Pyrrole degrader and pharmaceutical use thereof

Abstract

Disclosed in the present invention are a Bruton's tyrosine kinase degrader, or a stereoisomer thereof, a mixture of the stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the use thereof in the preparation of a drug for treating diseases, disorders or conditions that benefit from the degradation of Bruton's tyrosine kinase. The compound of the present invention can be used for degrading BTK proteins, has an inhibitory effect on tumor cell proliferation, and can be used for treating diseases related to the degradation of Bruton's tyrosine kinase.

Description

A pyrrole degradation agent and its pharmaceutical application Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a pyrrole degrader, a preparation method thereof, a pharmaceutical composition containing the degrader, and use of the degrader as a therapeutic agent, especially for targeting Bruton's tyrosine kinase. Background Art

[0002] Bruton's tyrosine kinase (BTK) is a tyrosine kinase found primarily in B lymphocytes and some other immune cells. It plays an important role in signal transduction pathways, particularly in the B cell receptor signaling pathway. BTK is a key regulator of B cell growth, development, activation, signal transduction, and survival. When the B cell receptor binds to an antigen, BTK is activated and initiates a series of signaling processes, including cell proliferation and antibody production.

[0003] Recent studies have shown that the BTK signaling pathway is a new hotspot in the clinical treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and autoimmune diseases. Small molecule BTK inhibitors act on the BCR signaling pathway, bind to BTK, inhibit BTK autophosphorylation, prevent BTK activation, thereby blocking cell conduction and inducing cell apoptosis. BTK inhibitors have shown great potential in the treatment of these diseases (Blood. 2020. 136(1): 93-105; JMed Chem. 2019. 62(17): 7923-7940).

[0004] With the clinical use of BTK inhibition, some patients have developed drug resistance, necessitating an urgent need for a new generation of BTK drugs to address this acquired resistance. Furthermore, while BTK inhibitors have demonstrated significant efficacy in CLL, their application in other indications requires further research and clinical trials. Therefore, the development of a new generation of drugs targeting BTK kinase is crucial.

[0005] In recent years, significant progress has been made in targeted protein degradation technology (PROTAC), which achieves target protein degradation by inducing ubiquitination of the target protein. PROTAC molecules do not need to continuously occupy the target protein, and catalytic concentration can achieve target degradation. PROTAC molecules need to form a ternary complex with the target protein and E3 ligase to exert their activity, which greatly improves the selectivity of the target and has a very significant advantage in improving activity. Therefore, the development of BTK-targeted degraders is expected to improve the efficacy and safety of drugs. Summary of the Invention

[0006] In order to solve the above technical problems, the purpose of the present invention is to provide a novel BTK degradation molecule with high BTK degradation activity and its optical isomers or pharmaceutically acceptable salts thereof that have not been reported in the literature.

[0007] The present invention relates to a class of degradation molecules capable of degrading BTK and optical isomers or pharmaceutically acceptable salts thereof, as well as drugs for treating tumors and autoimmune diseases.

[0008] The first aspect of the present invention provides a compound as shown in formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] R1 is selected from: H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, OH, NH2, CN, NO2 or COOH; the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further substituted by one or more selected from H, halogen, OH, NH2, CN, NO2, COOH, C(O)NH2, C 1-3 Alkyl or C 1-3 substituted by an alkoxy substituent;

[0011] R2 is selected from: H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, OH, NH2, CN, NO2, COOH or C(O)NH2;

[0012] L1 is selected from: 3-6 membered heterocyclic group;

[0013] L2 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-;

[0014] L3 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-;

[0015] L4 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-;

[0016] L5 is selected from: 3-6 membered heterocyclic group;

[0017] X is selected from: CH or N;

[0018] Ring A selection: 6-10 membered aryl, 6-10 membered heteroaryl, 6-10 membered fused ring;

[0019] R3 is selected from: H, halogen, C 1-3Alkyl or C 1-3 alkoxy;

[0020] n is selected from: 0, 1, 2, 3 or 4;

[0021] m is selected from: 0, 1, 2, 3 or 4;

[0022] p is selected from: 0, 1, 2, 3 or 4.

[0023] Furthermore, as a preferred embodiment, the compound provided by the present invention or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt has the structure shown in Formula II:

[0024] in:

[0025] Ring A is selected from:

[0026] Furthermore, as a preferred embodiment, R1 is selected from fluorine, chlorine, bromine, and trifluoromethyl.

[0027] Furthermore, as a preferred embodiment, R2 is selected from fluorine, chlorine, bromine, and trifluoromethyl.

[0028] Furthermore, as a preferred embodiment, the compound of the present invention, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, wherein:

[0029] Ring A is selected from:

[0030] Furthermore, as a preferred embodiment, the compound of the present invention, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt,

[0031] in:

[0032] Selected from:

[0033] Furthermore, as a preferred embodiment, the compound of the present invention, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt,

[0034] in:

[0035] Selected from

[0036] Preferably, the compound is selected from the following specific compounds:

[0037] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0038] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I) or (II) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0039] The present invention also provides the use of the compound of formula (I) or (II) disclosed herein, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable composition in the preparation of a drug for treating BTK-mediated diseases.

[0040] The present invention also provides the use of the compound of general formula (I) or (II) disclosed herein, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable composition in the preparation of a drug for treating BTK-mediated diseases, wherein the BTK-mediated diseases are preferably leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome or lupus, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, asthma, atopic dermatitis, or autoimmune thyroid disease.

[0041] Terminology Notes:

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. Unless otherwise indicated, all patent documents, public disclosures, and other materials referenced herein are incorporated by reference in their entirety. If multiple definitions of the same term are used herein, the definition in this section shall prevail.

[0043] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any claims. It should be noted that, throughout the specification and the appended claims, unless otherwise indicated, singular references such as "a," "an," and "the" include plural references. It should also be noted that "or" stands for "and / or" unless otherwise indicated. Furthermore, terms such as "include," "comprising," and similar terms are not limiting.

[0044] "Bond" means that the indicated substituent does not exist and the two end portions of the substituent are directly linked to form a bond.

[0045] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0046] "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight chain or branched. 10 Representative examples include, but are not limited to, vinyl, etc. The alkenyl group may be substituted or unsubstituted.

[0047] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group is more preferably a C2-C8 alkynyl group, and most preferably a C2-C4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl,

[0048] etc. The alkynyl group may be substituted or unsubstituted.

[0049] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl may be substituted or unsubstituted.

[0050] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings. The ring may contain one or more double bonds, but no ring has aromaticity. It is preferably 6 to 14 members, and more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0051] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrenyl.

[0052] "Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, and more preferably a bicyclic or tricyclic group. Examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl, and bicyclo[1.1.1]pentyl.

[0053] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups in which one or more atoms forming the ring are heteroatoms, such as N, O, S, P, Se, including monocyclic, fused, bridged and spirocyclic rings, and may contain one or more double bonds within the ring. Preferably, it has 3 to 12 ring atoms, more preferably a 4 to 7 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m(wherein m is selected from 0 or 1), an atom of Se. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, azetidinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, or 3,6-dihydro-2H-pyranyl. A heterocyclyl group may be substituted or unsubstituted.

[0054] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, which may contain one or more double bonds, but none of the rings are aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), Se heteroatom, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiro heterocyclyls are divided into monospiro heterocyclyls, bispiro heterocyclyls or polyspiro heterocyclyls according to the number of spiro atoms shared between rings, preferably monospiro heterocyclyls and bispiro heterocyclyls. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclyl. Examples of "spiro heterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0055] "Fused heterocyclic group" refers to a carbon-containing polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but none of the rings are aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0056] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings is aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0057] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. "Aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably phenyl. The aryl group may be substituted or unsubstituted.

[0058] "Heteroaryl" and "heteroaromatic ring" are used interchangeably in this application and refer to a monocyclic or polycyclic aromatic ring group containing 5 to 14 ring atoms, which may contain 1 to 4 atoms selected from N, O, S, and Se. Preferably, it contains 5 to 12 ring atoms, more preferably a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0059] Heteroaryl groups can be substituted or unsubstituted.

[0060] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, one or more of which may contain one or more double bonds, but at least one ring is not aromatic and at least one ring is aromatic, wherein zero, one or more of the ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m(wherein m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferably, it includes 7 to 14 members, more preferably 9 to 10 members. Examples of "fused rings" include but are not limited to:

[0061] The fused rings may be substituted or unsubstituted.

[0062] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C3 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Alkoxy groups may be substituted or unsubstituted.

[0063] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein halogen and alkyl are as defined herein.

[0064] "Haloalkoxy" refers to an alkoxy group substituted by a halogen, wherein halogen and alkoxy are as defined herein.

[0065] "Halohydroxyalkyl" refers to a hydroxyalkyl group substituted by a halogen, wherein halogen and hydroxyalkyl are as defined herein.

[0066] "Haloalkylamino" refers to an alkylamino group substituted by a halogen, wherein halogen and alkylamino are as defined herein.

[0067] "Cycloalkoxy" refers to a group of (cycloalkyl-O-) wherein cycloalkyl is as defined herein.

[0068] "Heterocyclyloxy" refers to a group of (heterocyclyl-O-), wherein heterocyclyl is as defined herein.

[0069] "Hydroxy" refers to an -OH group.

[0070] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0071] "Amino" refers to -NH2.

[0072] "Cyano" refers to -CN.

[0073] "Nitro" refers to -NO2.

[0074] "Carboxyl" refers to -C(O)OH.

[0075] "Amide" refers to -C(O)NH2.

[0076] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0077] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that the group may be substituted by one or more groups selected from the following groups: H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C8 alkyl, C3-C8 alkynyl, C3-C8 alkoxy, C3-C8 alkyl, C3-C8 alkoxy ... 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, aminosulfonyl, C6-C 10 Aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g 、-SR g 、-C1-C8 alkylene-R g 、-OC(O)R g 、-C(O)R g 、-C(O)OR g 、-C(O)N(R x )Ry、-NR x R y 、-N(CH3)R g 、-N(R x )C(O)R y 、-N(R x )C(O)NR x R y 、-N(R x )C(O)OR g 、-N(R x )S(O)NR x R y 、-N(R x )S(O)2NR x R y 、-N(R x )S(O)2R g 、-S(O)R g 、-S(O)2R g 、-S(O)2NR x R y 、-P(O)R x Ry The alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, aryl, heteroaryl, 3-12 membered ring, amino, hydroxyl or amide may be further substituted by one or more R o replace;

[0078] When 2 R o When substituted on the same atom, two R o Together with the atoms to which they are attached, they form a 3-6 membered ring, or when two R o When substituted on adjacent atoms, the two R o Together with the atoms to which they are attached, they form a 3-12 membered ring;

[0079] R g 、R x 、R y 、R o Each is independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, aminosulfonyl, C6-C 10 Aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR s 、-SR s 、-C1-C8 alkylene-R s 、-OC(O)R s 、-C(O)R s 、-C(O)OR s 、-C(O)N(R s )R t 、-NR s R t 、-N(CH3)R s 、-N(RL)C(O)R t 、-N(R s )C(O)NR s R t 、-N(R s )C(O)OR t 、-N(R s )S(O)NR s R t 、-N(R s )S(O)2NR s R t 、-N(R s )S(O)2Rt 、-S(O)R s 、-S(O)2R s 、-S(O)2NR s R t or-P(O)R s R t The alkyl, alkylene, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further replaced by one or more R r replace;

[0080] When 2 R r When substituted on the same atom, two R r Together with the atoms to which they are attached, they form a 3-6 membered ring, or when two R r When substituted on adjacent atoms, the two R r Together with the atoms to which they are attached, they form a 3-12 membered ring;

[0081] R r 、R s 、R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyalkyl, aminoalkyl, C1-C8 alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, carboxyl, amide, C6-C 10 aryl or 5-12 membered heteroaryl.

[0082] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0083] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0084] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may be optionally replaced by one or more of their corresponding isotopes, including but not limited to carbon isotopes. 12 C. 13 C. 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O. 17 O. 18 O, isotope of sulfur 32 S. 33 S. 34 S. 36 S, isotope of nitrogen 14 N. 15 N, an isotope of fluorine 17 F. 19 F, an isotope of chlorine 35 Cl, 37 Cl, an isotope of bromine 79 Br, 81 Br et al.

[0085] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, salts formed with suitable acids, or salts formed with suitable bases. A preferred salt type is a salt formed by a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, isethionic acid, pamoic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred salt is a salt formed by the compound of the present invention and a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0086] The present invention provides a pharmaceutical formulation comprising at least one active ingredient, wherein the active ingredient is one or more of the compounds described in any of the above technical solutions. The pharmaceutical formulation comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients. The active ingredient may be any one or more of the BTK inhibitor compound of the present invention, an optical isomer of the compound, a pharmaceutically acceptable salt of the compound or an optical isomer thereof, or a solvate of the compound or an optical isomer thereof.

[0087] The carrier includes conventional diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and flavoring agents, sweeteners, etc. may also be added if necessary.

[0088] The compounds of the present invention can be administered in the form of pharmaceutical compositions and can be administered by any conventional route, such as injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal, etc.), topical, oral, inhalation, rectal, transdermal, etc.; the compounds of the present invention can be formed into pharmaceutical preparations in solid, semisolid, liquid, or gaseous form, such as tablets, powders, granules, capsules, injections, suspensions, lotions, gels, ointments, creams, suppositories, inhalants, etc. The above-mentioned dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0089] The autoimmune disease of the present invention can be inflammatory bowel disease, arthritis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, axial spondyloarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, hyperthyroidism (Graves' disease), Ord's thyroiditis, Graves' disease, multiple sclerosis, infectious neuronitis (Guillain-Barré syndrome), acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, coeliac disease, Goodpasture's syndrome, syndrome), immune thrombocytopenic purpura (ITP), optic neuritis, scleroderma, dermatomyositis, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, vulvodynia, chronic graft-versus-host disease (cGvHD), polymyositis, Sjögren's syndrome, systemic vasculitis, eosinophilic fasciitis fasciitis), immune gastritis, autoimmune hepatitis, autoimmune hemolytic anemia, primary biliary cholangitis, lupus nephritis, autoimmune orchitis, autoimmune oophoritis, Goodpasture's syndrome, mixed connective tissue disease, erythroderma, vitiligo, acne vulgaris, acne vulgaris, asthma, atopic dermatitis, and autoimmune thyroid disease.

[0090] The tumor of the present invention can be a B cell or plasma cell proliferative disease, such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, multiple myeloma, or lymphomatoid granulomatosis.

[0091] The beneficial effects of the present invention are as follows: The inventors of the present invention have confirmed through experiments that the compounds of the present invention can degrade BTK kinase, and the compounds of the present invention have anti-proliferation and inhibitory effects on tumor cell lines. The present invention provides a novel BTK degradation molecule with high BTK degradation activity that has not been reported in the literature, and its optical isomers or pharmaceutically acceptable salts, which can be used as drugs to treat tumors and autoimmune diseases. DETAILED DESCRIPTION

[0092] Chemical substances represented by some abbreviations in the present invention:

[0093] DCM: dichloromethane

[0094] DMF: N,N-dimethylformamide

[0095] TFA: trifluoroacetic acid

[0096] DMSO: dimethyl sulfoxide

[0097] EDCI: carbodiimide hydrochloride

[0098] MeOH: methanol

[0099] DIPEA: N,N-diisopropylethylamine

[0100] HOBT: 1-Hydroxybenzotriazole

[0101] (Boc)2O: Di-tert-butyl dicarbonate

[0102] Example 1

[0103] Intermediate 1: Synthesis of tert-butyl 4-(4-amino-5-carbamoyl-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate

[0104] Synthesis Step 1: 4-Nitro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (A1-1)

[0105] p-Nitrobenzoic acid (702 mg, 4.20 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (635 mg, 5 mmol) and DMF (0.2 mL) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the mixture was dissolved in 5 mL of DMF. 2-amino-4-trifluoromethylpyridine (681 mg, 4.20 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. After completion of the reaction, TLC was performed, and the mixture was extracted with ethyl acetate and water. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain A1-1 in a 60% yield; ESI-MS: m / z = 312.1 [M+H] + .

[0106] Synthesis Step 2: 4-amino-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (A1-2)

[0107] A1-1 (837 mg, 2.70 mmol) was dissolved in 10 mL of ethanol, and iron powder (756 mg, 13.5 mmol), ammonium chloride (722 mg, 13.5 mmol), and water (10 mL) were added. The mixture was heated to 80°C and stirred for 1 hour. TLC indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through a Buchner funnel over celite to remove the iron powder. The filtrate was extracted with ethyl acetate and water. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford A1-2 (590 mg) in a 78% yield. ESI-MS: m / z = 282.1 [M+H] + .

[0108] Synthesis Step 3: 4-((Cyanomethyl)amino)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (A1-3)

[0109] A1-2 (590 mg, 2.10 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, and bromoacetonitrile (297 mg, 2.52 mmol) and triethylamine (1.5 mL) were added. The mixture was heated to reflux and reacted for approximately 12 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phases were separated and combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford A1-3 in a 70% yield. ESI-MS: m / z = 321.1 [M+H] + .

[0110] Synthesis Step 4: (Z)-tert-Butyl 4-(1-cyano-2-((cyanomethyl)(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)amino)vinyl)piperidine-1-carboxylate (A1-4)

[0111] tert-Butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (262 mg, 1.04 mmol) and A1-3 (400 mg, 1.25 mmol) were dissolved in 8 mL of toluene, p-toluenesulfonic acid (50 mg) was added, and the mixture was heated to reflux and allowed to react overnight. After TLC analysis, the reaction was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. Ethyl acetate and water were added for extraction. The organic phases were separated and combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford A1-4 in a 65% yield. ESI-MS: m / z = 555.2 [M+H] + .

[0112] Synthesis Step 5: tert-Butyl 4-(4-amino-5-cyano-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate (A1-5)

[0113] A1-4 (360 mg, 0.65 mmol) was dissolved in 10 mL of tert-butanol, and potassium tert-butoxide (0.35 g) was added. The mixture was heated to reflux and reacted for approximately 2 hours. After TLC analysis, the reaction was cooled to room temperature, and 10 mL of 2N hydrochloric acid was added and stirred for 10 minutes. The mixture was then extracted with ethyl acetate. The organic phases were separated and combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the solid product A1-5 in a 58% yield. ESI-MS: m / z = 555.2 [M+H] + .

[0114] Synthesis Step 6: tert-Butyl 4-(4-amino-5-carbamoyl-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate (Intermediate 1)

[0115] A1-5 (208 mg, 0.38 mmol) was dissolved in TFA (3 mL), and concentrated sulfuric acid (0.2 mL) was added dropwise with stirring. The mixture was heated to 60°C and stirred overnight. After completion of the reaction, the mixture was cooled and placed in an ice bath. Aqueous sodium carbonate solution was added and stirred until the solution became weakly alkaline. The mixture was extracted with ethyl acetate. The organic phases were separated and combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford Intermediate 1 in a 68% yield. ESI-MS: m / z = 573.2 [M+H] + .

[0116] Example 2

[0117] Intermediate 2: Synthesis of tert-butyl 4-(4-amino-5-carbamoyl-1-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate

[0118] Synthesis step 1:

[0119] Referring to the synthetic route and method of intermediate 1, the p-nitrobenzoic acid in synthetic step 1 was replaced with 3-fluoro-4-nitrobenzoic acid to obtain intermediate 2, ESI-MS: m / z = 591.2 [M+H] + .

[0120] Example 3

[0121] Intermediate 3: Synthesis of tert-butyl 4-(4-amino-5-carbamoyl-1-(4-((4-fluoropyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate

[0122] Synthesis step 1:

[0123] Referring to the synthetic route and method of intermediate 1, 2-amino-4-trifluoromethylpyridine in synthetic step 1 was replaced with 4-fluoropyridin-2-amine to synthesize intermediate 3. ESI-MS: m / z = 523.2 [M+H] + .

[0124] Example 4

[0125] Intermediate 4: Synthesis of tert-butyl 4-(4-amino-5-carbamoyl-1-(4-((4-chloropyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidine-1-carboxylate

[0126] Referring to the synthetic route and method of intermediate 1, 2-amino-4-trifluoromethylpyridine in synthetic step 1 was replaced with 4-chloropyridin-2-amine to synthesize intermediate 4. ESI-MS: m / z = 539.2 [M+H] + .

[0127] Example 5

[0128] Synthesis of 3-amino-4-(1-(1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3′-diazetidine]-3-yl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide (001)

[0129] Synthesis Step 1: tert-Butyl 3-(4-(4-amino-5-carbamoyl-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidin-1-yl)azetidine-1-carboxylate (001-1)

[0130] Intermediate 1 (146 mg, 0.26 mmol) was dissolved in DCM (5 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-amino-4-(piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide. The above product was dissolved in DMF (5 mL), and DIPEA (100 mg, 0.75 mmol) and 1-Boc-3-azetidinone (86 mg, 0.50 mmol) were added in sequence. After stirring at room temperature for 10 minutes, acetic acid (0.1 mL) and sodium cyanoborohydride (50 mg, 0.75 mmol) were added to the system, and the reaction was stirred at room temperature overnight. The reaction was complete by TLC, and the mixture was adjusted to alkaline by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were separated and combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM / MeOH) to obtain compound 001-1. ESI-MS: m / z = 628.3 [M+H] + .

[0131] Synthesis step 2: tert-Butyl 3-(4-(4-amino-5-carbamoyl-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrol-3-yl)piperidin-1-yl)-[1,3′-diazetidine]-1′-carboxylate (001-2)

[0132] Compound 001-1 (142 mg, 0.23 mmol) was dissolved in DCM (5 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 3-amino-4-(1-(azetidin-3-yl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide. The above product was dissolved in DMF (5 mL), and DIPEA (100 mg, 0.75 mmol) and 1-Boc-3-azetidinone (86 mg, 0.50 mmol) were added in sequence. After stirring at room temperature for 10 minutes, acetic acid (0.1 mL) and sodium cyanoborohydride (50 mg, 0.75 mmol) were added to the system, and the reaction was stirred at room temperature overnight. The reaction was complete by TLC. The mixture was adjusted to alkaline with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The organic phases were separated and combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM / MeOH) to obtain compound 001-2 in an 85% yield. ESI-MS: m / z = 683.3 [M+H] + .

[0133] Synthesis Step 3: 3-amino-4-(1-(1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3′-diazetidine]-3-yl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide (001)

[0134] Compound 001-2 (133 mg, 0.19 mmol) was dissolved in DCM (5 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 4-(1-([1,3′-diazetidine]-3-yl)piperidin-4-yl)-3-amino-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide. The above product was dissolved in DMSO (10 mL), and DIPEA (77 mg, 0.60 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (166 mg, 0.60 mmol) were added to the system in sequence. The reaction was carried out at 90°C for 12 hours. The reaction was complete by TLC. Solids precipitated after addition of water, and the mixture was extracted three times with ethyl acetate. The organic phases were separated and combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM / MeOH) to obtain compound 001. ESI-MS: m / z = 839.3 [M+H] + .

[0135] Referring to the synthetic route and method of Example 5, the following compound was synthesized:

[0136] Example 6: Synthesis of 3-amino-4-(1-(2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)acetyl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide (005)

[0137] Synthesis step 1: Synthesis of 005-1

[0138] Intermediate 1 (114 mg, 0.20 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 3-amino-4-(piperidin-4-yl)-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide. The above product was dissolved in 5 mL of acetonitrile, and EDAC HCl (38.3 mg, 0.2 mmol), 1-tert-butyloxycarbonyl-4-piperidinylacetic acid (58 mg, 0.24 mmol), and HOBT (27.0 mg, 0.2 mmol) were added. The reaction was stirred at room temperature overnight. TLC confirmed the reaction was complete. Solids precipitated upon addition of water. The mixture was extracted three times with ethyl acetate. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 005-1. ESI-MS: m / z = 698.3 [M+H] + .

[0139] Synthesis step 2: Synthesis of 005-2

[0140] Compound 005-1 (70 mg, 0.1 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-amino-4-(1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)piperidin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carboxamide (60 mg). The above product was dissolved in DMF (5 mL), and DIPEA (100 mg, 0.75 mmol) and 1-Boc-3-azetidinone (43 mg, 0.25 mmol) were added in sequence. After stirring at room temperature for 10 minutes, acetic acid (0.1 mL) and sodium cyanoborohydride (50 mg, 0.75 mmol) were added to the system, and the reaction was stirred at room temperature overnight. The reaction was complete by TLC, and the mixture was adjusted to alkaline by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were separated and combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM / MeOH) to obtain compound 005-2. ESI-MS: m / z = 753.4 [M+H] + .

[0141] Synthesis step 3: Synthesis of 005

[0142] 005-2 (150.6 mg, 0.20 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 3-amino-4-(1-(2-(1-(monoheterocyclobutyl-3-yl)piperidin-4-yl)acetyl)piperidin-4-yl)-1-(4-((4-(trifluoromethyl)piperidin-2-yl)carbamoyl)phenyl)-1H-pyrrole-2-carbamoyl). The above product was dissolved in DMSO (5 mL), and DIPEA (54 mg, 0.42 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (166 mg, 0.60 mmol) were added sequentially. The reaction was continued at 90°C for 12 hours. The reaction was complete by TLC. Water was added to precipitate a solid, which was extracted three times with ethyl acetate. The organic phases were separated and combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with DCM / MeOH) to obtain compound 005. ESI-MS: m / z = 909.4 [M+H] + .

[0143] Example 7: Tumor cell proliferation inhibitory activity test

[0144] The anti-tumor efficacy of the compound was detected by measuring its inhibitory effect on Mino cell proliferation. Mino cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were digested and seeded into 96-well plates at a concentration of 10,000 Mino cells / well and incubated overnight at 37°C, 5% CO2. Compounds of different concentrations (1000nM, 4-fold dilution, 8 points) were added to the 96-well plate and incubated at 37°C, 5% CO2 for 72 hours. After that, 20uL MTS was added to each well. After incubation for 2h, 25μl 10% SDS was added to each well to terminate the reaction. The MTS method detected cell activity at 490nm and 690nm. IC was calculated using GraphPad Prism 8.0. 50 %.

[0145] +:IC 50 <1nM;++:1nM <IC 50 <10nM;+++:10nM <IC 50 <100nM;++++:100nM <IC 50

[0146] Compound a is selected from compound 70 in patent 2020113656033,

[0147] The results showed that the compounds of the present invention can inhibit the proliferation of tumor cells Mino, and the compounds disclosed in the present invention IC 50 IC value of positive compounds 50 The value is lower, indicating that the inhibitory effect of the compounds disclosed in the present invention on tumor cell growth is better than that of positive compound a.

[0148] Example 8: BTK degradation activity test

[0149] Mino cells were cultured at a rate of 5 × 10 5Cells / well were seeded in a 12-well plate, and 800 μL of cell suspension was added to each well. The test compound was diluted starting from a maximum concentration of 10 mM, diluted to 0.5 mM with DMSO, and then serially diluted according to experimental needs. The test compound was diluted 100-fold with culture medium (2.5 μL compound + 247.5 μL culture medium). The diluted compound was added to the cell wells at 200 μL / well. Incubated in a 37°C 5% CO2 incubator for 16 hours. After the drug effect ended, the cells were collected in a 1.5 ml EP tube, centrifuged at 3000 rpm for 3 minutes, washed once with PBS, and lysed with 100 μL of 1x Laemmli buffer and incubated at 100°C for 10 minutes. The protein collected after cell lysis was subjected to electrophoresis with a sample volume of 8 μL / well and the program was set to run at 60 V for 30 minutes and 80 V for 2 hours. According to the operating instructions of the rapid wet transfer instrument, the transfer system was assembled in a sandwich structure and the membrane was transferred. Then, the antibody was incubated and the protein bands were developed and imaged using an exposure instrument. The bands were processed and grayscale analyzed using Image Lab software. DC was calculated using the software Graphpad Prism 8 using the formula log (inhibitor) vs. normalized response--Variable slope. 50 Curve fitting and calculation of DC 50 value.

[0150] +:DC 50 <1nM;++:1nM <DC 50 <100nM;+++:100nM <DC 50 <1μM;++++: 1μM<DC 50

[0151] The results showed that the compound of the present invention can degrade BTK protein in tumor cells Mino, while the positive control compound a only inhibits the kinase activity of BTK protein and cannot achieve degradation of BTK protein.

[0152] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A compound, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in general formula (I): in: R1 is selected from: H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, OH, NH2, CN, NO2 or COOH; the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl may be further substituted by one or more selected from H, halogen, OH, NH2, CN, NO2, COOH, C(O)NH2, C 1-3 Alkyl or C 1-3 substituted by an alkoxy substituent; R2 is selected from: H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, OH, NH2, CN, NO2, COOH or C(O)NH2; L1 is selected from: 3-6 membered heterocyclic group; L2 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-; L3 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-; L4 is selected from: absent, methylene, 3-6 membered heterocyclyl or -C(O)-; L5 is selected from: 3-6 membered heterocyclic group; X is selected from: CH or N; Ring A is selected from: 6-10 membered aryl, 6-10 membered heteroaryl, 6-10 membered fused ring; R3 is selected from: H, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; n is selected from: 0, 1, 2, 3 or 4; m is selected from: 0, 1, 2, 3 or 4; p is selected from: 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, characterized in that: It has the structure shown in general formula (II): in: Ring A is selected from:

3. The compound according to claim 2, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from:

4. The compound according to claim 3, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein: The Selected from:

5. The compound according to claim 1, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein: The Selected from 6. The compound according to claim 1, or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, characterized in that: Selected from the following compounds:

7. A pharmaceutical composition, characterized in that The pharmaceutical composition contains an effective dose of one or more of the compounds according to any one of claims 1 to 6 or their stereoisomers, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a disease associated with Bruton's tyrosine kinase activity or expression alone or in combination with other drugs.

9. The use according to claim 8, characterized in that: The disease associated with the activity or expression of Bruton's tyrosine kinase is selected from tumors or autoimmune diseases.

10. The use according to claim 9, characterized in that: The tumor is selected from leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome; the autoimmune disease is selected from lupus, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, asthma, atopic dermatitis, and autoimmune thyroid disease.

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