Imidazopyrazine benzamide compound and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to imidazopyrazine benzamide compounds and application thereof, and a pharmaceutical composition containing the compounds, which can be used as Bruton's tyrosine kinase (BTK) inhibitors. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in prevention or treatment of BTK-related diseases.

Description

Invention Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to imidazopyrazine benzamide compounds and their uses. The imidazopyrazine benzamide compounds of this invention can act as Bruton's tyrosine kinase (BTK) inhibitors. This invention also relates to pharmaceutical compositions of such compounds, methods for preparing such compounds and pharmaceutical compositions, and their use for the prevention or treatment of BTK-related diseases. Background Technology

[0002] Bruton's tyrosine kinase (BTK) is one of the five members of the Tec family of non-receptor tyrosine protein kinases. It consists of 659 amino acids and contains multiple domains, such as the Pleckstrin homology (PH) domain, Tec homology (TH) domain, Src homology 3 (SH3) domain, SH2 domain, and SH1 domain (Future Med Chem, 2014, 6(6):675-695). BTK is a signaling enzyme expressed in all hematopoietic cells except natural killer cells and T lymphocytes. BTK plays a crucial role in the B-cell signaling pathway, which links stimulation of the cell surface B-cell receptor to downstream intracellular responses. Studies have shown that BTK, as an important component of the B-cell receptor (BCR) signaling pathway, plays a vital role in many physiological processes such as B-cell development, maturation, differentiation, and proliferation (Nature, 1993, 361(6409):226-233).

[0003] Precise regulation of BTK is crucial for maintaining normal physiological function of B cells (Anticancer Agents MedChem, 2007, 7(6): 624-632). Excessive activation of BTK can slow down B cell apoptosis and increase the likelihood of autoimmune reactions, thereby inducing the occurrence and development of diseases such as B-cell lymphoma and inflammation (Int Rev Immunol, 2012, 31(2): 119-132).

[0004] BTK plays a crucial role in the occurrence and development of tumors and is essential for the survival of various B-cell malignant tumor cells, such as leukemia. Small molecule BTK inhibitors have shown unexpectedly excellent anti-tumor activity in clinical trials (Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia[J]. N Engl J Med, 2013, 369(1):32-42; Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia[J]. N Engl J Med, 2016, 374(4):323-332), attracting great attention.

[0005] Currently, BTK inhibitors are not only used to treat B-cell malignancies, but are also undergoing clinical trials for the treatment of solid tumors and other hematologic and immune system malignancies. However, there are currently few BTK inhibitors with good drug-like properties, and their structures are relatively simple. Therefore, the development of new BTK inhibitors is of great significance. Summary of the Invention

[0006] The following is a summary description of some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0007] This invention relates to a novel class of substituted pyrimidine compounds. Experimental results show that the compounds of this invention exhibit significant inhibitory activity against BTK, demonstrating unexpectedly excellent BTK inhibitory activity. Therefore, the compounds of this invention can be used as BTK inhibitors for the prevention or treatment of BTK-related diseases, including but not limited to tumors, thromboembolism, inflammatory diseases, and autoimmune diseases, particularly tumors.

[0008] The compounds of this invention are stable, have good safety, few toxic side effects, and possess pharmacodynamic and pharmacokinetic advantages, such as a good brain-plasma ratio, good bioavailability, or good metabolic stability, thus showing good prospects for clinical application.

[0009] The present invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

[0010] On the one hand, the present invention provides a compound, which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0011]

[0012] in,

[0013] R 1 for Where R n -C(=O)-R x Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; t is 0, 1, 2, 3, or 4; R x It is a C2-C6 alkenyl or C2-C6 alkynyl, wherein the C2-C6 alkenyl and C2-C6 alkynyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl and heterocyclic groups consisting of 3 to 6 atoms;

[0014] R 2 It is H, D, C1-C6 alkyl or C1-C6 haloalkyl;

[0015] R 3 for Among them, each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms; each R 3g and R 3hIndependently, it can be F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms;

[0016] Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms; each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms;

[0017] Each R 4 and R 5 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0018] n is 0, 1, 2, 3 or 4;

[0019] m can be 0, 1, or 2.

[0020] In some embodiments, R 1 for

[0021] R n -C(=O)-R x Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy;

[0022] R xIt is a C2-C4 alkenyl or C2-C4 alkynyl, wherein the C2-C4 alkenyl and C2-C4 alkynyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl and heterocyclic groups consisting of 3 to 6 atoms;

[0023] t has the meaning described in this invention.

[0024] In some embodiments, R 1 for

[0025] Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, ethynyl, propynyl, propynyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, or difluoromethoxy;

[0026] R 1a It can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms;

[0027] t has the meaning described in this invention.

[0028] In some embodiments, the compound represented by formula (I) of the present invention is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0029]

[0030] Among them, R 1a R 2 R 3 R 4 R 5 R y m, n, and t each have the meaning described in any of the inventions described herein.

[0031] In some embodiments, the compound represented by formula (I) of the present invention is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0032]

[0033] Among them, R 1a R 2 R 3 R 4 R 5 R y m, n, and t each have the meaning described in any of the inventions described herein.

[0034] In some embodiments, R 1a The following are possible values: H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

[0035] In some embodiments, each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms;

[0036] Each R 3g and R 3h Independently, it can be F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR. d -CONR e R fC3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms;

[0037] Each R a and R d Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms;

[0038] Each R b R c R e and R f Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0039] In some embodiments, each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -COOR a -CONR b R c , phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, furanyl, pyridyl, pyrazinyl or pyrimidinyl;

[0040] Each R 3g and R 3h Independently, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R fCyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl or pyrimidinyl;

[0041] Each R a and R d Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl;

[0042] Each R b R c R e and R f Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0043] In some embodiments, R 2 The following are the possible values: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, or difluoromethyl.

[0044] Each R 4 and R 5 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, or difluoromethoxy.

[0045] In some embodiments, the compound of the present invention is one of the following compounds or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof:

[0046]

[0047]

[0048] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein and a pharmaceutically acceptable carrier, excipient or excipient.

[0049] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to prevent or treat diseases related to BTK.

[0050] In some embodiments, the BTK-related diseases described in this invention are tumors, thromboembolic events, inflammatory conditions, and / or autoimmune diseases.

[0051] In some embodiments, the BTK-related disease described in this invention is a tumor.

[0052] In some embodiments, the tumors described in this invention are B-cell lymphomas, solid tumors, and / or hematologic and immune system tumors.

[0053] In some embodiments, the B-cell lymphoma described in this invention is diffuse large B-cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and / or chronic lymphocytic leukemia.

[0054] In other embodiments, the solid tumors described in this invention are gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, urogenital tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0055] In some other embodiments, the hematologic and immune system tumors described in this invention are acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, and / or chronic myeloid leukemia.

[0056] In some embodiments, the inflammatory conditions or autoimmune diseases described in this invention are asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

[0057] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0058] Detailed instructions

[0059] Definitions and general terms

[0060] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0061] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0062] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0063] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0064] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0065] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0066] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0067] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0068] "Chirality" refers to molecules that have the property that they cannot be superimposed on their mirror image; while "chirality" refers to molecules that can be superimposed on their mirror image.

[0069] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0070] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0071] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0072] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0073] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0074] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0075] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0076] The term "optional" or "optionally" means that an event or situation described below may, but is not guaranteed to, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optional key" means that the key may or may not be present, and the description includes single, double, or triple keys.

[0077] The term "substituted" indicates that one or more hydrogen atoms in the given structure are replaced by a specific substituent. As described in this invention, the compounds of this invention may optionally be substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention.

[0078] Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at each position in the same or different manner.

[0079] The term "unsubstituted" means that the specified group does not have substituents.

[0080] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0081] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, the invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0082] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0083] The term "C1-C6 alkyl" as used in this invention refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 6 carbon atoms. Unless otherwise specified, the alkyl group described in this invention contains 1-6 carbon atoms; in some embodiments, the alkyl group contains 1-4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (... t-Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2 -Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3) )CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), etc.

[0084] The term "C2-C6 alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond includes the orientation of "cis" and "tans", or the orientation of "E" and "Z". Unless otherwise stated, the alkenyl group described in this invention comprises 2-6 carbon atoms; in one embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of the alkenyl group include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0085] The term "C2-C6 ynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond. Unless otherwise stated, the ynyl group described in this invention comprises 2-6 carbon atoms; in some embodiments, the ynyl group comprises 2-4 carbon atoms. Examples of the ynyl group include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0086] The term "C1-C6 alkoxy" indicates that an alkyl group is attached to the remainder of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group described in this invention contains 1-6 carbon atoms; in some embodiments, the alkoxy group contains 1-4 carbon atoms; in other embodiments, the alkoxy group contains 1-3 carbon atoms. Examples of the alkoxy group include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2 -propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0087] The term “haloalkyl” or “haloalkoxy” means that an alkyl or alkoxy group is replaced by one or more halogen atoms. Examples of such replacements include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, etc.

[0088] The term "C3-C6 cycloalkyl" refers to a monovalent or polyvalent non-aromatic saturated monocyclic system containing 3-6 carbon atoms. Unless otherwise stated, the cycloalkyl groups described in this invention comprise 3-6 carbon atoms. Examples of cycloalkyl groups described in this invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0089] The terms “heterocyclic,” “heterocyclic group,” or “heterocyclic” are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic system comprising 3-14 ring atoms, in which one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but no aromatic rings are permitted. Unless otherwise stated, the “heterocyclic,” “heterocyclic group,” or “heterocyclic” group as used herein consists of the aforementioned atoms. For example, a heterocyclic group consisting of 3-6 atoms refers to a monocyclic ring of 3-6 members (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain groups like SO, SO2, PO, PO2). The heterocyclic group described in this invention can be a carbon-based or heteroatom-based group; wherein, the -CH2- group of the ring can optionally be replaced by -C(=O)-, the sulfur atom of the ring can optionally be oxidized to an S-oxide, and the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of the heterocyclic group described in this invention include, but are not limited to, ethylene oxide, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, thiaoxyl, etc. Examples of heterocyclic groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, pyrimidinedionyl, etc. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholino 1,1-dioxide, etc.

[0090] Unless otherwise stated, the term "aryl" in this invention refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene.

[0091] Unless otherwise stated, the term "heteroaryl" or "heteroaromatic ring" as used in this invention refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 5-10 or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, a heteroaryl consisting of 5-10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, a heteroaryl consisting of 5-6 ring atoms is a monocyclic system and contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Examples of heteroaryl groups described in this invention include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyridyl, 4-pyrimidin ... -Pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl Azolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinoline). (e.g., linyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0092] The term "composed of x atoms" or "x-ary," where x is an integer, typically describes the number of atoms forming a ring in a molecule. For example, piperidinyl is a heterocyclic alkyl group consisting of 6 atoms, while 1,2,3,4-tetrahydronaphthalene is a cycloalkyl group consisting of 10 atoms.

[0093] The term "unsaturated" as used in this invention means that the group contains one or more degrees of unsaturation.

[0094] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0095] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0096] As described in this invention, a substituent R formed by a single bond connecting to a central bicyclic ring (as shown in formula c) means that the substituent R can be substituted at any substituted or reasonable position on the ring it is connected to (as shown in ring B in formula c). For example, formula c represents that any substituted position on ring B can be substituted by R, as shown in formula c. 1-3 As shown.

[0097]

[0098] As described in this invention, substituent (R) f A ring system formed by a single bond connecting to a central ring represents f substituents R that can be substituted at any substituted or reasonable position on the ring. For example, formula d represents that ring G can be substituted by f Rs, where when f is greater than 1, each R can be independently selected from the same or different substituents.

[0099]

[0100] As described in this invention, the attachment point can be connected to the rest of the molecule at any connectable location on the ring. For example, formula e represents any possible connectable location on ring A or ring B as the attachment point.

[0101]

[0102] The term "pharmaceuticalally acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar undesirable reactions, such as gastrointestinal upset, dizziness, etc. Preferably, as used herein, the term "pharmaceuticalally acceptable" refers to those listed in pharmacopoeias approved / recognized by national government agencies or other pharmacopoeias generally recognized in the art that are used in animals, and more particularly in humans.

[0103] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0104] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0105] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0106] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0107] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0108] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0109] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0110] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0111] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0112] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0113] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotope-labeled reagents instead of the previously used unlabeled reagents, as described in the examples and preparation processes of the present invention.

[0114] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0115] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention

[0116] According to another aspect, the pharmaceutical compositions of the present invention are characterized by comprising compounds represented by formula (I) or (II), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers, excipients, or excipients. The amounts of compounds in the compositions of the present invention are effective in treating or alleviating BTK-related diseases in patients.

[0117] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0118] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0119] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0120] Preferably, the compound is mixed with a suitable drug diluent, excipient, or carrier (in this case, a drug carrier) selected according to the form of administration and conventional pharmaceutical practice, and the administration method may be oral tablets, capsules, elixirs, syrups, etc.

[0121] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be conjugated with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical ingredient can be conjugated with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerin, water, etc. Furthermore, suitable binders, lubricants, dissolving agents, and colorants can be added to the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Decomposing agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0122] The compounds of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0123] The compounds of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0124] The compounds of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0125] The compounds of this invention are also coupled with soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0126] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0127] The compounds and pharmaceutical compositions provided by this invention exhibit excellent BTK inhibitory activity and low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Furthermore, the compounds or pharmaceutical compositions are excellent in terms of oral absorption, duration of action, stability, and pharmacokinetics. The compounds or pharmaceutical compositions thereof involved in this invention can be effectively used to prevent, treat, or alleviate BTK-related diseases in patients.

[0128] In some embodiments, the diseases associated with BTK overactivation described in this invention are tumors, thromboembolism, inflammatory conditions, and / or autoimmune diseases.

[0129] In some embodiments, the disease caused by BTK overactivation described in this invention is a tumor.

[0130] In some embodiments, the tumors described in this invention are B-cell lymphomas, solid tumors, and / or hematologic and immune system tumors.

[0131] In some embodiments, the B-cell lymphoma described in this invention is diffuse large B-cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and / or chronic lymphocytic leukemia.

[0132] In other embodiments, the solid tumors described in this invention are gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, urogenital tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0133] In some other embodiments, the hematologic and immune system tumors described in this invention are acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, and / or chronic myeloid leukemia.

[0134] In some embodiments, the inflammatory conditions or autoimmune diseases described in this invention are asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

[0135] The compounds and pharmaceutical compositions of the present invention, in addition to their therapeutic benefits for humans, can also be used in veterinary treatment of mammals, including pets, introduced breeds of animals, and farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0136] General Synthesis Process

[0137] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0138] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0139] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0140] The examples described below, unless otherwise stated, all temperatures are in degrees Celsius. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification. Unless otherwise stated, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0141] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0142] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0143] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0144] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1¹H NMR spectra are performed using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0145] The following abbreviations are used throughout this invention:

[0146] μM, nmol / L (micromoles per liter) nM, nmol / L (nanomoles per liter)

[0147] M, mol / L (mg per liter)

[0148] g gram kg kilogram

[0149] mL, ml, milliliters, μL, μl, microliters

[0150] rt, RT (room temperature, min)

[0151] h hour NBS N-bromosuccinimide

[0152] HOBt 1-hydroxybenzotriazole DMF N,N-dimethylformamide

[0153] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0154] The following reaction scheme describes the steps for preparing the compounds disclosed in this invention.

[0155] Synthesis scheme

[0156]

[0157] Among them, R 3 R 4 R y R 1a , t and n have the meanings as described in this invention.

[0158] Mode( 12 The compound shown in formula () can be prepared by the following process: 1The optionally substituted (2S)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid compound shown in the figure is similar to that of the compound of formula ( 2 The condensation of 3-chloropyrazine-2-methylamine dihydrochloride as shown in the figure yields formula ( 3 The compound shown in the formula () 3 The compound shown in the figure undergoes cyclization under the action of phosphorus oxychloride to obtain the compound of formula ( 4 The compound shown was subsequently brominated in a solvent (such as N,N-dimethylformamide) to give the compound of formula ( 5 The compound shown in the formula () 5 The compound shown in the figure reacts with ammonia in an autoclave to obtain the product of formula ( 6 The compound shown is shown in the figure.

[0159] Mode( 7 The optionally substituted 4-bromobenzoic acid compound shown in the figure is related to R. 3 -NH2 condenses in a solvent (such as N,N-dimethylformamide) to obtain formula ( 8 The compound shown in the formula () 8 The compound shown in the figure reacts with pinacol diboronate under palladium catalysis to obtain the product of formula ( 9 The compound shown in the formula () 9 The compound shown in the figure is similar to that of formula ( 6 The compound shown in the figure, under the action of a palladium catalyst, yields the product of formula ( 10 The compound shown in the figure was subsequently deprotected under acidic conditions (such as in a hydrobromic acid solution of acetic acid) to obtain the compound of formula ( 11 The compound shown in the formula () 11 The compound shown in the figure is condensed with an alkynyl acid compound in a solvent (such as dichloromethane) (e.g., in a HOBT / EDCI system) to obtain the compound of formula ( 12 The compound shown is shown in the figure. Example

[0160] Example 1: Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,5-dimethylthiazo-2-yl)benzamide

[0161]

[0162] Step 1: Synthesis of (S)-2-(((3-chloropyrazin-2-yl)methyl)formamido)pyrrolidine-1-carboxylic acid benzyl ester

[0163] (2S)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid (10.00 g, 40.10 mmol), N,N-dimethylformamide (80 mL), 3-chloropyrazine-2-methylamine dihydrochloride (8.69 g, 40.10 mmol), and N,N-diisopropylethylamine (27.5 mL, 160.44 mmol) were added sequentially to a 250 mL reaction flask. The mixture was stirred until the system was clear. Then, 1-hydroxybenzotriazole (8.30 g, 60.15 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (11.77 g, 60.15 mmol) were added. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction was stopped, water (400 mL) was added, and the mixture was extracted three times with dichloromethane (150 mL). The organic phases were combined and washed successively with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give the title compound as a colorless oil (13.82 g, 92%).

[0164] MS(ESI,pos.ion)m / z:375.10[M+H] + ;

[0165] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.53(d,J=2.4Hz,1H),8.39(d,J=2.4Hz,1H),7.31- 7.24(m,5H),5.04(d,J=13.0Hz,1H),4.98(d,J=13.0Hz,1H),4.49(dd,J=16.2,5. 4Hz,1H),4.43(dd,J=16.2,5.4Hz,1H),4.29(dd,J=8.6,3.5Hz,1H),3.48-3.42(m ,1H),3.40-3.34(m,1H),2.21-2.12(m,1H),1.93-1.85(m,1H),1.84-1.75(m,2H).

[0166] Step 2: Synthesis of (S)-2-(8-chloroimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0167] (S)-2-(((3-chloropyrazin-2-yl)methyl)formamide)pyrrolidine-1-carboxylic acid benzyl ester (2.00 g, 5.34 mmol), dichloromethane (20 mL), and N,N-dimethylformamide (390 mg, 5.34 mmol) were added sequentially to a 100 mL reaction flask. Phosphorus oxychloride (2.5 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. The reaction was then stopped, and quenched by adding saturated sodium bicarbonate solution (50 mL) in an ice bath. The mixture was separated, and the organic phase was collected. The phase was washed sequentially with water (50 mL) and saturated brine (50 mL), the solvent was evaporated, and the solution was concentrated to obtain the title compound as an orange-yellow oil (1.80 g, 95%).

[0168] MS(ESI,pos.ion)m / z:357.20[M+H] + ;

[0169] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.25 (d, J = 4.7Hz, 1H), 7.79 (d, J = 48.5Hz, 1H), 7.49–7.30 (m, 4H), 7.19 (t, J = 6.9Hz, 1H), 6.91 (dd, J = 5 6.6,5.6Hz,1H),5.32(s,1H),5.08(dd,J=74.7,12.2Hz,2H),3.73(dd,J=54.6,6.3Hz,2H),2.58–2.33(m,3H),2.18–2.03(m,1H).

[0170] Step 3: Synthesis of (S)-2-(1-bromo-8-chloroimidozono[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0171] (S)-2-(8-chloroimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (11.50 g, 32.23 mmol) and N,N-dimethylformamide (80 mL) were added sequentially to a 250 mL reaction flask. NBS (5.85 g, 32.23 mmol) was added with stirring at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction was then stopped, and water (160 mL) was added. The mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was dried to give the title compound as a white solid (13.62 g, 97%).

[0172] MS(ESI,pos.ion)m / z:435.20[M+H] + ;

[0173] 1H NMR(400MHz, DMSO-d6)δ(ppm)8.41(dd,J=93.8,4.9Hz,1H),7.47–7.10(m,5H),6.70(d,J=7.3 Hz,1H),5.42(dd,J=7.6,4.6Hz,1H),5.07–4.56(m,2H),3.66–3.49(m,2H),2.40–1.87(m,4H).

[0174] Step 4: Synthesis of (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester become

[0175] (S)-2-(1-bromo-8-chloroimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (11.00 g, 25.25 mmol), isopropanol (80 mL), and ammonia (50 mL, 28% mass) were added sequentially to an autoclave, and the mixture was heated to 95 °C and reacted for 18 hours. The reaction was stopped, cooled to room temperature, and the reaction solution was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (9.99 g, 95%).

[0176] MS(ESI,pos.ion)m / z:416.00[M+H] + ;

[0177] 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.67(dd,J=59.3,4.8Hz,1H),7.42–7.11(m,4H),6.95(dd,J=49.6,4.8Hz,1H),6.76(d,J=6.9Hz,1 H),6.63(brs,2H),5.39–5.26(m,1H),4.92(dt,J=110.6,12.7Hz,2H),3.64–3.47(m,2H),2.37–2.06(m,2H),2.03–1.88(m,2H).

[0178] Step 5) Synthesis of 4-bromo-N-(4,5-dimethylthiazol-2-yl)benzamide

[0179] 4,5-Dimethylthiazol-2-amine hydrochloride (2.00 g, 12.15 mmol), 4-bromobenzoic acid (2.44 g, 12.15 mmol), tetrahydrofuran (30 mL), and N,N-diisopropylethylamine (6.37 mL, 37.35 mmol) were added sequentially to a 100 mL reaction flask. Then, 1-hydroxybenzotriazole (2.51 g, 18.23 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (3.53 g, 18.23 mmol) were added with stirring. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was stopped, and water (20 mL) was added. The mixture was stirred at room temperature for 3 minutes, allowed to stand, and separated. The aqueous layer was extracted with ethyl acetate (20 mL). The organic phases were combined and concentrated. The resulting solid was placed in methanol (15 mL) and stirred at room temperature for 1 hour. The solid was filtered, and the filter cake was dried to give the title compound as a white solid (3.40 g, 90%).

[0180] MS(ESI,pos.ion)m / z:311.00[M+H] + ;

[0181] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.91 (s, 1H), 7.73 (d, J = 8.5Hz, 2H), 7.55 (d, J = 8.5Hz, 2H), 2.28 (s, 3H), 1.87 (s, 3H).

[0182] Step 6) N-(4,5-dimethylthiazolyl-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane- Synthesis of 2-yl)benzamide

[0183] 4-Bromo-N-(4,5-dimethylthiazol-2-yl)benzamide (3.38 g, 10.86 mmol), pinacol diborate (4.18 g, 16.29 mmol), potassium acetate (2.13 g, 21.72 mmol), and 1,4-dioxane (35 mL) were added sequentially to a 100 mL reaction flask. The system was purged with nitrogen three times. [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (811 mg, 1.086 mmol) was added, and the mixture was heated to 95 °C for 6 hours under nitrogen protection. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 4:1) to give the title compound as a yellow viscous substance (3.7 g, 95%).

[0184] MS(ESI,pos.ion)m / z:359.15[M+H] + ;

[0185] 1H NMR (400MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 7.75 (d, J = 8.5Hz, 2H), 7.53 (d, J = 8.5Hz, 2H), 2.28 (s, 3H), 1.86 (s, 3H), 1.25 (s, 12H).

[0186] Step 7)(S)-2-(8-amino-1-(4-((4,5-dimethylthiazol-2-yl)formamido)phenyl)imidazolide Synthesis of [1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0187] Add (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.00 g, 2.40 mmol), N-(4,5-dimethylthiazol-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (1.12 g, 3.12 mmol), potassium carbonate (1.00 g, 7.20 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (88 mg, 0.12 mmol), 1,4-dioxane (20 mL), and water (4 mL) to a 100 mL reaction flask in sequence. Under nitrogen protection, heat to 95 °C and react overnight. The reaction was stopped, the mixture was allowed to stand and separate into layers, the organic phase was collected and concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a yellow solid (535 mg, 39%).

[0188] MS(ESI,pos.ion)m / z:568.15[M+H] + ;

[0189] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.06 (brs, 1H), 8.07 (d, J = 8.2Hz, 2H), 7.86–7.67 (m, 2H), 7.35 (brs, 2H), 7.21–6.89 (m, 4H), 5.31 (brs,1H),5.14(dd,J=44.5,12.5Hz,2H),3.86–3.63(m,2H),2.57–2.38(m,2H),2.33(s,3H),2.30–2.24(m,2H),2.18(s,3H).

[0190] Step 8)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,5-di) Synthesis of methylthiazol-2-yl)benzamide

[0191] (S)-2-(8-amino-1-(4-(((4,5-dimethylthiazol-2-yl)formamido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (530 mg, 0.93 mmol), acetic acid (3 mL), and hydrobromic acid in acetic acid solution (2.5 mL, 5.1 M) were added sequentially to a 100 mL reaction flask. After the addition was complete, the reaction was allowed to proceed at room temperature for 40 minutes. The reaction was then stopped, and water (50 mL) and dichloromethane (20 mL) were added sequentially. The mixture was allowed to stand and separated. The aqueous layer was washed with dichloromethane (20 mL), and the aqueous phase was collected. The pH of the solution was adjusted to >10 with 30% sodium hydroxide aqueous solution, and the solution was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound as a pale yellow solid (230 mg, 57%).

[0192] MS(ESI,pos.ion)m / z:434.10[M+H] + ;

[0193] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.19 (d, J = 8.3Hz, 2H), 7.77 (t, J = 7.0Hz, 3H), 7.10 (d, J = 4.9Hz, 1H), 6.12 (s, 2H) ,4.60(t,J=7.2Hz,1H),2.93(t,J=6.8Hz,2H),2.28(s,3H),2.22(s,3H),2.18–2.08(m,1H),1.96–1.72(m,3H).

[0194] Step 9)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of pyrazin-1-yl)-N-(4,5-dimethylthiazol-2-yl)benzamide

[0195] (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,5-dimethylthiazo-2-yl)benzamide (210 mg, 0.48 mmol), 2-butynic acid (45 mg, 0.53 mmol), N,N-diisopropylethylamine (125 mg, 0.96 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to a 100 mL reaction flask. The system was stirred in an ice bath, and 1-hydroxybenzotriazole (101 mg, 0.72 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (138 mg, 0.72 mmol) were added sequentially. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. The reaction was stopped, water (20 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined and washed twice with water (15 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 15:1) to give the title compound as a pale yellow solid (189 mg, 78%).

[0196] MS(ESI,pos.ion)m / z:500.10[M+H] + ;

[0197] 1 H NMR (600MHz, DMSO-d6) δ (ppm) 12.48 (brs, 1H), 8.20 (s, 2H), 7.80 (d, J = 59.0Hz, 3H), 7.14 (d, J = 23.2Hz, 1H), 6.15 (brs ,2H),5.83–5.37(m,1H),3.76(d,J=72.4Hz,1H),3.61(d,J=23.5Hz,1H),2.46–2.09(m,9H),2.01(s,3H),1.62(s,1H).

[0198] Example 2: Synthesis of (S)-2-(4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxylic acid methyl ester

[0199]

[0200] Step 1) Synthesis of methyl 2-(4-bromobenzamido)-4-methylthiazole-5-carboxylic acid ester

[0201] 2-Amino-4-methylthiazol-5-carboxylic acid methyl ester (3.50 g, 20.35 mmol), DMF (35 mL), and 4-bromobenzoic acid (4.90 g, 24.51 mmol) were added sequentially to a 250 mL reaction flask. N,N-diisopropylethylamine (11.80 mL, 67.74 mmol) was added under magnetic stirring. After the addition was complete, the mixture was heated to 60 °C and stirred for 30 minutes. An ethyl acetate solution of 1-propylphosphonic anhydride (24.2 mL, 81.36 mmol, 50% mass) was added. After the addition was complete, the mixture was stirred at 60 °C for 2 hours. The reaction was stopped, cooled to room temperature, and water (160 mL) was added. Then, sodium bicarbonate was added to adjust the pH of the solution to 8–9. The mixture was stirred at room temperature for 0.5 hours, filtered, and the filtrate was evaporated to dryness to obtain the title compound as a white solid (6.20 g, 86%).

[0202] MS(ESI,pos.ion)m / z:354.95[M+H] + ;

[0203] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.90 (s, 1H), 8.03 (d, J = 8.6Hz, 2H), 7.75 (d, J = 8.5Hz, 2H), 3.79 (s, 3H), 2.59 (s, 3H).

[0204] Step 2) 4-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide Synthesis of methyl thiazole-5-carboxylic acid

[0205] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, methyl 2-(4-bromobenzamido)-4-methylthiazol-5-carboxylic acid (3.00 g, 8.48 mmol), pinacol diboronate (2.93 g, 11.54 mmol), potassium acetate (1.67 g, 17.03 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (325 mg, 0.44 mmol) were reacted in ethylene glycol dimethyl ether (30 mL) under nitrogen protection at 90 °C. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give the title compound as a grayish-brown solid (2.65 g, 78%).

[0206] MS(ESI,pos.ion)m / z:403.15[M+H] + ;

[0207] 1H NMR (600MHz, CDCl3) δ (ppm) 11.88 (s, 1H), 8.03 (d, J = 8.1Hz, 2H), 7.95 (d, J = 8.1Hz, 2H), 3.87 (s, 3H), 2.58 (s, 3H), 1.36 (s, 12H).

[0208] Step 3)(S)-2-(4-(8-amino-3-(1-((benzyloxy)carbonyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrrolidine Synthesis of methyl 5-azinon-1-yl)benzamido)-4-methylthiazolyl-5-carboxylate

[0209] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, methyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamido)thiazol-5-carboxylic acid methyl ester (0.70 g, 1.68 mmol), (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.05 g, 2.52 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.13 g, 0.168 mmol), and potassium carbonate (0.70 g, 5.04 mmol) in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) under nitrogen protection at 105 °C. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1) to give the title compound as a pale yellow solid (0.77 g, 75%).

[0210] MS(ESI,pos.ion)m / z:612.20[M+H] + ;

[0211] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.09 (d, J = 8.2Hz, 2H), 7.81 (dd, J = 29.4, 8.7Hz, 2H), 7.60 (dd, J = 12.1, 7.1Hz, 1H), 7.43 (dd, J = 7.7, 2.6Hz,1H),7.35(s,3H),7.25–7.11(m,2H),5.27–5.03(m,3H),3.90(s,3H),3.79–3.70(m,2H),2.65(s,3H),2.55–2.32(m,4H).

[0212] Step 4)(S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamide Synthesis of methyl 4-methylthiazolyl-5-carboxylate

[0213] The title compound of this step was prepared according to the method described in step 8 of Example 1, namely, by reacting (S)-2-(4-(8-amino-3-(1-((benzyloxy)carbonyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxylic acid methyl ester (765 mg, 1.25 mmol), acetic acid (3 mL), and an acetic acid solution of hydrobromic acid (5 mL, 5.1 M) at room temperature for 1 hour. After the reaction was completed, water (40 mL) and dichloromethane (20 mL) were added sequentially. The mixture was stirred at room temperature for 3 minutes and then allowed to stand for separation. The aqueous phase was washed with dichloromethane (20 mL), and the pH of the solution was adjusted to alkaline with saturated sodium bicarbonate solution. The solution was extracted three times with dichloromethane (20 mL), the organic phases were combined, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to obtain the yellow solid (450 mg, 75%).

[0214] MS(ESI,pos.ion)m / z:478.20[M+H] + ;

[0215] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.22 (d, J = 8.3Hz, 2H), 7.76 (d, J = 5.0Hz, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.08 (d, J = 4.9Hz, 1H), 6 .09(s,2H),4.59(t,J=7.2Hz,1H),3.77(s,3H),2.93(t,J=6.8Hz,2H),2.57(s,3H),2.30–2.11(m,2H),1.94–1.75(m,2H).

[0216] Step 5)(S)-2-(4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1, Synthesis of methyl 5-a]pyrazin-1-yl)benzamido)-4-methylthiazol-5-carboxylic acid ester

[0217] The title compound of this step was prepared according to the method described in step 9 of Example 1, namely, (S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxylic acid methyl ester (400 mg, 0.84 mmol), 2-butynic acid (74 mg, 0.88 mmol), N,N-diisopropylethylamine (0.35 mL, 2.00 mmol), 1-hydroxybenzotriazole (168 mg, 1.25 mmol), and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol) reacted in N,N-dimethylformamide (5 mL) at room temperature for 5 hours. After the reaction was completed, water (20 mL) was added, and the mixture was filtered. The filtrate was extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (320 mg, 70%).

[0218] MS(ESI,pos.ion)m / z:544.10[M+H] + ;

[0219] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.21 (d, J = 8.2Hz, 2H), 7.94–7.71 (m, 3H), 7.14 (dd, J = 16.3, 4.9Hz, 1H), 6.17 (d, J = 24. 9Hz,2H),3.82(d,J=11.9Hz,4H),3.66–3.48(m,2H),2.60(s,3H),2.46–2.17(m,2H),2.00(s,3H),1.30–0.78(m,2H).

[0220] Example 3: Synthesis of (S)-2-(4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxylic acid ethyl ester

[0221]

[0222] Step 1) Synthesis of ethyl 2-(4-bromobenzamido)-4-methylthiazole-5-carboxylate

[0223] The title compound in this step was prepared according to the method described in step 5 of Example 1, namely, ethyl 2-amino-4-methylthiazolium-5-carboxylate (2.00 g, 10.74 mmol), 4-bromobenzoic acid (2.16 g, 10.74 mmol), N,N-diisopropylethylamine (3.75 mL, 21.48 mmol), 1-hydroxybenzotriazole (2.18 g, 16.11 mmol), and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (3.09 g, 16.11 mmol) reacted overnight at room temperature in tetrahydrofuran (20 mL). After the reaction was completed, the mixture was filtered, and the filter cake was placed in methanol (20 mL) and stirred at room temperature for 1 hour. The mixture was then filtered again, and the filter cake was dried to obtain the title compound as a white solid (2.50 g, 63%).

[0224] MS(ESI,pos.ion)m / z:369.20[M+H] + ;

[0225] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.10 (s, 1H), 8.03 (d, J = 7.5Hz, 2H), 7.77 (d, J = 7.6Hz, 2H), 4.26 (d, J = 6.7Hz, 2H), 2.59 (s, 3H), 1.27 (t, J = 8.0Hz, 3H).

[0226] Step 2) 4-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide Synthesis of ethyl thiazole-5-carboxylate

[0227] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, ethyl 2-(4-bromobenzamido)-4-methylthiazol-5-carboxylic acid (2.44 g, 6.61 mmol), pinacol diboronate (1.86 g, 7.27 mmol), potassium acetate (1.30 g, 13.22 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (493 mg, 0.66 mmol) were reacted in 1,4-dioxane (25 mL) under nitrogen protection at 95 °C. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give the title compound as a white solid (1.90 g, 69%).

[0228] MS(ESI,pos.ion)m / z:417.35[M+H] + ;

[0229] 1H NMR (400MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.2Hz, 2H), 7.97 (d, J = 8.2Hz, 2H), 4.35 (q, J = 7.1Hz, 2H), 2.58 (s, 3H), 1.41 (s, 3H), 1.38 (d, J = 4.0Hz, 12H).

[0230] Step 3)(S)-2-(4-(8-amino-3-(1-((benzyloxy)carbonyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrrolidine Synthesis of ethyl azinon-1-yl)benzamido)-4-methylthiazol-5-carboxylate

[0231] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.60 g, 3.84 mmol), 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamido)thiazole-5-carboxylic acid ethyl ester (1.92 g, 4.61 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (143 mg, 0.19 mmol) and sodium carbonate (1.22 g, 11.52 mmol) reacted in a mixed solvent of 1,4-dioxane (15 mL) and water (6 mL) at 95 °C for 18 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain the title compound as a yellow solid (600 mg, 25%).

[0232] MS(ESI,pos.ion)m / z:626.20[M+H] + ;

[0233] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.09 (d, J = 8.2Hz, 2H), 7.81 (dd, J = 29.4, 8.7Hz, 2H), 7.60 (dd, J = 12.1, 7.1Hz, 1H), 7.43 (dd, J = 7.7, 2.6Hz, 1 H),7.35(s,3H),7.25–7.11(m,2H),5.27–5.03(m,2H),4.33(q,J=7.1Hz,2H),3.90(s,3H),2.58(s,3H),2.55–2.32(m,4H),1.41(s,3H).

[0234] Step 4)(S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamide Synthesis of ethyl 4-methylthiazol-5-carboxylate

[0235] The title compound of this step was prepared according to the method described in step 8 of Example 1, namely, by reacting (S)-2-(4-(8-amino-3-(1-((benzyloxy)carbonyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazol-5-carboxylic acid ethyl ester (500 mg, 0.80 mmol) and an acetic acid solution of hydrobromic acid (2.5 mL, 5.1 M) in acetic acid (3 mL) at room temperature for 1 hour. After the reaction was completed, water (40 mL) and dichloromethane (20 mL) were added sequentially. The mixture was stirred at room temperature for 3 minutes and then allowed to stand for separation. The aqueous phase was washed with dichloromethane (20 mL), and the pH of the solution was adjusted to alkaline with saturated sodium bicarbonate solution. The solution was extracted three times with dichloromethane (20 mL), the organic phases were combined, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to obtain the yellow solid (250 mg, 64%).

[0236] MS(ESI,pos.ion)m / z:492.10[M+H] + ;

[0237] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.24 (d, J = 8.4Hz, 2H), 7.84–7.75 (m, 3H), 7.14 (d, J = 4.9Hz, 1H), 6.18 (s, 2H), 4.74 (t, J = 7.3Hz, 1H), 4.2 7(q,J=7.1Hz,2H),3.02(t,J=6.9Hz,2H),2.61(s,3H),2.36–2.16(m,3H),2.01–1.93(m,1H),1.89–1.79(m,1H),1.31(t,J=7.1Hz,3H).

[0238] Step 5)(S)-2-(4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1, Synthesis of ethyl 5-a]pyrazin-1-yl)benzamido)-4-methylthiazol-5-carboxylate

[0239] The title compound of this step was prepared according to the method described in step 9 of Example 1, namely, (S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxylic acid ethyl ester (492 mg, 1.00 mmol), 2-butynic acid (92 mg, 1.1 mmol), N,N-diisopropylethylamine (0.35 mL, 2.00 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.50 mmol) reacted in N,N-dimethylformamide (10 mL) at room temperature for 5 hours. After the reaction was completed, water (20 mL) was added, and the mixture was filtered. The filtrate was extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (470 mg, 84%).

[0240] MS(ESI,pos.ion)m / z:558.15[M+H] + ;

[0241] 1 H NMR(600MHz,DMSO-d6)δ(ppm)13.08(brs,1H),8.21(dd,J=27.3,23.6Hz,2H),7.91–7.69(m,3H),7.15(dd,J=24.2,4.8Hz,1H),6.1 9(d,J=36.3Hz,2H),4.28(q,J=6.0Hz,2H),3.66–3.56(m,3H),2.61(s,3H),2.44–2.07(m,4H),2.01(s,3H),1.31(t,J=7.0Hz,3H).

[0242] Example 4: Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-cyano-4-methylthiazo-2-yl)benzamide

[0243]

[0244] Step 1) Synthesis of 4-bromo-N-(5-cyano-4-methylthiazolyl-2-yl)benzamide

[0245] 2-Amino-4-methylthiazolyl-5-onitrile (3.00 g, 21.6 mmol), DMF (40 mL), and 4-bromobenzoic acid (4.52 g, 22.7 mmol) were added sequentially to a 250 mL reaction flask. N,N-diisopropylethylamine (10.71 mL, 64.8 mmol) was added under magnetic stirring. After the addition was complete, the mixture was heated to 60 °C and stirred for 30 minutes. An ethyl acetate solution of 1-propylphosphonic anhydride (13.7 g, 46.2 mmol, 50% mass) was added. After the addition was complete, the mixture was stirred at 60 °C for 4 hours. The reaction was stopped, cooled to room temperature, and water (160 mL) was added. Then, sodium bicarbonate was added to adjust the pH of the solution to 8–9. The mixture was stirred at room temperature for 0.5 hours, filtered, and the solvent was evaporated to dryness to obtain the title compound as a pale yellow solid (2.25 g, 37%).

[0246] MS(ESI,pos.ion)m / z:321.90[M+H] + ;

[0247] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.91 (s, 1H), 7.98 (d, J = 8.2Hz, 2H), 7.91 (d, J = 8.2Hz, 2H), 2.37 (s, 3H).

[0248] Step 2) N-(5-cyano-4-methylthiazo-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron) Synthesis of alkyl-2-yl)benzamide

[0249] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, 4-bromo-N-(5-cyano-4-methylthiazolyl-2-yl)benzamide (2.00 g, 6.23 mmol), pinacol diborate (2.16 g, 8.51 mmol), potassium acetate (1.23 g, 12.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (227 mg, 0.31 mmol) were reacted in 1,4-dioxane (20 mL) under nitrogen protection at 90 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 4:1) to give the title compound as a white solid (1.75 g, 76%).

[0250] MS(ESI,pos.ion)m / z:370.15[M+H] + ;

[0251] 1H NMR (400MHz, CDCl3) δ (ppm) 11.88 (s, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.90 (d, J = 8.2Hz, 2H), 2.38 (s, 3H), 1.37 (s, 12H).

[0252] Step 3)(S)-2-(8-amino-1-(4-((5-cyano-4-methylthiazolyl-2-yl)formamido)phenyl)imidazolium Synthesis of [1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0253] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.83 g, 2.00 mmol), N-(5-cyano-4-methylthiazolyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide (1.00 g, 2.40 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (185 mg, 0.24 mmol), and potassium carbonate (1.00 g, 7.21 mmol) in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) under nitrogen protection and heated to 105 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand and separate into layers, the organic phase was collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1) to give the title compound as a yellow solid (0.85 g, 61%).

[0254] MS(ESI,pos.ion)m / z:579.25[M+H] + ;

[0255] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.89 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.91–7.64 (m, 3H), 7.35 (brs, 3H), 7.27–7. 11(m,2H),6.93(s,1H),5.33(s,2H),5.12–5.06(m,1H),3.80-3.69(m,2H),2.56(s,3H),2.52–2.30(m,4H).

[0256] Step 4)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-cyano- Synthesis of 4-methylthiazolyl-2-yl)benzamide

[0257] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely... (S)-2-(8-amino-1-(4-(((5-cyano-4-methylthiazolyl-2-yl)carboxamido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.80 g, 1.38 mmol) was reacted with acetic acid (3 mL) and hydrobromic acid in acetic acid solution (5 mL, 33% mass) at room temperature for 2 hours with stirring. After the reaction was completed, dichloromethane (40 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was dissolved in water (20 mL). The pH of the solution was adjusted to >10 with saturated sodium bicarbonate solution, and the solution was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the title compound as a pale yellow solid (0.50 g, 81%).

[0258] MS(ESI,pos.ion)m / z:445.25[M+H] + ;

[0259] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.24 (d, J = 8.2 Hz, 2H), 7.83–7.67 (m, 1H), 7.33 (s, 2H), 7.25–6.91 (m, 1H), 6.76 (d, J =7.2Hz,1H),5.42(dd,J=19.4,7.2Hz,1H),3.67–3.52(m,2H),2.52(s,3H),2.38–2.16(m,2H),2.11–1.92(m,2H).

[0260] Step 5)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of pyrazin-1-yl)-N-(5-cyano-4-methylthiazo-2-yl)benzamide

[0261] The title compound in this step was prepared according to the method described in step 9 of Example 1, namely, (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-cyano-4-methylthiazo-2-yl)benzamide (300 mg, 0.67 mmol), 2-butynic acid (59 mg, 0.71 mmol) and N,N-diisopropylethylamine (173 mg, 1.34 mmol) were added to DMF (5 mL), and 1-hydroxybenzotriazole (137 mg, 1.01 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (194 mg, 1.01 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours to prepare the compound. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with water (15 mL × 2), collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (258 mg, 75%).

[0262] MS(ESI,pos.ion)m / z:511.10[M+H] + ;

[0263] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.02 (d, J = 7.9Hz, 2H), 7.73 (d, J = 7.8Hz, 2H), 7.65 (d, J = 4.4Hz, 1H), 6.99 (d, J = 3.7Hz,1H),3.86–3.75(m,1H),2.52(s,3H),2.50–2.31(m,4H),2.06(dt,J=17.5,8.3Hz,2H),1.94(s,3H).

[0264] Example 5 (S)-2-(4-(8-amino-3-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxamide

[0265]

[0266] Step 1)(S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamide Synthesis of 4-methylthiazol-5-carboxamide

[0267] (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-cyano-4-methylthiazolyl-2-yl)benzamide (200 mg, 0.45 mmol) and dimethyl sulfoxide (10 mL) were added sequentially to a 100 mL reaction flask. The system was cooled to 0 °C, and 30% hydrogen peroxide solution (1.2 mL) and potassium carbonate (0.13 g, 0.90 mmol) were added sequentially. After the addition was complete, the mixture was transferred to room temperature and stirred for 1 hour. The reaction was stopped, water (50 mL) was added, and the mixture was filtered. The filtrate was evaporated to dryness to give the title compound as a pale yellow solid (180 mg, 87%).

[0268] MS(ESI,pos.ion)m / z:463.20[M+H] + ;

[0269] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.23 ​​(d, J = 8.2Hz, 2H), 7.80–7.66 (m, 1H), 7.58–7.52 (m, 2H), 7.33 (s, 2H), 7.25–6.91 (m, 1H), 6.76 ( d,J=7.2Hz,1H),5.42(dd,J=19.4,7.2Hz,1H),5.03(s,2H),3.67–3.52(m,2H),2.52(s,3H),2.38–2.16(m,2H),2.11–1.92(m,2H).

[0270] Step 2)(S)-2-(4-(8-amino-3-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of α]pyrazin-1-yl)benzamido)-4-methylthiazol-5-carboxamide

[0271] The title compound of this step was prepared according to the method described in step 9 of Example 1, namely, (S)-2-(4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)benzamido)-4-methylthiazolyl-5-carboxamide (170 mg, 0.37 mmol), 2-butynic acid (33 mg, 0.39 mmol) and N,N-diisopropylethylamine (95 mg, 0.74 mmol) were added to DMF (5 mL), and 1-hydroxybenzotriazole (75 mg, 0.55 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (105 mg, 0.55 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours to prepare the compound. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with water (15 mL × 2), collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (153 mg, 79%).

[0272] MS(ESI,pos.ion)m / z:529.25[M+H] + ;

[0273] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.05 (d, J = 7.9Hz, 2H), 7.75 (d, J = 7.8Hz, 2H), 7.60 (d, J = 4.4Hz, 1H), 6.92 (d,J=3.7Hz,1H),3.83–3.72(m,1H),2.72(s,3H),2.53–2.29(m,4H),2.20–1.95(m,2H),1.88(s,3H).

[0274] Example 6: Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide

[0275]

[0276] Step 1) Synthesis of 4-bromo-N-(pyrimidin-2-yl)benzamide

[0277] 2-Aminopyrimidine (1.30 g, 13.67 mmol) and pyridine (25 mL) were stirred in an ice bath for 5 minutes, followed by the addition of a 5 mL solution of 4-bromobenzoyl chloride (3.30 g, 15.04 mmol) in dichloromethane. After the addition was complete, the mixture was transferred to room temperature and reacted for 17 hours. The reaction was stopped, quenched with water, and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give the title compound as a pale yellow solid (3.70 g, 97%).

[0278] MS(ESI,pos.ion)m / z:278.00[M+H] + ;

[0279] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.79 (s, 1H), 8.65 (d, J = 4.6Hz, 2H), 7.81 (d, J = 8.3Hz, 2H), 7.63 (d, J = 8.3Hz, 2H), 7.07 (t, J = 4.6Hz, 1H).

[0280] Step 2) N-(pyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzyl Synthesis of amides

[0281] 4-Bromo-N-(pyrimidin-2-yl)benzamide (3.50 g, 12.59 mmol), pinacol diborate (4.80 g, 18.89 mmol), potassium carbonate (3.48 g, 25.18 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 1.26 mmol), and 1,4-dioxane (35 mL) were added sequentially to the reaction flask. The system was protected with nitrogen, and the temperature was raised to 100 °C for 11 hours. The reaction was stopped, cooled to room temperature, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 4:1) to give the title compound as a pale yellow solid (3.90 g, 95%).

[0282] MS(ESI,pos.ion)m / z:326.20[M+H] + ;

[0283] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.80 (s, 1H), 8.66 (d, J = 4.6Hz, 2H), 7.80 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.3Hz, 2H), 7.08 (t, J = 4.6Hz, 1H), 1.25 (s, 12H).

[0284] Step 3)(S)-2-(8-amino-1-(4-(pyrimidin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazine-3- Synthesis of benzyl pyrrolidine-1-carboxylate

[0285] (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.00 g, 2.40 mmol), N-(pyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (1.02 g, 3.12 mmol), potassium carbonate (1.00 g, 7.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (90 mg, 0.12 mmol), 1,4-dioxane (10 mL), and water (4 mL) were added sequentially to the reaction flask. The system was protected with nitrogen and the temperature was raised to 95 °C for 16 hours. The reaction was stopped, cooled to room temperature, allowed to stand, and the organic phase was collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a yellow solid (515 mg, 40%).

[0286] MS(ESI,pos.ion)m / z:535.20[M+H] + ;

[0287] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.95 (s, 1H), 8.69 (d, J = 4.8Hz, 2H), 8.05 (d, J = 7.9Hz, 2H), 7.81 (d, J = 7.8Hz, 1H), 7.74–7.71 (m, 1H), 7.33 (s ,4H),7.22–7.07(m,4H),6.90(d,J=7.4Hz,2H),5.23–5.12(m,2H),5.04(d,J=12.4Hz,1H),3.75–3.66(m,2H),2.02(s,2H),1.92(s,2H).

[0288] Step 4)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl) Synthesis of (Bento) Benzamide

[0289] (S)-2-(8-amino-1-(4-(pyrimidin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (490 mg, 0.92 mmol), acetic acid (3 mL), and an acetic acid solution of hydrobromic acid (3 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction was stopped, and water (80 mL) and dichloromethane (25 mL) were added. The mixture was allowed to stand and separated. The aqueous phase was collected, and the pH of the solution was adjusted to 10 with 30% sodium hydroxide solution. The mixture was extracted twice with dichloromethane (50 mL). The organic phases were combined, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 15:1) to give the title compound as a pale yellow solid (210 mg, 57%).

[0290] MS(ESI,pos.ion)m / z:401.20[M+H] + ;

[0291] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 8.75 (d, J = 4.8Hz, 2H), 8.09 (d, J = 8.3Hz, 2H), 7.77 (dd, J = 13.8, 6.6Hz, 3H), 7.28 (t, J = 4.8Hz, 1H), 7.1 0(d,J=4.9Hz,1H),6.13(s,2H),4.60(t,J=7.2Hz,1H),2.93(t,J=6.8Hz, 2H), 2.28(dt,J=15.6,7.2Hz,1H),2.19–2.08(m,1H),1.96–1.73(m,3H).

[0292] Step 5)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide

[0293] (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-2-yl)benzamide (200 mg, 0.50 mmol), 2-butynic acid (50 mg, 0.60 mmol), N,N-diisopropylethylamine (129 mg, 1.0 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to the reaction flask. The reaction system was stirred in an ice bath. 1-hydroxybenzotriazole (101 mg, 0.75 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol) were added sequentially. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. The reaction was stopped, water (20 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with water (15 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 15:1) to give the title compound as a pale yellow solid (180 mg, 77%).

[0294] MS(ESI,pos.ion)m / z:467.20[M+H] + ;

[0295] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.75 (d, J = 4.8Hz, 2H), 8.09 (d, J = 8.3Hz, 2H), 7.77 (dd, J = 13.8, 6.6Hz, 3H), 7.28 (t, J = 4.8Hz, 1H), 7.10 (d, J = 4.9Hz ,1H),6.13(s,2H),4.60(t,J=7.2Hz,1H),2.93(t,J=6.8Hz,2H),2.28(dt ,J=15.6,7.2Hz,1H),2.19–2.08(m,1H),2.01(s,1H),1.96–1.73(m,3H).

[0296] Example 7 Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-dimethylpyrimidin-2-yl)benzamide

[0297]

[0298] Step 1) Synthesis of 4-bromo-N-(4,6-dimethylpyrimidin-2-yl)benzamide

[0299] 4,6-Dimethylpyrimidin-2-amine (1.10 g, 8.90 mmol) and pyridine (20 mL) were added sequentially to the reaction flask. After stirring for 5 minutes in an ice bath, a solution of 4-bromobenzoyl chloride (2.58 g, 9.8 mmol) in dichloromethane (5 mL) was added. After the addition was complete, the mixture was transferred to room temperature and reacted for 4 hours. The reaction was stopped, water (60 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give the title compound as a yellow solid (1.80 g, 66%).

[0300] MS(ESI,pos.ion)m / z:306.05[M+H] + ;

[0301] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.90 (s, 1H), 8.37 (s, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.63 (d, J = 8.5Hz, 2H), 2.25 (s, 6H).

[0302] Step 2) N-(4,6-dimethylpyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane- Synthesis of 2-yl)benzamide

[0303] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, 4-bromo-N-(4,6-dioxypyrimidin-2-yl)benzamide (1.80 g, 5.90 mmol), pinacol diborate (2.30 g, 9.0 mmol), potassium acetate (1.20 g, 12.0 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (440 mg, 0.589 mmol) were reacted in 1,4-dioxane (20 mL) under nitrogen protection at 95 °C for 10 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by chromatography (dichloromethane:methanol (v:v) = 50:1) to give the title compound as a pale yellow solid (1.60 g, 77%).

[0304] MS(ESI,pos.ion)m / z:354.20[M+H] + ;

[0305] 1 H NMR (400MHz, CDCl3) δ (ppm) 11.08 (s, 1H), 8.32 (s, 1H), 7.78 (d, J = 8.5Hz, 2H), 7.65 (d, J = 8.5Hz, 2H), 2.23 (s, 6H), 1.24 (s, 12H).

[0306] Step 3)(S)-2-(8-amino-1-(4-((4,6-dimethylpyrimidin-2-yl)formamido)phenyl)imidazo Synthesis of [1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0307] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.40 g, 3.36 mmol), N-(4,6-dimethylpyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (1.54 g, 4.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (126 mg, 0.168 mmol) and potassium carbonate (1.41 g, 10.10 mmol) reacted in a mixed solvent of 1,4-dioxane (15 mL) and water (5 mL) under nitrogen protection at 95 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, separated, and the organic phase was collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1) to give the title compound as a yellow solid (1.50 g, 79%).

[0308] MS(ESI,pos.ion)m / z:563.20[M+H] + ;

[0309] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.49 (s, 1H), 8.02 (d, J = 8.2Hz, 2H), 7.86 (d, J = 7.6Hz, 2H), 7.70 (s, 1H), 7.35 (s, 2H), 7.14 (s, 2H) ),6.91(s,1H),5.29(s,1H),5.11(dd,J=27.8,10.9Hz,2H),3.72(s,3H),2.35(s,2H),2.25(s,6H),1.98(d,J=47.8Hz,2H).

[0310] Step 4)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-di) Synthesis of methylpyrimidin-2-yl)benzamide

[0311] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, (S)-2-(8-amino-1-(4-((4,6-dimethylpyrimidin-2-yl)carboxamido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (700 mg, 1.25 mmol) was reacted with acetic acid (3 mL) and hydrobromic acid in acetic acid solution (2.5 mL, 33% mass) at room temperature for 2.5 hours with stirring. After the reaction was completed, dichloromethane (40 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was dissolved in water (20 mL). The pH of the solution was adjusted to >10 with saturated sodium bicarbonate solution, and the solution was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the title compound as a pale yellow solid (290 mg, 54%).

[0312] MS(ESI,pos.ion)m / z:429.20[M+H] + ;

[0313] 1 H NMR (400MHz, CDCl3) δ (ppm) 10.88 (s, 1H), 8.46 (s, 1H), 8.02 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.1Hz, 2H), 7.58 (d, J = 4.9Hz, 1H), 7 .11(d,J=5.0Hz,1H),3.48(s,1H),3.28–3.22(m,1H),3.08–3.03(m,1H),2.28–2.22(m,2H),2.20(s,6H),2.01–1.93(m,3H).

[0314] Step 5)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of pyrazin-1-yl)-N-(4,6-dimethylpyrimidin-2-yl)benzamide

[0315] The title compound of this step was prepared according to the method described in step 9 of Example 1, namely, (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-dimethylpyrimidin-2-yl)benzamide (430 mg, 1.00 mmol), 2-butynic acid (74 mg, 0.76 mmol) and N,N-diisopropylethylamine (258 mg, 2.00 mmol) were added to DMF (5 mL), and 1-hydroxybenzotriazole (147 mg, 1.09 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (209 mg, 1.09 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours to prepare the compound. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with water (15 mL × 2), concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (365 mg, 73%).

[0316] MS(ESI,pos.ion)m / z:495.25[M+H] + ;

[0317] 1 H NMR (400MHz, CDCl3) δ (ppm) 10.88 (s, 1H), 8.46 (s, 1H), 8.02 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.1Hz, 2H), 7.58 (d, J = 4.9Hz, 1H), 7.11 (d ,J=5.0Hz,1H),3.48(s,1H),3.28–3.22(m,1H),3.08–3.03(m,1H),2.28–2.22(m,2H),2.20(s,6H),2.01–1.93(m,2H),1.62(s,3H).

[0318] Example 8: Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-dimethoxypyrimidin-2-yl)benzamide

[0319]

[0320] Step 1) Synthesis of 4-bromo-N-(4,6-dimethoxypyrimidin-2-yl)benzamide

[0321] 2-Amino-4,6-dimethoxypyrimidine (1.50 g, 9.70 mmol) and pyridine (25 mL) were added sequentially to a 100 mL reaction flask. The mixture was stirred in an ice bath for 5 minutes. A solution of 4-bromobenzoyl chloride (2.30 g, 11.0 mmol) in dichloromethane (5 mL) was added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred for 15 hours. The reaction was stopped, and water (60 mL) was added. The mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give the title compound as a pale yellow solid (1.98 g, 61%).

[0322] MS(ESI,pos.ion)m / z:338.05[M+H] + ;

[0323] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.37 (s, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.63 (d, J = 8.5Hz, 2H), 5.82 (s, 1H), 3.92 (s, 6H).

[0324] Step 2) N-(4,6-dimethoxypyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron) Synthesis of alkyl-2-yl)benzamide

[0325] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, 4-bromo-N-(4,6-dimethoxypyrimidin-2-yl)benzamide (1.90 g, 5.60 mmol), pinacol diboronate (2.20 g, 8.40 mmol), potassium acetate (1.20 g, 11.0 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (410 mg, 0.56 mmol) were reacted in 1,4-dioxane (20 mL) under nitrogen protection at 95 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by chromatography (dichloromethane:methanol (v:v) = 30:1) to obtain the title compound as a pale yellow solid (2.10 g, 97%).

[0326] MS(ESI,pos.ion)m / z:386.25[M+H] + ;

[0327] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.38 (s, 1H), 7.73 (d, J = 8.5Hz, 2H), 7.65 (d, J = 8.5Hz, 2H), 5.83 (s, 1H), 3.95 (s, 6H), 1.20 (s, 12H).

[0328] Step 3)(S)-2-(8-amino-1-(4-((4,6-dimethoxypyrimidin-2-yl)formamido)phenyl)imidazo Synthesis of [1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester

[0329] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.80 g, 1.92 mmol), N-(4,6-dimethoxypyrimidin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (1.11 g, 2.88 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (71 mg, 0.096 mmol) and potassium carbonate (0.81 g, 5.76 mmol) reacted in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) under nitrogen protection at 95 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, separated, and the organic phase was collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1) to give the title compound as a yellow solid (535 mg, 47%).

[0330] MS(ESI,pos.ion)m / z:595.30[M+H] + ;

[0331] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.48 (s, 1H), 8.01 (d, J = 8.2Hz, 2H), 7.81 (d, J = 7.6Hz, 2H), 7.73 (s, 1H), 7.33 (s, 2H), 7.14 (s, 2H) ),6.91(s,2H),5.83(s,1H),5.29(s,1H),5.11(dd,J=27.8,10.9Hz,3H),3.96(s,6H),2.35(s,2H),1.98(d,J=47.8Hz,2H).

[0332] Step 4)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-di) Synthesis of methoxypyrimidine-2-yl)benzamide

[0333] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, (S)-2-(8-amino-1-(4-((4,6-dimethoxypyrimidin-2-yl)carboxamido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (520 mg, 0.875 mmol) was reacted with acetic acid (3 mL) and hydrobromic acid (3 mL, 33% mass) in acetic acid solution at room temperature for 2.5 hours with stirring. After the reaction was completed, dichloromethane (40 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was dissolved in water (20 mL). The pH of the solution was adjusted to >10 with saturated sodium bicarbonate solution, and the solid was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the title compound as a pale yellow solid (180 mg, 45%).

[0334] MS(ESI,pos.ion)m / z:461.20[M+H] + ;

[0335] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.46 (s, 1H), 8.02 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.1Hz, 2H), 7.58 (d, J = 4.9Hz, 1H), 7 .11(d,J=5.0Hz,1H),3.96(s,6H),3.28–3.22(m,1H),3.08–3.03(m,1H),2.28–2.22(m,2H),2.01–1.93(m,3H).

[0336] Step 5)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of pyrazin-1-yl)-N-(4,6-dimethoxypyrimidin-2-yl)benzamide

[0337] The title compound in this step was prepared according to the method described in step 9 of Example 1, namely, (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,6-dimethoxypyrimidin-2-yl)benzamide (160 mg, 1.00 mmol), 2-butynic acid (67 mg, 1.05 mmol) and N,N-diisopropylethylamine (258 mg, 2.00 mmol) were added to DMF (5 mL), and 1-hydroxybenzotriazole (220 mg, 1.49 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.49 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours to prepare the compound. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with water (15 mL × 2), concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (410 mg, 78%).

[0338] MS(ESI,pos.ion)m / z:527.25[M+H] + ;

[0339] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.46 (s, 1H), 8.02 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.1Hz, 2H), 7.58 (d, J = 4.9Hz, 1H), 7.11 (d, J = 5.0 Hz,1H),3.96(s,6H),3.48(s,1H),3.28–3.22(m,1H),3.08–3.03(m,1H),2.28–2.22(m,2H),2.01–1.93(m,2H),1.62(s,3H).

[0340] Example 9: Synthesis of (S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide

[0341]

[0342] Step 1) Synthesis of 4-bromo-N-(pyridazine-3-yl)benzamide

[0343] The following compounds were added sequentially to the reaction flask: pyridazine-3-amine (1.50 g, 15.78 mmol), 4-bromobenzoic acid (3.80 g, 19.00 mmol), DMF (15 mL), and N,N-diisopropylethylamine (9.15 mL, 52.53 mmol). After the addition was complete, the mixture was heated to 60 °C and reacted for 30 minutes. Then, a 50% mass solution of ethyl acetate in 1-propylphosphonic anhydride (18.80 mL, 63.21 mmol) was added. After the addition was complete, the mixture was stirred at 60 °C for 4 hours. The reaction was stopped, cooled to room temperature, and 60 mL of water was added. The pH of the solution was adjusted to 8–9 with sodium bicarbonate. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was evaporated to dryness to obtain the title compound as a grayish-brown solid (3.90 g, 89%).

[0344] MS(ESI,pos.ion)m / z:278.00[M+H] + ;

[0345] 1 H NMR (600MHz, CDCl3) δ (ppm) 9.62 (s, 1H), 8.97 (d, J = 3.7Hz, 1H), 8.60 (d, J = 8.9Hz ,1H),7.88(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.55(dd,J=9.0,4.7Hz,1H).

[0346] Step 2) N-(pyridazin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl Synthesis of amides

[0347] The title compound in this step was prepared according to the method described in step 6 of Example 1, namely, 4-bromo-N-(pyridazin-3-yl)benzamide (3.50 g, 12.64 mmol), pinacol diborate (4.37 g, 17.21 mmol), potassium acetate (2.50 g, 25.49 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (485 mg, 0.663 mmol) were reacted in ethylene glycol dimethyl ether (35 mL) under nitrogen protection at 95 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by chromatography (dichloromethane:methanol (v:v) = 30:1) to obtain the title compound as a brown solid (2.45 g, 60%).

[0348] MS(ESI,pos.ion)m / z:326.20[M+H] + ;

[0349] 1H NMR (600MHz, CDCl3) δ (ppm) 9.34 (s, 1H), 8.97 (d, J = 3.5Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 8.00–7.91 (m, 4H), 7.54 (dd, J = 9.0, 4.7Hz, 1H), 1.36 (s, 12H).

[0350] Step 3)(S)-2-(8-amino-1-(4-(pyridazin-3-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3- Synthesis of benzyl pyrrolidine-1-carboxylate

[0351] The title compound of this step was prepared according to the method described in step 7 of Example 1, namely, (S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.60 g, 1.44 mmol), N-(pyridazin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (0.56 g, 1.73 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (110 mg, 0.144 mmol), and potassium carbonate (0.60 g, 4.33 mmol) in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) under nitrogen protection at 105 °C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, allowed to stand, separated, and the organic phase was collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1) to give the title compound as a pale yellow solid (0.73 g, 96%).

[0352] MS(ESI,pos.ion)m / z:535.05[M+H] + ;

[0353] 1 H NMR (400MHz, CDCl3) δ (ppm) 9.72 (s, 1H), 8.98 (d, J = 3.9 Hz, 1H), 8.68 (dd, J = 9 .0,1.1Hz,1H),8.10(d,J=8.2Hz,2H),7.95–7.61(m,3H),7.56(dd,J=9.0,4. 7Hz,1H),7.33(s,3H),7.24–7.04(m,2H),6.90(d,J=7.0Hz,1H),5.29(s,2H) ,5.11–5.02(m,1H),3.77–3.63(m,2H),2.43–2.29(m,2H),1.33–1.23(m,2H).

[0354] Step 4)(S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-) Synthesis of (Bento) Benzamide

[0355] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, (S)-2-(8-amino-1-(4-(pyridazin-3-ylcarboxamido)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.65 g, 1.22 mmol) reacted with acetic acid (3 mL) and hydrobromic acid in acetic acid solution (5 mL, 33% mass) at room temperature for 2 hours. After the reaction was completed, dichloromethane (40 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was dissolved in water (20 mL). The pH of the solution was adjusted to >10 with saturated sodium bicarbonate solution, and the solution was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the title compound as an off-white solid (0.31 g, 64%).

[0356] MS(ESI,pos.ion)m / z:401.20[M+H] + ;

[0357] 1 H NMR(400MHz, DMSO-d6)δ(ppm)9.03(dd,J=4.7,1.2Hz,1H),8.42(dd,J=9.0,1.2Hz,1H),8.20(d,J=8.3Hz,2H),7.83–7 .70(m,4H),7.09(d,J=4.9Hz,1H),4.55(t,J=7.1Hz,1H),2.89(t,J=6.7Hz,2H),2.34–2.05(m,2H),1.96–1.69(m,2H).

[0358] Step 5)(S)-4-(8-amino-3-(1-(1-oxo-2-butyn-1-yl)pyrrolidine-2-yl)imidazo[1,5- Synthesis of α]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide

[0359] The title compound of this step was prepared according to the method described in step 9 of Example 1, namely, (S)-4-(8-amino-3-(pyrrolidone-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide (290 mg, 0.73 mmol), 2-butynic acid (64 mg, 0.76 mmol) and N,N-diisopropylethylamine (188 mg, 1.46 mmol) were added to DMF (5 mL), and 1-hydroxybenzotriazole (147 mg, 1.09 mmol) and 1-(3-dimethylamidopropyl)-3-ethylcarbodiimide hydrochloride (209 mg, 1.09 mmol) were added sequentially under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 3 hours to prepare the compound. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with water (15 mL × 2), collected, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 20:1) to give the title compound as a pale yellow solid (252 mg, 74%).

[0360] MS(ESI,pos.ion)m / z:467.15[M+H] + ;

[0361] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.02 (d, J = 3.5 Hz, 1H), 8.40 ( d, J = 8.9 Hz, 1H), 8.17 ( d, J = 8.2 Hz, 2H), 7.90 ( dd, J = 31.1, 5.0 Hz ,1H),7.74(dd,J=8.3,3.5Hz,3H),7.13(dd,J=15.5,5.0Hz,1H),4.28–3.90(m,2H),2.94–2.55(m,2H),2.27–1.75(m,6H).

[0362] Biological experiments

[0363] Example A: Experiment on the inhibitory effect of the compound of the present invention on BTK

[0364] Experimental methods

[0365] Prepare 1x kinase base buffer and 1x stop buffer. Prepare a 50x compound solution at the starting well concentration using DMSO (e.g., prepare a 500μM compound solution if the starting well concentration is 10μM), and perform a 4-fold serial dilution, resulting in 10 dilutions. Simultaneously prepare two wells containing only 100% DMSO; the well without BTK kinase will serve as a negative control, and the well without the drug will serve as a positive control. Negative and positive control wells without BTK kinase and the drug are also prepared. Transfer at least 20μL of each prepared compound concentration to a 96-well plate, add 180μL of 1x kinase base buffer to each well, and mix thoroughly. Then, transfer 5μL to each well in a 384-well plate, with two replicates per concentration. Prepare a 2.5x BTK solution and a FAM-labeled substrate peptide (Peptide FAM-P2) solution. Except for the negative control well, which contained 10 μL of 1x kinase base buffer, the remaining wells contained 10 μL of BTK solution (2.5x) and were incubated at room temperature for 10 min. Then, 10 μL of FAM-labeled substrate peptide solution (2.5x) was added to each well, and the mixture was incubated at 28°C for a specific time. Finally, 25 μL of 1x stop buffer was added to each well to terminate the reaction. The data was detected using a Caliper instrument. The kinase inhibition rate was calculated using the formula: (max-sample) / (max-min)*100, where max represents the positive control group data value, min represents the negative control group data value, and sample represents the data value at different drug concentrations. The equation Y = Bottom + (Top-Bottom) / (1 + (IC)) was used. 50 Fit the HillSlope data and calculate IC. 50 Values. See Table A for experimental results.

[0366] Table A: Experimental results of the inhibitory effect of the compounds of this invention on BTK

[0367] Example No. <![CDATA[IC 50 (nM)]]> Example 1 17 Example 2 18 Example 3 6.9

[0368] Experimental results show that the compound of this invention has a significant inhibitory effect on BTK.

[0369] Example B: Pharmacokinetic evaluation of the compounds of the present invention in rats, dogs, and monkeys after intravenous injection or gavage.

[0370] 1) Test animals The test animals were rats, dogs, and monkeys, as detailed in Table 1.

[0371] Table 1

[0372] phylogenetics grade gender quantity weight source SD rats SPF level male 6 180-220g Changzhou Cavens Beagle dog Normal male 3 5-7kg Beijing Mars monkey Normal male 3 5-6kg Guangdong Landao

[0373] 2) Analytical Methods :

[0374] The LC-MS / MS system used for analysis included an Agilent 1200 series vacuum degasser, a quaternary pump, an autosampler for well plates, a constant temperature column oven, and an API4000Qtrap triple quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and the source parameters for MRM conversion are shown in Table 2.

[0375] Table 2

[0376]

[0377]

[0378] Analysis was performed using a Waters Xbridge C18 column (2.1 × 50 mm, 3.5 μM column, 0.5 μL sample injection). The analytical conditions were as follows: mobile phase A consisted of water + 2 mM ammonium formate + 0.1% formic acid, and mobile phase B consisted of methanol + 2 mM ammonium formate + 0.1% formic acid. The flow rate was 0.5 mL / min. The mobile phase gradient is shown in Table 3.

[0379] Table 3

[0380] time gradient of mobile phase B 0.3min 10％ 0.7min 90％ 2.0min 90％ 2.01min 10％ 3.0min termination

[0381] 3) Test methods :

[0382] The pharmacokinetic evaluation of the compounds of the present invention in rats, dogs, and monkeys was carried out in the following steps:

[0383] Each animal species was divided into two groups: one group was administered the compound via intravenous injection, and the other group was administered it via gavage. The compound was administered to the test animals as a homogeneous suspension of 10% DMA + 89.5% saline + 0.5% (2M HCl) (pH: 4-5) or 5% DMA + 95% (2% HPMC). For the intravenous injection group, the dose was 0.5 mg / kg, and blood samples (0.3 mL) were collected intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. The plasma solution was collected by centrifugation at 4,000 rpm for 5 minutes and stored at -20°C or -70°C. For the gavage administration group, the dose was 2.5 mg / kg. Blood samples (0.3 mL) were collected intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration. The plasma solution was collected by centrifugation at 4,000 rpm for 5 minutes and stored at -20°C or -70°C.

[0384] Take 30 μl of plasma, add 120 μl of 50 ng / ml propranolol internal standard aqueous solution, mix well, and extract with 1.0 ml of methyl tert-butyl ether (MTBE). Take 0.7 ml of supernatant, dry it under nitrogen, and redissolve it in 120 μl of methanol-water (methanol:water = 1:1). The concentration of the target compound was determined by LC-MS / MS, and pharmacokinetic parameters were calculated using a non-compartmental model.

[0385] Test results show that the compounds of the present invention, administered via intravenous injection and gavage in rats, dogs, and / or monkeys, exhibit good pharmacokinetic properties.

[0386] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0387] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I). in, R 1 for Where R n -C(=O)-R x Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; t is 0, 1, 2, 3, or 4; R x It is a C2-C6 alkenyl or C2-C6 alkynyl, wherein the C2-C6 alkenyl and C2-C6 alkynyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl and heterocyclic groups consisting of 3 to 6 atoms; R 2 It is H, D, C1-C6 alkyl or C1-C6 haloalkyl; R 3 for Among them, each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms; each R 3g and R 3h Independently, it can be F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R 4 and R 5 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; n is 0, 1, 2, 3 or 4; m can be 0, 1, or 2.

2. The compound according to claim 1, wherein, R 1 for R n -C(=O)-R x , Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; R x It is a C2-C4 alkenyl or C2-C4 alkynyl group, wherein the C2-C4 alkenyl and C2-C4 alkynyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl and heterocyclic groups consisting of 3 to 6 atoms.

3. The compound according to claim 1 or 2, wherein, R 1 for Each R y Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propynyl, ethynyl, propynyl, propynyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, or difluoromethoxy; R 1a It can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms.

4. The compound according to claim 3, wherein it is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

5. The compound according to claim 3 or 4, wherein, R 1a The following are possible values: H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, propargyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

6. The compound according to any one of claims 1-5, wherein, Each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R 3g and R 3h Independently, it can be F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R a and R d Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R b R c R e and R f Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

7. The compound according to any one of claims 1-6, wherein, Each R 3a R 3b R 3c R 3d R 3e and R 3f Independently, H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, -COOR a -CONR b R c , phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, furanyl, pyridyl, pyrazinyl or pyrimidinyl; Each R 3g and R 3h Independently, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl or pyrimidinyl; Each R a and R d Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl; Each R b R c R e and R f Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.

8. The compound according to any one of claims 1-7, wherein it is a compound or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, which is one of the following:

9. A pharmaceutical composition comprising the compound of any one of claims 1-8 and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament, wherein, The drug is used to prevent or treat diseases related to BTK; Optionally, the BTK-related diseases are tumors, thromboembolic diseases, inflammatory conditions, and / or autoimmune diseases; Optionally, the tumor is a B-cell lymphoma, a solid tumor, and / or a hematologic and immune system tumor; Optionally, the inflammatory condition or autoimmune disease is asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

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