as described in any one of claims 13-14, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: A1, A2 and A3 are all CH, or A1 is N and A2 and A3 are all CH, or A3 is N and A1 and A2 are all CH.

16. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from: Among them, R 21 C 1-6 Alkyl; R 22 Selected from hydrogen, C 1-6 alkyl and 4-membered heterocyclic group; A1 and A2 are CH; and R 24 and R 24 'are independently selected from hydrogen and C 1-6 alkyl.

17. A compound according to any one of claims 4 to 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: yes Where R 11 C 1-6 Alkyl or C 1-6 Deuterated alkyl.

18. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1 and X2 are CH, or one of X1 and X2 is N and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 alkyl)-OH; U is CH, V is N or CH, and R 11 C 1-3 Alkyl; R5 is selected from Where: R 24 and R 24 'are independently selected from hydrogen, oxo and C 1-6 Alkyl, A1 and A2 are both CH, or A1 is N and A2 is CH; R6 is C 1-6 alkyl; and m is 0 or 2.

19. A compound according to any one of claims 4 to 18, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: U and V are both CH, and R 11 It is methyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R6 is C 1-3 An alkyl group; and m is 2.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R6 together with the five-membered ring to which it is connected forms 22. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1 and X2 are CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 U and V are both CH, and R 11 is methyl; R5 is selected from Where: R 24 C 1-3 Alkyl, A1 and A2 are CH; R6 together with the five-membered ring to which it is connected forms 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: The compound is a compound of formula (IB) 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound is a compound of formula (IV): in: X1 and X2 are independently CH or N; or, X1 is N, X2 is CR 14 , where R 14 Selected from C 1-6 alkyl; Y2 is CH or N; R3 is hydrogen, deuterium, halogen or C 1-6 Haloalkyl; R4 is hydrogen, halogen, -CN, C 1-6 Alkyl, -(C 1-3 Alkyl)-OH, -(C 1-3 Deuterated alkyl)-OH, -(C 1-3 alkyl)-O-(C 1-3 Alkyl), -O-(C 1-3 alkyl), -CHO, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2 or 3-hydroxy-oxetane-3-yl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens; U and V are each independently selected from N or CH; Z is N or CH; R5 is hydrogen, C 1-6 Alkyl, -C(O)-(C 1-6 alkyl), -C(O)-(C 3-6 Cycloalkyl), -C(O)-phenyl, C(O)NH-(C 1-6 alkyl), -C(O)NH-(C 3-6 Cycloalkyl), -C(O)N(C 1-6 alkyl)2, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl are each optionally substituted by one or more groups selected from the following: 1) Halogen; 2) Oxo; 3) – CN; 4) C 1-6 alkyl; 5) C 2-6 alkenyl; 6) C 2-6 Alkynyl; 7) C 1-6 Alkoxy; 8) C 1-6 Haloalkyl; 9)-(C 1-6 Alkyl)-OH; 10)-(C 1-6 alkyl)-O-(C 1-6 alkyl); 11) C 3-6 Cycloalkyl; 12) 3-12 membered heterocyclic group, which is optionally substituted by one or more selected from halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 alkyl)-OH, 4-6 membered heterocyclic group, 4-6 membered fluorinated heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups; 13) 5-6 membered monocyclic heteroaryl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-O-(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 14) phenyl, which is optionally substituted by one or more selected from halogen, -CN, -(C 1-6 Alkyl)-CN, -(C 1-6 Alkyl)-OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-O(C 1-6 Alkyl), -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 cycloalkyl) and 4-6 membered heterocyclic group; 15)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by one or more -(C 1-6 alkyl)-OH is substituted by a substituent, wherein the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; 16)-C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are commonly attached, form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more selected from halogen, -OH, C 1-6 Alkyl, -(C 1-6 Alkyl)-NH2, -(C 1-6 Alkyl)-NH(C 1-6 Alkyl), -(C 1-6 Alkyl)-N(C 1-6 Alkyl)2, -(C 1-6 Alkyl)-NH(C 3-6 Cycloalkyl) and -(C 1-6 alkyl)-OH is substituted with a substituent; and 17)-C(O)R c , where R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl); R6 is halogen, C 1-6 Alkyl or hydroxyl; m is 0, 1, 2 or 3; and R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Deuterated alkyl.

25. A compound as described in any one of claims 23-24, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: Y2 is CH.

26. A compound as described in any one of claims 23 to 25, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R5 is selected from: in: R 21 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and -(C 1-6 alkyl)-O-(C 1-6 alkyl); n is 0, 1 or 2; R 22 and R 23 are independently selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl); R 24 Selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), or -C(O)NR b 'R b ”, where R b ' and R b "Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group; A1, A2 and A3 are each independently CH or N; and R 13 Selected from: 1) Hydrogen; 2) C 1-6 alkyl; 3) C 1-6 Alkoxy; 4) Halogen; 5) C 3-6 Cycloalkyl; 6) 4-8 membered heterocyclic group, which is optionally substituted by one or more selected from oxo, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkyl)-CN, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group and deuterated 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally substituted with one or more -OH groups; 7) phenyl, which is optionally substituted by one or more substituents selected from 4-6 membered heterocyclic groups; 8)-NR a 'R a ”, where R a ' and R a " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl) and 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl is optionally substituted by one or more -(C 1-6 Alkyl)-OH substituted, the C 1-6 The alkyl group is optionally substituted with one or more -NR e 'R e "Replace, R e ' and R e " are independently selected from hydrogen, C 1-6 Alkyl, -(C 1-6 alkyl)-OH and 4-6 membered heterocyclic group; and 9)-C(O)NR b 'R b ”, where R b ' and R b " together with the nitrogen atom to which they are commonly attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by one or more C 1-6 Alkyl substitution.

27. A compound as described in any one of claims 23-26, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1 and X2 are both CH, or one of X1 and X2 is N and the other is CH; Y2 is CH; R3 is hydrogen; R4 is -(C 1-3 Alkyl)-OH; Z is CH; U is CH, V is N or CH; R5 is wherein A1 and A2 are independently CH or N, and R 13 Serves 4- 6-membered heterocyclic group, which is optionally substituted by one or more selected from oxo, C 1-6 Alkyl, C 1-6 Alkoxy, - (C 1-6 alkyl)-O-(C 1-6 alkyl) and a 4-6 membered heterocyclic group; R 22 Selected from hydrogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkyl)-O-(C 1-6 alkyl), 4-6 membered heterocyclic group or -C(O)R c , R c Selected from hydrogen, C 1-6 Alkyl or -(C 1-6 alkyl)-O-(C 1-6 alkyl); R6 is hydrogen or halogen; m is 0, 1 or 2; and R 11 C 1-3 alkyl.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from:

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

30. A method for inhibiting BTK activity in vivo or in vitro, comprising contacting BTK with an effective amount of the compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof.

31. Use of the compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease mediated or at least partially mediated by BTK, preferably for treating or preventing cancer, inflammatory diseases or autoimmune diseases; The cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B cell acute lymphocytic leukemia disease (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (e.g., high-risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (e.g., multiple myeloma) or transplantation versus host disease; the inflammatory disease or autoimmune disease is preferably selected from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, pityriasis vulgaris, and diseases associated with kidney transplantation.

32. A method for treating or preventing a disease in an individual, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof, wherein the disease is mediated by BTK or at least partially mediated by BTK; the disease is preferably cancer, inflammatory disease or autoimmune disease; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, myeloma, Diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, extranodal marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia ( The inflammatory disease or autoimmune disease is preferably selected from the group consisting of systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, pityriasis vulgaris, and diseases associated with kidney transplantation.

33. A compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof for use as a medicament.

34. A compound according to any one of claims 1 to 28 and / or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease mediated or at least partially mediated by BTK, preferably for treating or preventing cancer, inflammatory diseases or autoimmune diseases; the cancer is preferably a solid tumor or a hematological malignancy, including lymphoma, leukemia and myeloma; the cancer is more preferably selected from B cell malignancies, diffuse large B cell lymphoma (DLBCL), large B cell lymphoma (LBCL), B cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, Burkitt lymphoma, non-Burkitt's high grade B cell lymphoma, extranodal marginal zone B cell lymphoma, small lymphocytic lymphoma (SLL), lymphoblastic lymphoma, lymphocytic leukemia, myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), human acute monocytic leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), hairy cell leukemia, chronic lymphocytic leukemia (CLL) (e.g., high-risk CLL), myelodysplastic syndrome, acute lymphoblastic leukemia, myeloma (e.g., multiple myeloma) or transplantation versus host disease; the inflammatory disease or autoimmune disease is preferably selected from: systemic inflammation and local inflammation, arthritis, rheumatoid arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, ulcerative colitis, Crohn's disease, dermatitis, asthma, lupus erythematosus, Sjögren's syndrome, multiple sclerosis, scleroderma, multiple sclerosis osteoporosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody vasculitis, chronic obstructive pulmonary disease, psoriasis, Sjögren's syndrome, pityriasis vulgaris, and diseases associated with kidney transplantation.

35. A drug combination comprising a compound and / or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 28, and at least one additional therapeutic agent, wherein the therapeutic agent is preferably selected from: an anti-inflammatory agent, an immunomodulator or an anti-tumor agent, wherein the anti-tumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

36. Compound of formula (VI): or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: X1, X2, X3, X4, R1, R2 and R3 are as defined in any one of claims 1 to 28; R 31’ -CHO, -C 1-3 Alkyl-OH, -C 1-3 Alkyl-OAc, C 1-3 Alkyl, -C(O)-C 1-3 Alkyl or C 1-3 a haloalkyl group, and R 32 Halogen, -B(OH)2, -B(OC 1-6 Alkyl)2, R d is hydrogen or C 1-6 alkyl.

37. The compound of claim 36, which is: in: Z is N or CR7; R7 and R8 are independently hydrogen or halogen; R9 is halogen or C 1-6 Alkyl; n is 1 or 2.

38. The compound of claim 36, selected from:

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