9-membered heteroaryl compound, pharmaceutical composition containing 9-membered heteroaryl compound, and preparation method and application of 9-membered heteroaryl compound

Abstract

The invention relates to a 9-membered heteroaryl compound, a pharmaceutical composition containing the 9-membered heteroaryl compound and a preparation method and application of the 9-membered heteroaryl compound, and the 9-membered heteroaryl compound has a structure as shown in a formula I. The 9-membered heteroaryl compound can be used for treating BTK-related diseases such as tumors or autoimmune system diseases. # imgabs0 #

Description

9-membered heteroaryl compound, pharmaceutical composition containing same, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a 9-membered heteroaryl compound, a pharmaceutical composition containing the same, and a preparation method and application thereof. Background Art

[0002] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor protein tyrosine kinases, is a key regulator of the B cell antigen receptor (BCR) signaling pathway, expressed in lymphoid tissues, bone marrow, and spleen. Aberrant activation of the BCR signaling pathway triggers downstream signaling pathways, including tumor cell proliferation, differentiation, and angiogenesis. BTK mutations lead to X-linked agammaglobulinemia (XLA), in which B cell maturation is impaired, resulting in reduced immunoglobulin production (Hendriks et al.; Expert Opin Ther Targets 15; 1002-1021, 2011). BTK's central role in B cell signaling and function makes it an attractive therapeutic target for B cell malignancies, as well as autoimmune and inflammatory diseases.

[0003] CRBN is a brain-associated protein with ionase activity. It interacts with DNA damage binding protein-1 (DDB1), cullin 4 (CUL4A), and the regulatory factor cullins1 (ROC1) to form a functional E3 ubiquitin ligase complex (CRBN-CRL4). This complex recognizes specific proteins through substrate receptors (SRs), promoting the specific binding of ubiquitin to the substrates, marking them for degradation and initiating degradation. This complex primarily participates in cell cycle regulation, embryonic development, and carcinogenesis by regulating DNA repair, replication, and transcription. Anticancer drugs of the doxorubicin class target CRBN. They inhibit CRBN autoubiquitination and prevent CRBN from forming CRBN-CRL4 (an E3 ubiquitin ligase) with DDB1, CUL4A, and ROC1, thereby modulating downstream signaling and exerting regulatory functions.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce target proteins to be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. Degrading BTK protein can significantly affect B cell function by effectively blocking BCR signaling. Removing BTK will eliminate BTK kinase activity and any protein interaction or scaffold function of BTK. By recruiting BTK to the ubiquitin ligase CRBN through heterologous bifunctional small molecules, thereby promoting BTK ubiquitination and proteasomal degradation, specific degradation of BTK can be achieved. BTK (C481S) mutations cause resistance to covalent BTK inhibitors such as ibrutinib (Woyach, et al.; Blood, 120(6):1175-1184, 2012.), and this degradation method can also effectively target BTK (C481S) mutations. WO2020239103, CN110845500, US11028088, etc. have demonstrated PROTAC compounds with excellent performance.

[0005] Because the BTK-PROTAC molecule contains an amine compound structural group, it may degrade the amine compound substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3), causing various toxic side effects such as thrombocytopenia and neutropenia.

[0006] Therefore, there is a need in the art to develop a PROTAC compound with good efficacy, good bioavailability, greater safety, and the ability to inhibit or degrade BTK protein.

[0007] Summary of the Invention

[0008] The present invention aims to provide a PROTAC compound with good efficacy, good bioavailability, and enhanced safety, capable of inhibiting or degrading the BTK protein, for the treatment of BTK-related diseases such as tumors, autoimmune diseases, or inflammatory diseases. This PROTAC compound can attenuate substrate degradation caused by immunomodulatory imide drugs (IMiDs), thereby reducing IMiD activity.

[0009] In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof, or a hydrate thereof.

[0010] in,

[0011] is a single bond or a double bond;

[0012] A1 is a 9-membered heteroaryl group, wherein the 9-membered heteroaryl group contains 1, 2, 3, 4, 5 or 6 heteroatoms, at least one of which is N; the remaining heteroatoms are independently selected from N, O or S; preferably, A1 is wherein A'1 is a 5-membered heteroaryl, a 5-membered heterocyclic group or a C5 cycloalkyl group, and A"1 is a phenyl group or a 6-membered heteroaryl group, wherein the heteroaryl group contains 1, 2, 3, 4 or 5 heteroatoms, at least one of which is N, and the remaining heteroatoms are independently selected from N, O or S; more preferably, A1 is wherein Z1, Z2, Z3, Z4 and Z5 are each independently selected from: N, NR1 or CR1; Z6 and Z7 are each independently selected from: N or C; the 9-membered heteroaryl is optionally substituted by a group selected from the group consisting of: halogen, oxo (=O), cyano, C1-4 alkyl, halogenated C1-4 alkyl;

[0013] A2 is phenyl, 6-membered heteroaryl or 5-membered heteroaryl, wherein the 6-membered heteroaryl and 5-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms, and the heteroatoms are each independently selected from O, S or N;

[0014] A5 is selected from: 5-15 membered heterocyclyl, C5-C12 cycloalkyl, 5-15 membered heteroaryl, C6-C15 aryl, wherein Cy2, Cy4 and Cy6 are each independently selected from: a 5-15 membered heterocyclic group or a C5-C12 cycloalkyl group, and Cy3 and Cy5 are each independently selected from: a 5-15 membered heteroaryl group or a C6-C15 aryl group;

[0015] Z8 and Z9 are each independently selected from: C, N or CR3;

[0016] Z 15 Select from: N or CR 10 ;

[0017] X and Y are each independently selected from: N or CR6;

[0018] W1 is selected from: -CF2-, -CH2-, -CHR4-、-O-、-S-、-NR4-、 or key;

[0019] Cy1 is selected from: C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl, wherein the heterocyclyl and heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms, and the heteroatoms are each independently selected from O, S or N;

[0020] AL1, AL2, AL3 and L4 are each independently selected from: a bond, -(CH2)NHCO-, -(CHMe)NHCO-, -(CR 11 R 12 )NHCO-、-(CR 11 R 12 ) n8 NR 13 CO-, -(CH2)NHSO2-, -(CHMe)NHSO2-, -(CR 11 R 12 )NHSO2-、-(CR 11 R 12 ) n8 NR 13 SO2-, -CH2-, -CF2-, -NHSO2-, -SO2NH-, -SO2NR 12 -、-O-、-S-、-SO2-、-NR 11 -、-(CH2) n8 -、-CO-、-(CH2) n8 NR 11 -、-CONR 11 -、-NR 11 CO- or -(CH2) n8 NR 11 CO-;

[0021] R1, R2, R3, R4, R5, R6, R7, R 10 、R 11 、R 12 and R 13 Each is independently selected from: H, halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R a replace;

[0022] R8 is selected from: H, C1-C6 alkyl, The H in the above-CH2- is optionally replaced by R a replace;

[0023] R9 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH2, CN, OMe, Me, -CH2OH, -CH2CH2OH, CO2H, CF3, CHF2, CONH2, or a 5- or 6-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; each of the aromatic rings is optionally substituted with halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl, CN, NO2, OR d 、SO2R d 、COR d 、CO2R d 、CONR d R b 、C(=NR d )NR b R c NR d R b 、NHR d 、COR b NR d CONR b R c NR d CO2R b NR d SONR b R c NR d SO2NR b R c or NR d SO2R b , wherein the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl is optionally substituted with halogen, hydroxy, halogenated C1-C8 alkyl, C1-C8 alkoxy, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl;

[0024] Alternatively, two adjacent R2 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 R e replace;

[0025] Alternatively, two adjacent R3 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally replaced by 1, 2, 3 or 4 R e replace;

[0026] Alternatively, two adjacent R5 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally replaced by 1, 2, 3 or 4 R e replace;

[0027] Alternatively, two adjacent R6 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally replaced by 1, 2, 3 or 4 R e replace;

[0028] Alternatively, two adjacent R7 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally replaced by 1, 2, 3 or 4 R e replace;

[0029] R a 、R b 、R c 、R d and R e Each is independently selected from: halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is optionally further substituted with 1, 2, 3 or 4 groups selected from the group consisting of halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo (=O), C1-C6 alkyl and C1-C6 alkoxy;

[0030] n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from: 0, 1, 2, 3, 4 or 5.

[0031] In another preferred embodiment, A1 is a 5-membered heteroaryl group and a 6-membered heteroaryl group.

[0032] In another preferred embodiment, Z1 is selected from: N or CH.

[0033] In another preferred embodiment, Z2 is selected from: N or CH.

[0034] In another preferred embodiment, Z3 is selected from: N, O, S, NH, CH or CH2; preferably, Z3 is selected from: N, NH or CH.

[0035] In another preferred embodiment, Z4 is selected from: N, O, S, NH, CH or CH2; preferably, Z4 is selected from: N, NH or CH.

[0036] In another preferred embodiment, Z5 is selected from: N, O, S, NH, CH or CH2; preferably, Z5 is selected from: N or CH.

[0037] In another preferred embodiment, Z6 is C or N.

[0038] In another preferred embodiment, Z7 is C or N; preferably, Z7 is C.

[0039] In another preferred embodiment, A1 is selected from:

[0040] In another preferred embodiment, Cy1 is selected from: a 5-12 membered heterocyclic group, a 4-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group;

[0041] Preferably, Cy1 is selected from the group consisting of piperazinyl, piperidinyl, phenyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 7-11 membered spiroheterocyclic group, 7-12 membered fused heterocyclic group or bridged heterocyclic group.

[0042] In another preferred embodiment, Cy1 is selected from:

[0043] In another preferred embodiment, R5 is selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkylOH; preferably, R5 is selected from: H.

[0044] In another preferred embodiment, n5 is 0, 1 or 2; preferably, n5 is 0.

[0045] In another preferred embodiment, L4 is a bond.

[0046] In another preferred embodiment, R9 is selected from: H or

[0047] In another preferred embodiment, A2 is phenyl.

[0048] In another preferred embodiment, R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy; preferably, R2 is H or F.

[0049] In another preferred embodiment, n2 is 0 or 1.

[0050] In another preferred embodiment, Selected from: Preferably, Selected from:

[0051] In another preferred embodiment, part B is selected from:

[0052] In another preferred embodiment, A5 is selected from: phenyl, pyridyl, pyrazinyl, thiazolyl, thienyl, furyl, oxazolyl, Preferably, A5 is selected from: The above groups may be optionally substituted by 1, 2, 3 or 4 R7.

[0053] In another preferred embodiment, R7 is selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy, more preferably, R7 is selected from: H or methyl.

[0054] In another preferred embodiment, n7 is 0 or 1.

[0055] In another preferred embodiment, W1 is selected from: a bond or CONH.

[0056] In another preferred embodiment, Z 15 Selected from: N or CH.

[0057] In another preferred embodiment, R8 is H.

[0058] In another preferred embodiment, part K is selected from:

[0059] In another preferred embodiment, is a double bond, and Z9 is C.

[0060] In another preferred embodiment, Z8 is selected from: CH or N.

[0061] In another preferred embodiment, Z9 is selected from: CH or N; preferably, Z9 is N.

[0062] In another preferred embodiment, R3 is H, methyl, halogen or OH; preferably, R3 is H.

[0063] In another preferred embodiment, n3 is selected from: 0 or 1; preferably, n3 is 0.

[0064] In another preferred embodiment, Selected from:

[0065] In another preferred embodiment, X is selected from: CH or N.

[0066] In another preferred embodiment, Y is selected from: CH or N; preferably, Y is N.

[0067] In another preferred embodiment, n1 is 0, 1 or 2; preferably, n1 is 2.

[0068] In another preferred embodiment, n4 is 0, 1 or 2; preferably, n4 is 2.

[0069] In another preferred embodiment, R6 is selected from: H, methyl, halogen or OH; preferably, R6 is H.

[0070] In another preferred embodiment, n6 is 0 or 1; preferably, n6 is 0.

[0071] In another preferred embodiment, Selected from: key,

[0072] In another preferred embodiment, AL1 is a bond.

[0073] In another preferred embodiment, AL2 is selected from: a bond, O, SO2, NH, CH2, CHCH3, CH2CH2 or CH2CF2, preferably, AL2 is CH2.

[0074] In another preferred embodiment, AL3 is a bond.

[0075] In another preferred embodiment, partL is selected from: Wherein, the above groups are optionally substituted by 1, 2, 3 or 4 R3 or R6, and R3 or R6 are as defined above.

[0076] In another preferred embodiment, the compound has a structure shown in Formula II:

[0077] in,

[0078] Y1, Y2 and Y3 are each independently selected from CH, N or CR2;

[0079] Y4 and Y5 are each independently selected from CH, N or CR7;

[0080] X, Y, Z8, Z9, Z 15 , R2 and R7 are as defined above;

[0081] Preferably, the compound has a structure shown in Formula III:

[0082] in,

[0083] Y1, Y2 and Y3 are each independently selected from: CH, N or CR2;

[0084] Y4 and Y5 are each independently selected from: CH, N or CR7;

[0085] R2 and R7 are defined as above. In another preferred embodiment, in formula III, Y1, Y2 and Y3 are each independently selected from: N or CR 2； R2 is H, halogen, C1-3 alkyl or halogenated C1-C3 alkyl.

[0086] In another preferred embodiment, in Formula III, Y4 and Y5 are each independently selected from: CH, N or CR7; wherein, R7 is halogen, C1-C3 alkyl or halogenated C1-C3 alkyl.

[0087] In another preferred embodiment, the compound is selected from:

[0088] In another preferred embodiment, the compound is the compound prepared in Examples 1, 3, 8, and 9.

[0089] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, and one or more pharmaceutically acceptable carriers or excipients.

[0090] In a third aspect, the present invention provides a compound as described in the first aspect, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof or a hydrate thereof, or a pharmaceutical composition as described in the second aspect for use in the preparation of a medicament for treating BTK-mediated diseases.

[0091] In another preferred embodiment, the autoimmune disease is selected from: lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, complications caused by organ transplantation, diabetes, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia or lymphoma.

[0092] In another preferred embodiment, the inflammatory disease is selected from: keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis or appendicitis.

[0093] In another preferred embodiment, the tumor is selected from: small lymphocytic lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, multiple myeloma or mantle cell lymphoma.

[0094] In a fourth aspect, the present invention provides a compound as described in the first aspect, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof or a hydrate thereof, or a pharmaceutical composition as described in the second aspect for use in the preparation of a drug for inhibiting or regulating the activity of BTK protein kinase.

[0095] Preferably, the BTK protein kinase is a non-mutated BTK protein kinase or a mutated BTK protein kinase.

[0096] Wherein, the mutant BTK protein kinase is preferably a C481S mutant BTK protein kinase.

[0097] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0098] Through extensive and in-depth research, the present inventors have discovered for the first time a new PROTAC compound with excellent efficacy, bioavailability, safety, the ability to inhibit and degrade BTK protein, and minimal or no IMiD degradation. This invention was completed on this basis.

[0099] Unless otherwise specified herein, the terms used have the general meanings commonly understood by those skilled in the art.

[0100] When substituents are described by a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents that would result when the formula is written from right to left.

[0101] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0102] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0103] As used herein, the term "alkyl" includes straight-chain or branched alkyl groups. The alkyl group may be, for example, a C1-C6 alkyl group, which represents a straight-chain or branched alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0104] As used herein, the term "alkenyl" includes straight or branched alkenyl groups. Alkenyl groups may be, for example, C2-C8 alkenyl groups, which refer to straight or branched alkenyl groups having 2-8 (e.g., 2, 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C2-C6 alkenyl or C2-C4 alkenyl groups, examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0105] As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. Alkyl groups can be, for example, C2-C8 alkynyl groups, which refer to straight-chain or branched alkynyl groups having 2-8 (e.g., 2, 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C2-C6 alkynyl groups or C2-C4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, or similar groups.

[0106] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group containing a specific number of carbon atoms, such as a "C3-C20 cycloalkyl" refers to a cycloalkyl group having 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, and a "C5-C12 cycloalkyl" refers to a cycloalkyl group having 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. Preferably, it is a C3-C6 cycloalkyl group. A cycloalkyl group can be a monocyclic ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar group. It can also be a bicyclic form, such as a bridged ring or spirocyclic form. As used herein, cycloalkyl is intended to include substituted cycloalkyl groups.

[0107] As used herein, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1-6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6); it has the formula C1-C6 alkyl-O- or -C1-C5 alkyl-O-C1-C5 alkyl (e.g., -CH2-O-CH2CH3, -CH2-O-(CH2)2CH3, -CH2CH2-O-CH2CH3), preferably C1-C6 alkyl-O-, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, etc.

[0108] As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms of N, S and O (including but not limited to 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring systems). For example, it may be a "3-20 membered heterocyclyl", which refers to a saturated or partially saturated cyclic group having 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) atoms, wherein 1-4 (e.g., 1, 2 or 3) atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic or bicyclic form, such as a bridged ring or spirocyclic form. The heterocyclyl is preferably a 5-15 membered heterocyclyl or a 4-12 membered heterocyclyl, more preferably a 4-8 membered or 4-6 membered heterocyclyl. Specific examples may include oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.

[0109] As used herein, "aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring. "C6-C15 aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring and has 6 to 15 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) carbon atoms. A C6-C15 aryl group is preferably a C6-C10 aryl group. The aryl group may be optionally substituted or unsubstituted.

[0110] As used herein, "heteroaryl" refers to a cyclic aromatic group having 1 to 4 (e.g., 1, 2, or 3) heteroatoms selected from the group consisting of N, S, and O. "5-15 membered heteroaryl" refers to a cyclic aromatic group having 5 to 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) atoms, of which 1 to 4 (e.g., 1, 2, or 3) atoms are heteroatoms selected from the group consisting of N, S, and O. The heteroaryl group is preferably a 5-12 membered heteroaryl group or a 5-10 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group, which may be a monocyclic ring or a condensed ring form. Specific examples can be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, formyl, formamide, carboxyl and carboxylate, etc.

[0111] As used herein, "aromatic ring" refers to an aryl group or a heteroaryl group, wherein a 5- or 6-membered aromatic ring refers to a 5- or 6-membered heteroaryl group and a 6-membered aryl group.

[0112] As used herein, "halogen" refers to F, Cl, Br and I. More preferably, the halogen is selected from F, Cl or Br.

[0113] As used herein, "amino" refers to -NH2.

[0114] As used herein, "carboxyl" refers to -COOH.

[0115] As used herein, the term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. Examples of ester groups include, but are not limited to: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2.

[0116] As used herein, the term "amido" refers to a group having the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of amide groups include, but are not limited to, -CONH2, -CONHCH3, -CON(CH3)2, and the like.

[0117] As used herein, the term "sulfonamide" refers to a group having the structure -SO2NRR' or RSO2NR'-, wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of sulfonamide groups include, but are not limited to: -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, CH3SO2NH-, CH3SO2NCH3-, and the like.

[0118] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or as appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specified group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0119] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl.

[0120] As used herein, "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0121] As used herein, the term "plurality" independently refers to a positive integer of 2, 3, 4, 5 or more.

[0122] When the linking group -L1- listed in the present invention does not specify its connection direction, its connection direction can be connected in the same direction as the reading order from left to right, or it can be connected in the opposite direction to the above direction. For example, the connection direction of the linking group listed in the present invention is connected in the same direction as the reading order from left to right. The following examples are provided. The connecting group -L1- is -CD-, if -CD- connects ring A and ring B in the same direction as reading from left to right to form If -CD- connects ring A and ring B in the opposite direction to the above direction, it will form

[0123] Active ingredient

[0124] As used herein, "compounds of the present invention" refer to compounds represented by Formula I, and also include stereoisomers, isotopic derivatives, pharmaceutically acceptable salts, prodrugs or solvates (including hydrates) of the compounds represented by Formula I.

[0125] Unless otherwise specified, the structural formulas described herein are intended to include all stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or conformational isomers are all within the scope of the present invention.

[0126] The compounds of the present invention may contain cis- and trans-isomers, one or more chiral carbon atoms, and thus may produce stereoisomeric forms such as cis- and trans-isomers, chiral isomers, enantiomers, diastereomers, and other combinations thereof. Cis- and trans-isomerism refers to the diastereoisomerism that occurs due to restrictions on the free rotation of the compound molecule, resulting in different spatial arrangements of the various groups. These restrictions are generally caused by the presence of functional groups in the organic compound structure that cannot rotate freely, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis- and trans-isomers. The cis form refers to the presence of ligands of the same type in adjacent positions, typically designated "cis" or "cis-"; the trans form refers to the presence of ligands of the same type in diagonal positions, typically designated "trans" or "trans-". Each chiral carbon atom can be defined as either (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, cis-trans isomers, chiral isomers, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0127] Conventional techniques for preparing / isolating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from appropriate cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, as described, for example, in Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0128] If a synthesis of a specific stereoisomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting stereomixture and removal of the chiral auxiliary to obtain a pure cis-trans monomer, chiral monomer, or mixed stereoisomer. If the molecule contains a cis-trans isomeric center, pure cis- or trans-forms can be obtained by purification via column chromatography (normal-phase silica gel or reverse-phase high-performance liquid chromatography). Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomers.

[0129] The present invention also includes isotopically labeled compounds (i.e., isotopic derivatives) that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. The isotopic derivatives of the compounds of the present invention are all within the scope of protection of the present invention. 3 H-labeled compounds and 14 C-labeled compounds are useful in drug and substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 The preparation and detection of C) labeled compounds are relatively easy and are the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain situations. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0130] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0131] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0132] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known to the profession.

[0133] Metabolites of the compound of formula I and its pharmaceutically acceptable salts, as well as prodrugs that can be converted into the compound of formula I and its pharmaceutically acceptable salts in vivo, are also included in the scope of protection of the present invention.

[0134] As used herein, the term "solvate" refers to a complex formed by the compound represented by Formula I and solvent molecules in a specific ratio.

[0135] As used herein, the term "hydrate" refers to a complex formed by the compound represented by Formula I coordinated with water molecules to form a specific ratio.

[0136] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" refers to the replacement of a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted with multiple substituents of a specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible organic group substitutions. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. Herein, for example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic groups described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible organic groups in any way. The present invention recognizes that combinations of substituents and variable groups are advantageous for the treatment of diseases by forming stable compounds. The term "stable" herein refers to compounds that are stable and maintain the structural integrity of the compound over a sufficient period of time for testing, preferably for a sufficient period of time for efficacy, and is used herein for such purposes.

[0137] Pharmaceutical compositions and methods of administration

[0138] Since the compounds of the present invention have excellent BTK kinase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) BTK kinase-related diseases (autoimmune diseases, inflammatory diseases or tumors, etc.).

[0139] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0140] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0141] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration, or subcutaneous administration).

[0142] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0143] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0144] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0145] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0146] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0147] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0148] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, anti-HBV agents).

[0149] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat BTK, especially diseases related to BTK mutations.

[0150] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0151] The main advantages of the present invention are:

[0152] 1. The compounds of the present invention have novel structures and excellent BTK and BTK(C481S) kinase inhibitory effects;

[0153] 2. The compounds of the present invention have good efficacy, good bioavailability, are safer, and can inhibit and degrade BTK and BTK (C481S) proteins.

[0154] 3. The compounds of the present invention can weaken the substrate degradation caused by immunomodulatory imine drugs (IMiDs), thereby reducing the activity of IMiDs.

[0155] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.

[0156] Herein, all temperatures are in °C unless otherwise specified.

[0157] Herein, v% refers to volume percentage.

[0158] Herein, unless otherwise specified, percentages have meanings well known to those skilled in the art. For example, the percentages for purity and yield are mass percentages; when a solid is dissolved to prepare a solution, the percentages are mass percentages; when a liquid is dissolved to prepare a solution, the percentages are volume percentages; and the percentages for gases are volume percentages, for example, 5% in 5% CO2 is a volume percentage.

[0159] Herein, unless otherwise specified, the ratio has a meaning commonly known to those skilled in the art. For example, the ratio of two solids is a mass ratio, and the ratio of two liquids or two gases is a volume ratio.

[0160] Herein, preparative PTLC or TLC (thin layer chromatography) was performed on 20 x 20 cm plates (500 micron thick silica gel); silica gel chromatography was performed using a Biotage flash chromatography system.

[0161] In this article, 1 H NMR (hydrogen spectrum) was performed using a Bruker AscendTM400 spectrometer, 400 MHz, 298 ° K, and the chemical shifts (ppm) of the residual protons in the deuterated reagent were given as reference: δ (chemical shift) of CDCl3 was 7.26 ppm, δ of CD3OD was 3.31 ppm, and δ of DMSO-d6 was 2.50 ppm.

[0162] In this article, in the LCMS (liquid chromatography-mass spectrometry) test, the liquid chromatography was performed using an Agilent Technologies 1200 series or 6120 quadrupole spectrometer; for the liquid chromatography, the mobile phase was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was: 5-95% A in 6.0 minutes, 60-95% A in 5.0 minutes, 80-100% A in 5.0 minutes, and 85-100% A in 10 minutes, using an SBC1850 mm × 4.6 mm × 2.7 μm capillary column; mass spectrometry (MS) was measured by electrospray ionization mass spectrometry (ESI).

[0163] In this article, the high performance liquid chromatography (HPLC)-mass spectrometry (MS) analysis conditions are:

[0164] LC1 column: SB-C18 50 mm × 4.6 mm × 2.7 μm;

[0165] Temperature: 50℃;

[0166] Eluent: 5:95 to 95:5 acetonitrile / water (the above ratios are by volume) + 0.01% formic acid, 6 minutes;

[0167] Flow rate: 1.5 mL / min, injection 5 μL;

[0168] Detection: PDA detector, 200-600 nm;

[0169] MS: mass range 150-750 amu; positive ion electrospray ionization.

[0170] LC2 column: SB-C18 50 mm × 4.6 mm × 2.7 μm;

[0171] Temperature: 50℃;

[0172] Eluent: 5:95 to 95:5 acetonitrile / water (the above ratios are by volume) + 0.05% TFA (trifluoroacetic acid) gradient over 3.00 minutes;

[0173] Flow rate: 1.5 mL / min, injection 5 μL;

[0174] Detection: PDA detector, 200-600 nm;

[0175] MS: mass range 150-750 amu; positive ion electrospray ionization.

[0176] LC3 column: SB-C18 50 mm × 4.6 mm × 2.7 μm;

[0177] Temperature: 50℃;

[0178] Eluent: 10:90 to 98:2 acetonitrile / water (the above ratios are by volume) + 0.05% TFA gradient over 3.75 minutes;

[0179] Flow rate: 1.0 mL / min, injection 10 μL;

[0180] Detection: PDA detector, 200-600 nm;

[0181] MS: mass range 150-750 amu; positive ion electrospray ionization.

[0182] In this article, the meanings of the abbreviations are as follows:

[0183] AcOH = acetic acid; Alk is an alkyl group; AR is an aryl group; Boc = tert-butyloxycarbonyl; CH2Cl2 = dichloromethane; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EA = ethyl acetate; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; HOAc = acetic acid; LiOH = lithium hydroxide; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MgSO4 = magnesium sulfate; NaCl = sodium chloride; NaOH = sodium hydroxide; Na2SO4 = sodium sulfate; PE = petroleum ether; Ph = phenyl; PG = protecting group; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Ts = p-toluenesulfonyl;

[0184] rt = room temperature; h = hours; min = minutes; bs = broad; s = singlet; d = doublet; dd = doublet of doublets; t = triplet; m = multiplet.

[0185] Example 1: (R)-1-(4-(4-(4-(2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidin-1-yl)-9hydro-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4-dione

[0186] Synthesis route:

[0187] Step 1: tert-Butyl 4-(4-((2-chloro-9-hydrogen-purin-6-yl)amino)phenyl)piperazine-1-carboxylate

[0188] 2,6-Dichloropurine (600 mg, 3.2 mmol) and 1-Boc-4-(4-aminophenyl)piperazine (1 g, 3.8 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (615 mg, 4.7 mmol) was added dropwise. The mixture was then heated to 100°C for 6 h. The reaction was complete as monitored by LCMS, and post-treatment was performed. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed three times with water (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (DCM / MeOH (v / v) = 60 / 1 to 30 / 1) to give tert-butyl 4-(4-((2-chloro-9-hydrogen-purin-6-yl)amino)phenyl)piperazine-1-carboxylate as a brown solid (800 mg, yield 59%). LCMS (m / z): 430.4 [M+H] + .

[0189] Step 2: tert-Butyl (R)-4-(4-(2-(3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperazin-1-yl)-9hydro-purin-6-yl)amino)phenyl)piperazine-1-carboxylate

[0190] 4-(4-((2-chloro-9-hydrogen-purine-6-yl)amino)phenyl)piperazine-1-carboxylate (800 mg, 1.9 mmol), (3R)-3-(3-methyl-2-oxoimidazolamide-1-yl)piperidine hydrochloride (685 mg, 3.7 mmol) and triethylamine (760 mg, 7.4 mmol) were dissolved in dimethyl sulfoxide (12 mL), heated to 150° C., sealed and reacted for 12 h. LCMS monitored the reaction and the reaction was no longer in progress. The reaction solution was post-treated and cooled to room temperature. The reaction solution was washed with water (60% ethanol, 4% HCl, 0.1% HCl, 0.2% HCl, 0.3% HCl, 0.4% HCl, 0.5% HCl, 0.6% HCl, 0.7% HCl, 0.8% HCl, 0.9% HCl, 1.0% HCl, 0.9% HCl, 1.1% HCl, 0.8% HCl, 0.9% HCl, 1.0% HCl, 0.9% HCl, 0.9% HCl, 1.1% HCl, 0.9 ... The mixture was diluted with 1% paraformaldehyde (5% ethanol) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed three times with water (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to obtain tert-butyl (R)-4-(4-(2-(3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperazin-1-yl)-9hydro-purin-6-yl)amino)phenyl)piperazine-1-carboxylate as a yellow solid (100 mg, yield 10%). LCMS (m / z): 577.7 [M+H] + .

[0191] Step 3: (R)-1-Methyl-3-(1-(6-((4-(piperazin-1-yl)phenyl)amino)-9-hydrogen-purin-2-yl)piperidin-3-yl)imidazolidin-2-one

[0192] Tert-butyl (R)-4-(4-(2-(3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperazin-1-yl)-9-hydrogen-purin-6-yl)amino)phenyl)piperazine-1-carboxylate (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 h. The reaction was complete as monitored by LCMS. The reaction solution was post-treated and concentrated. The crude product was purified by reverse phase chromatography (TFA / H2O / MeCN) to give (R)-1-methyl-3-(1-(6-((4-(piperazin-1-yl)phenyl)amino)-9-hydrogen-purin-2-yl)piperidin-3-yl)imidazolidin-2-one as a yellow solid (70 mg, 85% yield). LCMS (m / z): 477.6 [M+H] + .

[0193] Step 4: (R)-1-(4-(4-(2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidin-1-yl)-9hydro-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4-dione

[0194] (R)-1-Methyl-3-(1-(6-((4-(piperazin-1-yl)phenyl)amino)-9-hydrogen-purin-2-yl)piperidin-3-yl)imidazolidin-2-one (70 mg, 0.15 mmol) and 1-(4-(2,6-dioxopiperidin-3-yl)phenyl-)piperidine-4-carbaldehyde (53 mg, 0.18 mmol) were dissolved in 1,2-dichloroethane (10 mL) and methanol (1 mL). Glacial acetic acid (9 mg, 0.15 mmol) was added dropwise and stirred at room temperature for 2 h. Sodium acetate borohydride (63 mg, 0.29 mmol) was then slowly added to the reaction solution. The reaction was allowed to react at room temperature for 16 h. The reaction was complete as monitored by LCMS. Aqueous sodium bicarbonate solution (30 mL) was added for washing and extracted with DCM (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain (R)-1-(4-(4-(4-(2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidin-1-yl)-9hydro-purin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4-dione as a white solid (32 mg, 29% yield). LCMS (ESI): [M+H] + =762.9; HPLC: purity 98.3%. 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.99–9.81(m,1H),9.58–9.43(m,1H),8.44(s,1H),7.68(d,J=9.0Hz ,2H),7.19(d,J=8.9Hz,2H),7.08–6.93(m,4H),4.51(dd,J=21.2,8.8Hz,4H),3.71(t,J=6.7Hz,4H),3.64( d,J=2.7Hz,1H),3.38–3.25(m,4H),3.23–3.11(m,4H),3.09–2.75(m,6H),2.71(s,3H),2.69(d,J=6.7Hz,2 H),2.21–1.90(m,2H),1.88(d,J=12.1Hz,2H),1.79(t,J=9.1Hz,2H),1.76–1.68(m,1H),1.61–1.24(m,4H).

[0195] With reference to the method of Synthesis Example 1, the following compounds were prepared using reactions similar to those of Synthesis Example 1:

[0196] Example 2: 1-[4-(4-{[4-(4-{[2-(hexahydropyridin-1-yl)-9H-purin-6-yl]amino}phenyl)piperazin-1-yl]methyl}hexahydropyridin-1-yl)-2-methylphenyl]-2-oxoylidenehexahydropyrimidin-4-one

[0197] White solid (37.9 mg). LCMS (ESI): [M+H] + =678.7; HPLC: purity 97.83%; 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),10.25(s,1H),9.17(s,1H),7.80(s,1H),7.72(d,J=8 .9Hz,2H),7.04(d,J=8.6Hz,1H),6.99–6.86(m,2H),6.86–6.74(m,2H),3.75–3.64(m,6H), 3.54–3.37(m,2H),3.22–3.02(m,4H),2.70(m,4H),2.23(d,J=6.9Hz,2H),2.12(s,3H),1.8 1(d,J=12.3Hz,2H),1.72(m,1H),1.67–1.56(m,2H),1.58–1.37(m,4H),1.35–1.10(m,4H).

[0198] Example 3: 1-{4-[4-({4-[4-({2-[(3R)-3-(3-methyl-2-oxoylidenetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-9H-purin-6-yl}amino)phenyl]piperazin-1-yl}methyl)hexahydropyridin-1-yl]-2-methylphenyl}-2-oxoylidenehexahydropyrimidin-4-one

[0199] Light brown solid (330 mg). LCMS (ESI): [M+H] + =776.8; HPLC: purity 99.68%; 1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),10.25(s,1H),9.24(s,1H),7.82(s,1H),7.76–7.5 8(m,2H),7.04(d,J=8.6Hz,1H),6.97–6.70(m,4H),4.60–4.46(m,2H),3.64(m,4H),3.46( dt,J=12.3,6.2Hz,1H),3.24(m,6H),3.07(s,3H),2.92–2.53(m,10H),2.35–2.16(m,2H) ,2.12(s,3H),1.91(s,2H),1.88–1.55(m,6H),1.49(dt,J=13.8,7.6Hz,1H),1.21(m,2H).

[0200] Example 4: 1-{4-[4-({4-[4-({7-[(3R)-3-(3-methyl-2-oxo-ylidenetetrahydro-1H-imidazol-1-yl)piperidin-1-yl][1,2,4]triazacyclopenta[5,1-f]pyrimidin-5-yl}amino)phenyl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-2-oxo-ylidenepiperidin-4-one

[0201] Gray solid (36.5 mg, yield 27.6%). LCMS (ESI): [M+H] + =762.80; HPLC: purity 92.10%; 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.71(s,1H),8.21(s,1H),7.61(d,J=8.6Hz,2H),7.1 4(d,J=8.8Hz,2H),7.01–6.77(m,4H),6.19(s,1H),4.25(d,J=12.5Hz,1H),4.11(d,J=13.3H z,1H),3.82–3.50(m,8H),3.31–3.06(m,8H),2.93(t,J=11.7Hz,1H),2.84(t,J=12.7Hz,1H ),2.76–2.57(m,8H),2.24(s,2H),1.91–1.62(m,6H),1.60–1.50(m,1H),1.27–1.21(m,2H).

[0202] Example 5: 1-{4-[4-({4-[4-({9-methyl-2-[(3R)-3-(1-methyl-2-oxoylidenetetrahydro-1H-imidazol-3-yl)hexahydropyridin-1-yl]purin-6-yl}amino)phenyl]piperazin-1-yl}methyl)hexahydropyridin-1-yl]phenyl}-2-oxoylidenehexahydropyrimidin-4-one

[0203] White solid (9.4 mg). LCMS (ESI): [M+H] + =776.30; HPLC: purity 97.79%. 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.45(s,1H),8.07(s,1H),7.74(d,J=9.0Hz,2H),7.1 8(d,J=9.0Hz,2H),6.99(dd,J=15.3,8.9Hz,4H),4.60(d,J=12.2Hz,2H),3.66–3.58(m,9H) ,3.37–3.13(m,9H),3.04(t,J=12.2Hz,2H),2.91(t,J=11.6Hz,1H),2.84–2.66(m,8H),2.1 2–2.02(m,1H),1.91–1.83(m,2H),1.83–1.73(m,2H),1.74–1.64(m,1H),1.57–1.33(m,5H).

[0204] Example 6: 1-{4-[4-({4-[4-({5-[(3R)-3-(3-methyl-2-oxo-ylidenetetrahydro-1H-imidazol-1-yl)piperidin-1-yl][1,3]thiazolino[5,4-d]pyrimidin-7-yl}amino)phenyl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}-2-oxo-ylidenepiperidin-4-one

[0205] White solid (23.5 mg). LCMS (ESI): [M+H] + =779.30; HPLC: purity 90.88%. 1H NMR (400MHz, DMSO-d6) δ10.73(s,1H),10.46(s,1H),9.02(s,1H),7.89(d,J=8.9Hz,2 H),7.67(d,J=8.6Hz,2H),7.53(d,J=8.8Hz,2H),7.03(d,J=8.7Hz,2H),4.52–4.39(m ,4H),4.05–3.93(m,6H),3.84–3.57(m,8H),3.40–3.02(m,8H),2.82–2.62(m,4H),2. 43(s,1H),2.22(d,J=13.6Hz,2H),2.06–1.91(m,2H),1.89–1.70(m,3H),1.60(s,1H).

[0206] Example 7: (R)-1-(4-(4-((4-(5-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0207] Off-white solid (21.3 mg). LCMS (ESI): [M+H] + =762.60; HPLC: purity 97.70%; 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),10.25(s,1H),9.45(s,1H),9.04(s,1H),7.98(s,1H),7.72(d,J=21.9Hz,2H ),7.14(d,J=8.7Hz,2H),6.95(d,J=8.5Hz,3H),4.52(s,2H),3.69(t,J=6.7Hz,3H),3.67–3.46(m,2H),3.10(dd,J =7.2,4.5Hz,6H),2.87(s,1H),2.70(s,3H),2.67(d,J=6.7Hz,2H),2.32(d,J=10.3Hz,3H),2.00(dd,J=14.7,7.0H z,1H),1.79(d,J=21.1Hz,4H),1.55–1.48(m,3H),1.38–1.21(m,6H),1.18(t,J=7.3Hz,2H),0.85(t,J=6.7Hz,1H).

[0208] Example 8: 1-{4-[4-({4-[2-fluoro-4-({2-[(3R)-3-(3-methyl-2-oxoylidenetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-9H-purin-6-yl}amino)phenyl]piperazin-1-yl}methyl)hexahydropyridin-1-yl]-2-methylphenyl}-2-oxoylidenehexahydropyrimidin-4-one

[0209] Beige solid (78.8 mg). LCMS (ESI): [M+H] + =794.60; HPLC: purity 97.92%. 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.24(s,1H),9.52(s,1H),7.86(s,1H),7.73(d,J=15.0Hz, 1H),7.63(d,J=8.6Hz,1H),7.04(d,J=8.6Hz,1H),6.97(t,J=9.4Hz,1H),6.82(s,1H),6.78(d,J=8 .8Hz,1H),4.53(d,J=12.4Hz,2H),3.73–3.46(m,10H),3.30–3.20(m,3H),3.04–2.89(m,5H),2.85 –2.63(m,9H),2.24(s,2H),2.12(s,3H),1.85–1.63(m,6H),1.59–1.45(m,1H),1.24–1.15(m,1H).

[0210] Example 9: 1-{4-[4-({4-[2-fluoro-4-({2-[(3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-9H-purin-6-yl}amino)phenyl]piperazin-1-yl}methyl)hexahydropyridin-1-yl]phenyl}-2-oxoylidenehexahydropyrimidin-4-one

[0211] Beige solid (110.6 mg). LCMS (ESI): [M+H] + =780.50; HPLC: purity 97.31%. 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.25(s,1H),9.51(s,1H),7.86(s,1H),7.73(d,J=15.4Hz,1H),7 .63(d,J=8.5Hz,1H),7.13(d,J=8.9Hz,2H),6.95(dd,J=21.0,9.3Hz,3H),4.57–4.47(m,2H),3.75–3.63( m,4H),3.63–3.52(m,1H),3.33–3.17(m,7H),3.05–2.86(m,5H),2.79(t,J=12.3Hz,1H),2.72–2.59(m,7H) ),2.53(d,J=5.7Hz,2H),2.24(d,J=7.0Hz,2H),1.86–1.61(m,6H),1.59–1.44(m,1H),1.27–1.18(m,1H).

[0212] Example 10: 4-({4-[4-({1-[4-(2,4-dioxoylidenehexahydropyrimidin-1-yl)phenyl]hexahydropyridin-4-yl}methyl)piperazin-1-yl]phenyl}amino)-2-[(3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-5-one

[0213] Synthesis route:

[0214] Step 1: 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid

[0215] 2,4,6-Trichloropyrimidine-5-carboxylic acid (2 g) and 2-methylpropan-2-yl ({2-[(4-aminophenyl)(methyl)amino]ethyl}amino)methane ester (2.6 g) were dissolved in acetonitrile (60 mL), triethylamine (2.1 g) was added, and the mixture was stirred at room temperature for 3 h. LCMS monitored the reaction for completion. Post-treatment: 1N citric acid was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was basified with saturated aqueous sodium bicarbonate, and the aqueous layer was washed with ethyl acetate. The washed aqueous layer was acidified with 1N citric acid and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid, as a brown oil (3.2 g). LCMS (m / z): 468.1 [M+H] +

[0216] Step 2: 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid methyl ester

[0217] Dissolve 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid (100 mg) and sodium bicarbonate (27 mg) in N,N-dimethylformamide (10 mL). Slowly add iodomethane (36 mg) in an ice bath at 0°C. Remove the ice bath and stir at room temperature for 3 hours. LCMS monitors the reaction for completion. Workup: Dilute the reaction mixture with water (100 mL) and extract with ethyl acetate (50 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product was then purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain methyl 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate as a light yellow solid (100 mg, 97% yield). LCMS (m / z): 481.1 [M+H] +

[0218] Step 3: 2,6-dicyano-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid methyl ester

[0219] Methyl 2,6-dichloro-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate (100 mg), zinc cyanide (12 mg), and tetrakis(triphenylphosphine)palladium (24 mg) were dissolved in N,N-dimethylformamide (10 mL). The mixture was microwaved at 120°C for 1 h under a nitrogen atmosphere. LCMS monitored the reaction completion. Workup: The reaction mixture was filtered to remove insoluble material. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was then separated and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain methyl 2,6-dicyano-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate as a red solid (80 mg, 83% yield). LCMS (m / z): 463.1 [M+H] + .

[0220] Step 4: 6-cyano-2-[(3R)-3-(3-methyl-2-oxoylidenetetrahydro-1H-imidazol-1-yl)piperidin-1-yl]-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylic acid methyl ester

[0221] Methyl 2,6-dicyano-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate (80 mg) and (3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)piperidine (38 mg) were dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (111 mg) was added, and the mixture was stirred at room temperature for 16 h. LCMS monitored the reaction completion. Workup: The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain methyl 6-cyano-2-[(3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)piperidin-1-yl]-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate as a brown solid (30 mg, 22% yield). LCMS (m / z): 620.3 [M+H] + .

[0222] Step 5: 2-Methylpropan-2-yl 4-[4-({2-[(3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-5-oxoylidene-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-4-yl}amino)phenyl]piperazine-1-carboxylate

[0223] Methyl 6-cyano-2-[(3R)-3-(3-methyl-2-oxoylidenetetrahydro-1H-imidazol-1-yl)piperidin-1-yl]-4-{[4-(4-{[(2-methylpropan-2-yl)oxy]carbonyl}piperazin-1-yl)phenyl]amino}pyrimidine-5-carboxylate (30 mg) and palladium on carbon (3.0 mg) were dissolved in a methanol solution of hydrogen chloride (20 mL). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, LCMS was performed. Post-processing was performed: concentration, dilution with water (100 mL), and extraction with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then separated and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 2-methylprop-2-yl 4-[4-({2-[(3R)-3-(3-methyl-2-oxyylidenetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-5-oxyylidene-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-4-yl}amino)phenyl]piperazine-1-carboxylate as a light yellow oil (20 mg, 80% yield). LCMS (m / z): 592.3 [M+H] + .

[0224] Step 6: 4-({4-[4-({1-[4-(2,4-dioxoylidenehexahydropyrimidin-1-yl)phenyl]hexahydropyridin-4-yl}methyl)piperazin-1-yl]phenyl}amino)-2-[(3R)-3-(3-methyl-2-oxoylidetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-5-one

[0225] 2-Methylpropane-2-yl-4-[4-({2-[(3R)-3-(3-methyl-2-oxyylidenetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-5-oxyylidene-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-4-yl}amino)phenyl]piperazine-1-carboxylate (20 mg) was dissolved in DCM (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude brown oil. The crude product was then dissolved in dichloromethane (20 mL), triethylamine (0.2 mL) was added, and the mixture was stirred at room temperature for 10 minutes. 1-[4-(2,4-dioxyylidenehexahydropyrimidin-1-yl)phenyl]hexahydropyridine-4-carbaldehyde (15 mg) was then added, and acetic acid (0.3 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (25 mg) was then added, and stirring was continued at room temperature for 1 h. After the reaction was complete, aqueous sodium bicarbonate (30 mL) was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography (DCM / MeOH (v / v) = 15 / 1) to obtain 4-({4-[4-({1-[4-(2,4-dioxyidenehexahydropyrimidin-1-yl)phenyl]hexahydropyridin-4-yl}methyl)piperazin-1-yl]phenyl}amino)-2-[(3R)-3-(3-methyl-2-oxyidenetetrahydro-1H-imidazol-1-yl)hexahydropyridin-1-yl]-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-5-one as a white solid (2 mg, 7% yield). LCMS (m / z): 777.6 [M+H] + . HPLC purity 98.2%.

[0226] 1 H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.43(s,1H),8.51(s,1H),8.07(s,1H ),7.63(d,J=8.9Hz,2H),7.26–7.15(m,2H),7.09–6.96(m,3H),4.62(d,J=12 .3Hz,2H),4.18(s,3H),3.66(m,10H),3.31(m,5H),3.18–2.95(m,6H),2.85 (m,3H),2.69(t,J=6.7Hz,5H),2.07(s,1H),1.96–1.63(m,5H),1.43(m,3H).

[0227] Reference Example 1: Reference Example 1 was synthesized according to the same synthesis method as compound 195 of patent WO2021113557A1.

[0228] Effect Example 1

[0229] 1.1 Molecular experiments

[0230] The activity of BTK (WT) and its mutant protein BTK (C481S) was detected using TK-s of homogeneous time-resolved fluorescence HTRF as the substrate. BTK can catalyze the phosphorylation modification of the biotin-labeled polypeptide substrate TK-s with the participation of ATP. The Eu-labeled TK-s specific phosphorylation antibody reacts with the substrate through an antigen-antibody reaction. At the same time, the streptavidin-labeled receptor XL665 interacts specifically with biotin, so that the Eu-labeled donor and the streptavidin-labeled receptor can be close to each other in space. Under 320nm excitation, the Eu-labeled donor can emit energy with a wavelength of 620nm. When the interaction of biological molecules causes the fluorescent groups of the donor and the acceptor to approach, part of the energy is resonantly transferred to the acceptor XL665, causing it to be excited and emit light with a wavelength of 665nm. The emission light of 665nm is only generated by FRET caused by the donor. After the TK-s substrate is phosphorylated by BTK, in Envision TM The excitation wavelength was set at 320 nm, and fluorescence values ​​were read at emission wavelengths of 620 nm and 665 nm. The initial BTK reaction velocity was calculated by measuring the change in the fluorescence ratio of 665 nm to 620 nm per unit time.

[0231] The compound and enzyme buffer were added to a 384-well plate (ProxiPlate™-384 Plus, PerkinElmer). After incubation at room temperature for half an hour, the substrate buffer was added to initiate the reaction. After incubation at room temperature for one hour, XL665 and the antibody were added and incubated for another hour. The ratio of the fluorescence signal at 665 nm to 620 nm was detected using Envision™. A blank control group without enzyme addition and a control group with DMSO replacing the compound solvent were also established. The final reaction volume was 10 μL, and the reaction system consisted of 2% by volume DMSO, 0.5 ng / μL BTK, 1 μM TK-s, 80 μM ATP, 5 mM MgCl2, 1 mM DTT, 20 nM SEB, and 1× kinase buffer. The results are shown in Table 1.

[0232] Table 1: Inhibitory activity of compounds against BTK and BTK(C481S) kinases

[0233] The above results show that the compounds of the present application have good inhibitory effects on BTK and BTK (C481) kinases, especially the IC values ​​of compounds 1, 3, 7, 8, and 9 for BTK kinase. 50The IC50 values ​​of compounds 1, 3, 5, 7, 8, and 9 against BTK mutant protein (C481S) are less than 0.5 μM.

[0234] 1.2 Cell experiments

[0235] 1.2.1 BTK protein degradation assay

[0236] Mino and HEK293 BTK (C481S) stably overtransfected cells were used to detect the degradation ability of the compounds on BTK (WT) and BTK (C481S) proteins, respectively. Mino human mantle cell lymphoma cell line was purchased from ATCC, and the culture medium was RPMI-1640 + 15v% FBS + 1v% double antibody; HEK293 OE BTK (C481S) human embryonic kidney cells 293 were overtransfected with BTK C481S plasmid to form BTK C481S overexpressing cells, and the culture medium was DMEM + 10v% FBS + 1v% double antibody. Mino cells and HEK293 OE BTK (C481S) stably transfected cell lines were added to 6-well plates and incubated at 37°C for 0.5 h. Different concentrations of the compound (1000 nM, 100 nM, 10 nM, and 1 nM) were then added to the cell suspension and incubated at 37°C, 5% CO2, and saturated humidity for 24 h. After incubation, the cells were harvested and 1× loading buffer (Biorad, Cat. 1610747) was added. BTK (CST, Cat. 8547S) and β-actin (CST, Cat. 4970S) expression was detected by Western blotting, and BTK expression relative to the internal reference β-actin was calculated. The experimental results are shown in Table 2. The degradation rate of BTK protein in the treatment group relative to the vehicle group (BTK%) was calculated according to the following formula:

[0237] BTK%=(1-(BTK 给药 / β-actin) / (BTK 溶媒 / β-actin))×100%

[0238] In the BTK(WT) degradation results, BTK 给药 is the expression level of BTK in Mino cells at different doses of the compound, BTK 溶媒 is the expression level of BTK in Mino cells of the control group, wherein the solvent is DMSO. The highest concentration of the compound in this experimental system is 1000nM, D max The maximum degradation value in the experimental concentration system was calculated using Graphpad 5.0 software according to the formula Y=100 / (1+10^((LogIC 50The DC value was fitted by ((-X)*HillSlope). 50 value.

[0239] In the degradation result of BTK(C481S), BTK 给药 represents the expression level of BTK in HEK293 cells at different doses of the compound, and BTK 溶媒 represents the expression level of BTK in control group HEK293 cells, where the solvent is DMSO. The highest concentration of the compound in this experimental system is 1000 nM, and D max represents the maximum degradation value within the experimental concentration system. And the DC 50 value was fitted by using Graphpad5.0 software according to the formula Y = 100 / (1 + 10^((LogIC 50 value.

[0240] Table 2: Degradation of compound on BTK(WT) and BTK(C481S)

[0241] Note: A < 1 nM; 1 nM < B < 10 nM; 10 nM < C < 1000 nM; 1000 nM < D; '-' indicates that the degradation rate of the compound is less than 30% within the test system range, and 'ND' indicates that this data is not measured.

[0242] 1.2.2 IKZF1 degradation experiment at the cell level

[0243] IKZF1 protein is one of the target protein substrates for the degradation of thalidomide compounds. The IMiD activity of the compound was judged by the IKZF1 protein degradation experiment. The Mino cell samples for detecting the above-mentioned BTK protein degradation were used to synchronously detect the IKZF1(CST, Cat.14859S) protein by Western blot method. The degradation rate of BTK protein in the dosing group relative to BTK protein in the solvent group (BTK%) was calculated according to the following formula:

[0244] IKZF1% = (1 - (IKZF1<​​​​​​​​​​​​50 DC was fitted by (-X)*HillSlope)) 50 The experimental results are shown in Table 3.

[0246] Table 3: Degradation effect of compounds on IKZF1

[0247] Remarks: A < 1 nM; 1 nM < B < 10 nM; 10 nM < C < 1000 nM; 1000 nM < D. '-' indicates that the degradation rate of the compound is less than 30% within the test system range, and 'ND' indicates that this data was not tested.

[0248] 1.2.3 Cell proliferation inhibition experiment

[0249] OCI-LY cells sensitive to the BTK target were used to evaluate the cell proliferation inhibition caused by BTK degradation, and MM.1S cells sensitive to IMiD activity were used to evaluate the cell proliferation inhibition caused by the compound on IMiD activity. After collecting OCI-LY10 and MM.1S cells respectively, they were centrifuged, the supernatant was removed, resuspended with 2 mL of complete medium, and the cell density was adjusted to 7.40×10 6 cells / mL after counting; inoculated into a 96-well plate at 80 μL per well, that is, 20,000 cells per well; the diluted compound was added to the 96-well cell plate at 20 μL per well, and the final initial highest concentration was 20 μM (the final concentration of DMSO was 0.2 v%). After culturing the OCI-LY10 cell plate in a 37 °C, 5 v% CO2 incubator for 3 days; after culturing the MM.1S cell plate in a 37 °C, 5 v% CO2 incubator for 7 days, the CellTiter 96 Aqueous Non-Radioactive cell proliferation kit (CCK8) was used for detection. 10 μL of CCK8 reagent was added to each well, the plate was gently tapped to mix it, and it was placed in the incubator for incubation. The absorbance at 450 nm and 650 nm was detected by an enzyme-labeled instrument until the absorbance value (OD 450 -OD 650 ) reached 0.6 - 0.8 for plate reading and detection. Using the calculation formula for cell viability: Cell viability (%) = (compound well value - medium well value) / (DMSO well value - medium well value) × 100%, using Graphpad Prism 5.0 software, according to the formula Y = 100 / (1 + 10^((LogIC 50 -X)*HillSlope)) to fit the IC 50 value. The experimental results are shown in Table 4.

[0250] Table 4: Proliferation inhibition activity of compounds on OCI-LY10 and MM.1S

[0251] Note: 'ND' means the data is not measured

[0252] The above results show that the compounds of the present application have good proliferation inhibitory activity against BTK target sensitive cells OCI-LY10, and the IC50 of most compounds is less than 25nM; in addition, for IMiD activity sensitive cells MM.1S, the compounds of the present application also have certain proliferation inhibitory activity.

[0253] 1.3 Pharmacokinetic analysis of compounds

[0254] 1.3.1 Compound liver microsome stability test

[0255] Liver microsome stability analysis uses microsomes extracted from liver cells to study the metabolic stability of the compound. In the reaction buffer 0.1M Tris, 5mM MgCl2, 0.005% BSA, pH 7.4 and 1μM final concentration of the test compound, liver microsomes of different species (final concentration of 0.33mg / mL) were incubated at 37°C for 10min. Subsequently, a final concentration of 1mM NADPH was added to start the reaction. Samples were collected at 0, 7, 17, 30 and 60min, and the reaction was terminated by adding 4°C cold methanol. After collecting the samples by centrifugation at 4000rpm for 5min, the drug content in the samples was analyzed by LC-MS / MS. Log (compound remaining percentage) was linearly regressed with the incubation time to calculate the slope -k, and the relevant metabolic stability parameters were calculated by the following formula:

[0256] T 1 / 2 =-0.693 / k

[0257] Intrinsic Clearance:

[0258] Body clearance:

[0259] Hepatic clearance:

[0260] Metabolic bioavailability:

[0261] Where, P: microsomal protein concentration (mg / mL)

[0262] Houston: Houston factor (45 mg microsomal protein / g liver)

[0263] LW: liver weight (g) (each species)

[0264] HBF: liver blood flow (mL / min) (each species)

[0265] fu: Unbound fraction (usually fu = 1)

[0266] Table 5: Metabolic stability of compounds in liver microsomes of different species

[0267] Note: Criteria for judging metabolic stability: MF% > 70%, good metabolic stability; 30% < MF% < 70%, moderate metabolic stability; MF% < 30%, poor metabolic stability.

[0268] Conclusion: As can be seen from Table 5, some compounds of the present invention have good metabolic stability in mouse liver microsomes, as shown in Examples 1, 3, etc.; some compounds have good metabolic stability in beagle dog liver microsomes, such as the compounds in Example 1, etc.; some compounds have good metabolic stability in human liver microsomes, such as the compounds in Examples 1, 3, etc.

[0269] 1.4 Mouse pharmacokinetic test

[0270] In this experiment, the test compound was orally administered to mice once, and the concentration of the test compound in the plasma of mice at different time points was measured to evaluate the oral metabolic characteristics of the test compound in mice. Each compound was tested on 3 mice, and different doses of the test drug were orally administered respectively. The solvent was: 5% DMSO + 5% Solutol HS15 + 90% NS. Blood was collected at 6 time points of 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration. At each time point, 50 μL of blood was taken from the retroorbital venous plexus of each animal and placed in an EDTA anticoagulant tube (EDTA: blood = 1:10), shaken evenly, placed on ice, centrifuged within 30 min at 12000 g at 4 °C for 3 min, and the supernatant was taken and stored at -20 °C. The drug content in the sample was analyzed by LC-MS / MS.

[0271] Table 6: Pharmacokinetic parameters of oral absorption of compounds

[0272] Conclusion: As can be seen from Table 6, compared with Reference Example 1, some compounds of the present invention have more advantages in oral absorption in mice, such as the compounds in Examples 1, Example 8, Example 9, etc. In particular, compared with Reference Example 1, the compound of Example 1 has a better half-life T 1 / 2 ; and at the same dose concentration of 10 mg / kg, the C max value of the compound of Example 8 is max 19.7 times that of the compound of Reference Example 1, and the C max value of the compound of Example 9 is 5.89 times that of the Cmax value of the compound of Reference Example 1; indicating that the compounds of the present application have more excellent C maxIn addition, the compounds of the present application also have a higher AUC, and the drug exposure at the same dose is greater. For example, the AUC of the compound in Example 8 is last The value is the AUC of the compound in Reference Example 1 last The AUC of the compound in Example 9 was 11.9 times that of last The value is the AUC of the compound in Reference Example 1 last From the above, it can be seen that the bioavailability of the compound of the present application is higher.

[0273] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof or a hydrate thereof, in, is a single bond or a double bond; A1 is a 9-membered heteroaryl group, wherein the 9-membered heteroaryl group contains 1, 2, 3, 4, 5 or 6 heteroatoms, at least one of which is N; and the remaining heteroatoms are independently selected from N, O or S. Preferably, A1 is wherein A'1 is a 5-membered heteroaryl, a 5-membered heterocyclic group or a C5 cycloalkyl group, and A"1 is a phenyl group or a 6-membered heteroaryl group, wherein the heteroaryl group contains 1, 2, 3, 4 or 5 heteroatoms, at least one of which is N, and the remaining heteroatoms are independently selected from N, O or S; more preferably, A1 is Wherein, Z1, Z2, Z3, Z4 and Z5 are each independently selected from: N, NR1 or CR1; Z6 and Z7 are each independently selected from: N or C; the 9-membered heteroaryl is optionally substituted by a group selected from the following group: halogen, oxo (=O), C1-4 alkyl, halogenated C1-4 alkyl; A2 is phenyl, 6-membered heteroaryl or 5-membered heteroaryl, wherein the 6-membered heteroaryl and the 5-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms, and the heteroatoms are each independently selected from O, S or N; A5 is selected from: 5-15 membered heterocyclyl, C5-C12 cycloalkyl, 5-15 membered heteroaryl, C6-C15 aryl, That wherein Cy2, Cy4 and Cy6 are each independently selected from: a 5-15 membered heterocyclyl or a C5-C12 cycloalkyl, and Cy3 and Cy5 are each independently selected from: a 5-15 membered heteroaryl or a C6-C15 aryl; Z8 and Z9 are each independently selected from: C, N or CR3; Z 15 Select from: N or CR 10 ; X and Y are each independently selected from: N or CR6; W1 is selected from: -CF2-, -CH2-, -CHR4-、-O-、-S-、-NR4-、 or key; Cy1 is selected from: C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl or 5-15 membered heteroaryl, wherein the heterocyclyl and the heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms, and the heteroatoms are each independently selected from O, S or N; AL1, AL2, AL3 and L4 are each independently selected from: a bond, -(CH2)NHCO-, -(CHMe)NHCO-, -(CR 11 R 12 )NHCO-、-(CR 11 R 12 ) n8 NR 13 CO-, -(CH2)NHSO2-, -(CHMe)NHSO2-, -(CR 11 R 12 )NHSO2-、-(CR 11 R 12 ) n8 NR 13 SO2-, -CH2-, -CF2-, -NHSO2-, -SO2NH-, -SO2NR 12 -、-O-、-S-、-SO2-、-NR 11 -、-(CH2) n8 -、-CO-、-(CH2) n8 NR 11 -、-CONR 11 -、-NR 11 CO- or -(CH2) n8 NR 11 CO-; R1, R2, R3, R4, R5, R6, R7, R 10 , R 11 , R 12 and R 13 Each is independently selected from: H, halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, or 5-15 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, or 5-15 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 R a replace; R8 is selected from: H, C1-C6 alkyl, The H in the above-CH2- is optionally replaced by R a replace; R9 is selected from: H, F, Cl, Br, I, OH, NH2, CN, OMe, Me, -CH2OH, -CH2CH2OH, CO2H, CF3, CHF2, CONH2, or a 5- or 6-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur; each of the aromatic rings is optionally substituted by halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl, CN, NO2, OR d 、SO2R d , COR d 、CO2R d ,CONR d R b 、C(=NR d )NR b R c NR d R b 、NHR d , COR b NR d CONR b R c NR d CO2R b NR d SONR b R c NR d SO2NR b R c or NR d S02R b , wherein the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C20 cycloalkyl, 3-20 membered heterocyclyl, C6-C10 aryl, 5-15 membered heteroaryl is optionally substituted with halogen, hydroxyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; Alternatively, two adjacent R2 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, Cyclic, aryl, phenyl, heteroaryl are optionally substituted by 1, 2, 3 or 4 R e replace; Alternatively, two adjacent R3 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 R e replace; Alternatively, two adjacent R5 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 R e replace; Alternatively, two adjacent R6 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 R e replace; Alternatively, two adjacent R7 and the ring atoms connected thereto together form a C3-C20 cycloalkyl, a 3-20 membered heterocyclyl, a C6-C10 aryl or a 5-15 membered heteroaryl, preferably a C5-C6 cycloalkyl, a 5-6 membered heterocyclyl, a phenyl or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, phenyl or heteroaryl is optionally substituted by 1, 2, 3 or 4 R e replace; R a , R b , R c , R d and R e Each is independently selected from: halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is optionally further substituted by 1, 2, 3 or 4 groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, carboxyl, amide, ester, oxo (=O), C1-C6 alkyl and C1-C6 alkoxy; n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from: 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, wherein A1 is selected from: and / or, Cy1 is selected from: 5-12 membered heterocyclyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, Cy1 is selected from: piperazinyl, piperidinyl, phenyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 7-11 membered spiroheterocyclyl, 7-12 membered fused heterocyclyl or bridged heterocyclyl; more preferably, Cy1 is selected from:

3. The compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: R5 is selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkylOH; preferably, R5 is selected from: H; and / or n5 is 0, 1 or 2; preferably, n5 is 0; and / or L4 is a bond; and / or R9 is selected from: H or and / or A2 is phenyl; and / or R2 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy; preferably, R2 is H or F; and / or n2 is 0 or 1; and / or Selected from: Preferably, Selected from: Wherein, in particular, part B is selected from:

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: A5 is selected from: phenyl, pyridyl, pyrazinyl, thiazolyl, thienyl, furanyl, oxazolyl, Preferably, A5 is selected from: The above groups may be optionally substituted by 1, 2, 3 or 4 R7; Preferably, R7 is selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy, more preferably, R7 is selected from: H or methyl; Preferably, n7 is 0 or 1.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: W1 is selected from: a bond or CONH; and / or Z 15 Selected from: N or CH; and / or R8 is H; Wherein, in particular, part K is selected from:

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: is a double bond, Z9 is C; Z8 is selected from: CH or N; and / or Z9 is selected from: CH or N; preferably, Z9 is N; and / or R3 is H, methyl, halogen or OH; preferably, R3 is H; and / or n3 is selected from: 0 or 1; preferably, n3 is 0; and / or X is selected from: CH or N; and / or Y is selected from: CH or N; preferably, Y is N; and / or n1 is 0, 1 or 2; preferably, n1 is 2; and / or n4 is 0, 1 or 2; preferably, n4 is 2; and / or R6 is selected from: H, methyl, halogen or OH; preferably, R6 is H; and / or n6 is 0 or 1; preferably, n6 is 0; and / or AL1 is a key; and / or AL2 is selected from: a bond, O, SO2, NH, CH2, CHCH3, CH2CH2 or CH2CF2, preferably, AL2 is CH2; and / or AL3 is the key.

7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: Selected from: or, Selected from: key, Alternatively, partL is selected from: Wherein, the above group is optionally substituted by 1, 2, 3 or 4 R3 or R6, and the definition of R3 or R6 is as described above.

8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: The compound has a structure shown in Formula II: in, Y1, Y2 and Y3 are each independently selected from CH, N or CR2; Y4 and Y5 are each independently selected from CH, N or CR7; X, Y, Z8, Z9, Z 15 , R2 and R7 are as defined above; Preferably, the compound has a structure shown in Formula III: in, Y1, Y2 and Y3 are each independently selected from: CH, N or CR2; Y4 and Y5 are each independently selected from: CH, N or CR7; R2 and R7 are as defined above.

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, characterized in that: The compound is selected from:

10. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.

11. Use of a compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a cis-trans isomer thereof, a chiral isomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a prodrug thereof, a solvate thereof or a hydrate thereof, or a pharmaceutical composition according to claim 10 in the preparation of a drug for treating a BTK-mediated disease; Preferably, the autoimmune disease is selected from: lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, complications caused by organ transplantation, diabetes, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia or lymphoma; Preferably, the inflammatory disease is selected from: keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis or appendicitis; Preferably, the tumor is selected from: small lymphocytic lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, multiple myeloma or mantle cell lymphoma.

12. Use of the compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, its cis-trans isomer, its chiral isomer, its enantiomer, its diastereomer, its isotopic derivative, its prodrug, its solvate or its hydrate, or the pharmaceutical composition according to claim 10 in the preparation of a drug for inhibiting or regulating the activity of BTK protein kinase; Preferably, the BTK protein kinase is a non-mutated BTK protein kinase or a mutated BTK protein kinase; the mutated BTK protein kinase is preferably a C481S mutated BTK protein kinase.

Images