CN113999233A

CN113999233A - BTK inhibitor ring derivative, preparation method and pharmaceutical application thereof

Info

Publication number: CN113999233A
Application number: CN202110840971.7A
Authority: CN
Inventors: 张晨; 廖雨亭; 何平; 陈孝刚; 宣兆利; 叶飞; 唐平明; 万松林; 李瑶; 倪佳; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Tibet Haisike Pharmaceutical Co ltd
Priority date: 2020-07-28
Filing date: 2021-07-26
Publication date: 2022-02-01

Abstract

The invention provides a BTK inhibitor ring derivative, a preparation method and a pharmaceutical application thereof. The BTK inhibitor ring derivative is a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof. The BTK inhibitor ring derivatives are useful for the treatment of BTK related diseases such as tumors or autoimmune diseases. B-L-K (I).

Description

BTK inhibitor ring derivative, preparation method and pharmaceutical application thereof

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in BTK related diseases such as tumors or autoimmune system diseases.

Background

Bruton's Tyrosine Kinase (BTK) is a member of the non-receptor protein tyrosine kinase Tec family, is a key regulator in the B cell antigen receptor (BCR) signaling pathway, and is distributed in the lymphatic, hematopoietic, and blood systems. BTK mutations cause activation of signal pathways such as proliferation, differentiation and angiogenesis of downstream tumor cells, leading to X-linked agammaglobulinemia, non-hodgkin's lymphoma (NHL) and many B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL), mantle cell lymphoma and diffuse large B-cell lymphoma. Because the BTK is mainly expressed in B cells and marrow cells, the BTK is a target with better targeting and safety.

PROTAC (protease targeting chimera) molecules are bifunctional compounds capable of simultaneously combining targeting proteins and E3 ubiquitin ligase, and the compounds can induce the recognition of the targeting proteins by proteasomes of cells, cause the degradation of the targeting proteins and effectively reduce the content of the targeting proteins in the cells. By introducing ligands capable of binding different target proteins into the ProTAC molecule, the application of the PROTAC technology to the treatment of various diseases becomes possible, and the technology has attracted much attention in recent years.

Disclosure of Invention

The invention develops a BTK inhibitor which has novel structure, good drug effect, high bioavailability and higher safety and is used for treating BTK related diseases such as tumors or autoimmune system diseases.

The invention develops a PROTAC compound of a BTK inhibitor and E3 ubiquitin ligase, which has novel structure, good drug effect, high bioavailability and higher safety and can inhibit or degrade BTK, and is used for treating BTK related diseases such as tumors or autoimmune system diseases.

The invention relates to a compound as shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

B-L-K (I)。

According to some embodiments of the invention, wherein L is selected from the group consisting of-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;

according to some embodiments of the invention, Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH₂、O、-NR^b0-C ═ O, C ≡ C or a bond;

according to some embodiments of the invention, wherein Ak1 and Ak5 are bonds, Ak2, Ak3 and Ak4 are each independently selected from CH₂、O、-NR^b0-or a bond;

according to some embodiments of the invention, B is selected from B1-W1-B2-B3-B4-, Ak1, Ak2, Ak3, Ak4 or Ak5, which are not bonds, are not directly linked to each other;

according to some embodiments of the invention, Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH₂O, C ═ O, C ≡ C or a bond, and at least 4 of Ak1, Ak2, Ak3, Ak4, and Ak5 are selected from the bonds;

according to some embodiments of the invention, wherein each of Cy1, Cy2, Cy3, and Cy4 is independently selected from 3-to 12-membered heterocycle, 3-to 12-membered cycloalkyl, 6-to 10-membered aryl, or bond, said heterocycle, cycloalkyl, or aryl optionally further substituted with 0, 1,2,3, or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、oxo、CF₃、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, CN, COOH or C_1-4Alkoxy, said heterocycle containing 1,2,3, or 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein each of Cy1, Cy2, Cy3, and Cy4 is independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 5-10 membered heterobicyclic ring, a 6-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a 4-7 membered monocycloalkyl, a 5-10 membered benzocycloalkyl, a 6-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, or a 6-10 membered aryl, said aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic, or heterobridged ring optionally further substituted with 0, 1,2,3, or 4 substituents selected from H, F, Cl, Br, I, OH, NH, F, Cl, Br, I, OH, and ci₂、oxo、CF₃、COOH、CN、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by alkoxy substituents, said hetero-monocyclic, hetero-monocyclicAnd the bicyclic, heterospirocyclic or heterobridged ring contains 1,2,3 or 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein each of Cy1, Cy2, Cy3 and Cy4 is independently selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexyl, cyclopropylcyclobutylcyclopentyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylcyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacylclocyclohexyl, Cyclopropylazapiperidinyl, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylazopiperidinyl, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclopentazacyclohexyl, cyclopentazacyclohexadinyl, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylazacyclobutylazetidinyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylboroazetidinyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylcyclopentylgroup, azetidinopentylazacyclopentyl, azetidinohexylazacyclohexadecylohexylyl, azacyclopentadipiperidinyl, azetidinylcyclobutyl, azetidinohexylazacyclopentyl, azacyclohexazacyclopentadinyl, azacyclohexadipinyl, azetidinyl, azetidinylcohexylazacyclohexadinyl, azacyclohexadinyl, azacyclohexylpiperidinyl, azacyclohexadipinyl, azacyclohexadinyl, and the like, Cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinylA group, a cyclohexylspiroazacyclohexylgroup, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclopentylpentyl group, an azetidinylspiroazacyclohexylgroup, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclohexylgroup, a cyclobutyl spiropiperidinyl group, a cyclopentylspiropiperidinyl group, a cyclohexylspiropiperidinyl group, an azetidinylspiropiperidinyl group, an azetidinylspiroazacylpiperidinyl group, an acid derivative thereof, a salt thereof, and a pharmaceutically acceptable salt thereof,

When substituted, is optionally further substituted with 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、oxo、CF₃、CN、C_1-4Alkyl, CF₃、CH₂OH, COOH or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, when B is selected from B1-W1-B2-B3-B4-, Cy1, Cy2, Cy3 and Cy4 cannot be bonds at the same time;

according to some embodiments of the invention, each of Cy1, Cy2, Cy3 and Cy4 is independently selected from one of the following substituted or unsubstituted groups: a bond, azetidinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentoazetidinyl, cyclohexyloazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl, and azetidinylAn azacyclopentyl, an azacyclopenta-azacyclohexyl, an azacyclopenta-piperidine, an azacyclohexa-azetidinyl, an azacyclohexa-azacyclopentyl, an azacyclohexa-azacyclohexyl, a cyclobutyl-spiroazetidinyl, a cyclopentyl-spiroazetidinyl, a cyclohexyl-spiroazetidinyl, an azetidinyl-spiroazetidinyl, an, Azacyclohexylspirocyclohexylpiperidine, cyclopentylspiropiperidine, cyclohexylspiropiperidine, azetidinylspiropiperidine, azacyclohexylspiropiperidine, azacyclobutylspiropiperidine, azacyclobutylpiperidine, or,

Or

When substituted, is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、COOH、CN、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, each Cy1, Cy2, Cy3, Cy4 is independently selected from one of the following substituted or unsubstituted groups: a bond,

When substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, CF₃Methyl, oxo, hydroxymethyl, COOH, CN or NH₂Substituted with the substituent(s);

according to some embodiments of the invention, wherein B is selected from B1-W1-B2-B3-B4-or

According to some embodiments of the invention wherein B1 is selected from a 6 membered heteroaromatic ring or phenyl further optionally substituted with 0, 1,2,3 or 4R^b1(iii) substituted, said heteroaromatic ring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein B1 is selected from phenyl or pyridyl, said phenyl or pyridyl further optionally substituted with 0, 1,2,3 or 4R^b1Substituted;

according to some embodiments of the invention, wherein W1 is selected from-O-, -S-, -NH-, -NHCO-, or-CONH-;

according to some embodiments of the invention, wherein W1 is selected from-O-, -NHCO-, or-CONH-;

according to some embodiments of the invention wherein B2 is selected from a 6 membered heteroaromatic ring or phenyl optionally further optionally substituted with 0, 1,2,3 or 4R^b2(iii) substituted, said heteroaromatic ring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein B2 is selected from phenyl or pyridyl, said phenyl or pyridyl further optionally substituted with 0, 1,2,3 or 4R^b2Substituted;

according to some embodiments of the invention, wherein B3 is selected from 8-10 membered heterorings, said heterorings optionally further optionally substituted with 0, 1,2,3 or4R^b3(iii) substituted, said heteroring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein B3 is selected from substituted or unsubstituted imidazopyrimidines, pyrazolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, when substituted, optionally further substituted with 0, 1,2,3, or 4R^b3Substituted;

according to some embodiments of the invention, wherein B4 is selected from the group consisting of 4-7 membered monocycloalkyl, 6-12 membered spirocycloalkyl, 5-10 membered benzocycloalkyl, and 7-10 membered bridged cycloalkyl, said monocycloalkyl, spirocycloalkyl, benzocycloalkyl, and bridged cycloalkyl groups optionally further optionally substituted with 0, 1,2,3, or 4R^b4Substituted;

according to some embodiments of the invention, wherein B4 is selected from cyclohexyl, cyclopentyl, cyclobutyl, said cyclohexyl, cyclopentyl, cyclobutyl being further optionally substituted by 0, 1,2,3 or 4R^b4Substituted;

according to some embodiments of the invention, B₅Or B₆Each independently selected from one of the following substituted or unsubstituted groups: phenyl or 5-6 membered heteroaryl, when substituted, optionally further substituted with 0 to 4R^b5(iii) substituted, said heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, B₅Or B₆Each independently selected from substituted or unsubstituted phenyl or 6 membered heteroaryl, when substituted, optionally further substituted with 0 to 4R^b1(iii) substituted, said heteroaryl contains 1 to 3N atoms;

according to some embodiments of the invention, B₅Or B₆Each independently selected from one of the following substituted or unsubstituted groups: phenyl or pyridyl, when substituted, optionally further substituted with 0 to 2R^b1Substituted;

according to some embodiments of the invention, wherein R^b0Selected from H, C_1-4Alkyl, 3 to 12 membered cycloalkyl or 3 to 12 membered heterocycle containing 1,2,3 or 4 substituents selected from O,S, N;

according to some embodiments of the invention, wherein R^b0Is selected from methyl;

according to some embodiments of the invention, wherein R^b1、R^b2、R^b3Or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、COOH、CONH₂、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

according to some embodiments of the invention, R^b5Each independently selected from H, F, Cl, Br, I, OH, CF₃、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

according to some embodiments of the invention, R^b5Each independently selected from H, F, Cl, Br, I, methoxy or ethoxy;

according to some embodiments of the invention, R^b6Selected from H, C_1-4Alkyl, halogen substituted C_1-4Alkyl or hydroxy substituted C_1-4An alkyl group;

according to some embodiments of the invention, R^b6Selected from H, C_1-4An alkyl group;

according to some embodiments of the invention, R^b6Is selected from H;

according to some embodiments of the invention, R^b7、R^b8Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

according to some embodiments of the invention, R^b7、R^b8Each independently selected from H, F, Cl, Br, I, NH₂、CF₃、-C(＝O)NH₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

according to some embodiments of the invention, R^b7、R^b8Each independently selected from H, F, NH₂、CF₃、-C(＝O)NH₂；

According to some embodiments of the invention, R^b7、R^b8Taken together with the carbon atoms to which they are attached form a 5-6 membered heteroaryl or phenyl group optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heteroaryl having 1 to 4 heteroatoms selected from O, S, N;

according to some embodiments of the invention, m is selected from 0, 1 or 2;

according to some embodiments of the invention, m is selected from 0 or 1;

according to some embodiments of the invention, m is selected from 1;

according to some embodiments of the invention, wherein B is selected from

According to some embodiments of the invention, wherein B is selected from

According to some embodiments of the invention, wherein B is selected from

According to some embodiments of the invention, wherein R^b1、R^b2、R^b3、R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、CF₃COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I;

according to some embodiments of the invention, wherein R^b1、R^b2Each independently selected from H, F, Cl, Br, OH, NH₂、CN、CF₃Hydroxymethyl, methyl or methoxy;

according to some embodiments of the invention, wherein each of n1, n2, n3, n4 is independently selected from 0, 1,2,3 or 4;

according to some embodiments of the invention, wherein B is selected from

According to the bookSome embodiments of the invention wherein L is selected from

Wherein the left side of the connecting rod is connected with the B,

according to some embodiments of the invention, wherein L may be selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L may be selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L is selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L is selected from the group consisting of a bond,

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L is selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L is selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein L is selected from

Wherein the left side is connected with B;

according to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein ring E or F is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1,2 heteroatoms selected from O, S, N;

according to some embodiments of the invention, wherein R^k2Is selected from CH₂、C＝O、S＝O、SO₂；

According to some embodiments of the invention, wherein R^k2Is selected from CH₂Or C ═ O;

according to some embodiments of the invention, wherein R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、CN、COOH、C_1-4Alkyl or C_1-4An alkoxy group;

according to some embodiments of the invention, wherein R^k1、R^k3Or R^k4Each independently selected from H, CH₃F, Cl, Br, I, OH or NH₂；

According to some embodiments of the invention, wherein R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH or NH₂；

According to some embodiments of the invention, wherein R^k5Is selected from C ═ O or

According to some implementations of the inventionScheme wherein, M₁Is selected from the group consisting of a bond, -CH₂-C (═ O) NH-or-C (═ O) CH₂NH-；

According to some embodiments of the invention, wherein M is₂Is selected from-NHC (═ O) -C_1-6Alkyl, 8-10 membered hetero-cyclic or-NHC (═ O) -C_3-6Cycloalkyl, said alkyl, hetero-fused ring or cycloalkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl, oxo or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, wherein M is₂Is selected from-NHC (═ O) -C_1-6Alkyl or-NHC (═ O) -C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, wherein M is₃Is selected from-NH-or-O-;

according to some embodiments of the invention, wherein R^k6Is selected from C_1-6Alkyl, said alkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, C_1-6Alkyl or C_3-6Cycloalkyl, substituted with a substituent;

according to some embodiments of the invention, wherein R^k6Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl;

according to some embodiments of the invention, wherein R^k7Each independently selected from H, F, Cl, Br, I, OH, SH, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Alkylthio radical, C_1-6Alkyl formyloxy, said alkyl, alkoxy or alkylthio being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, wherein R^k7Each independently selected from H, F, OH, SH, methyl, methoxy or-SCH₃；

According to some embodiments of the invention, wherein R^k8、R^k9Each independently selected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

according to some embodiments of the invention, wherein R^k8、R^k9Each independently selected from H, methyl, ethyl, cyclopropyl or cyclobutyl;

according to some embodiments of the invention, wherein R^k10Selected from 5-6 membered heteroaryl, said heteroaryl optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, substituted with a substituent;

according to some embodiments of the invention, wherein G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl is optionally further substituted with 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, said heteroaryl containing 1,2,3, or 4 heteroatoms selected from N, O, S;

according to some embodiments of the invention, wherein each of p1 or p2 is independently selected from 0, 1,2,3 or 4;

according to some embodiments of the invention, wherein each of p1 or p2 is independently selected from 0, 1 or 2;

according to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

According to some embodiments of the invention, wherein K is selected from

The present invention provides a first embodiment relating to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

B-L-K (I)；

L is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;

Ak1、Ak2、ak3, Ak4 and Ak5 are each independently selected from CH₂、O、-NR^b0-C ═ O, C ≡ C or a bond;

cy1, Cy2, Cy3 and Cy4 are each independently selected from 3 to 12 membered heterocyclic ring, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or bond, said heterocyclic, cycloalkyl or aryl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂Oxo ═ O), CF₃、CN、COOH、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1,2,3, or 4 heteroatoms selected from O, S, N;

cy1, Cy2, Cy3, and Cy4 cannot be bonds at the same time;

when Ak1, Ak2, Ak3, Ak4 or Ak5 are not bonds, the bonds can not be directly connected with each other;

b is selected from B1-W1-B2-B3-B4-or

B1 is selected from 6-membered heteroaromatic ring or phenyl further optionally substituted with 0, 1,2,3 or 4R^b1(iii) substituted, said heteroaromatic ring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

w1 is selected from-O-, -S-, -NH-, -NHCO-or-CONH-;

b2 is selected from 6-membered heteroaromatic ring or phenyl optionally further optionally substituted with 0, 1,2,3 or 4R^b2(iii) substituted, said heteroaromatic ring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

b3 is selected from 8-10 membered heteroring, optionally further optionally substituted with 0, 1,2,3 or 4R^b3(iii) substituted, said heteroring contains 1,2,3, or 4 heteroatoms selected from O, S, N;

b4 is selected from the group consisting of 4-7 membered monocycloalkyl, 6-12 membered spirocycloalkyl, 5-10 membered benzocycloalkyl, and 7-10 membered bridged cycloalkyl, said monocycloalkyl, spirocycloalkyl, benzocycloalkyl, and bridged cycloalkyl groups optionally further substituted with 0, 1,2,3, or 4R^b4Substituted;

B₅or B₆Each independently selected from one of the following substituted or unsubstituted groups: phenyl or 5-6 membered heteroaryl, when substituted, optionally further substituted with 0 to 4R^b5(iii) substituted, said heteroaryl contains 1 to 4 heteroatoms selected from O, S, N;

R^b0selected from H, C_1-4Alkyl, 3 to 12 membered cycloalkyl or 3 to 12 membered heterocycle containing 1,2,3 or 4 heteroatoms selected from O, S, N;

R^b1、R^b2、R^b3or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、COOH、CONH₂、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^b5each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b6selected from H, C_1-4Alkyl, halogen substituted C_1-4Alkyl or hydroxy substituted C_1-4An alkyl group;

R^b7、R^b8each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

or R^b7、R^b8Taken together with the carbon atoms to which they are attached form a 5-6 membered heteroaryl or phenyl group optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、-C(＝O)NH₂、-C(＝O)NH-C_1-4Alkyl, -C (═ O) N (C)_1-4Alkyl radical)₂、C_1-4Alkyl or C_1-4Alkoxy, said heteroaryl having 1 to 4 heteroatoms selected from O, S, N;

m is selected from 0, 1 or 2;

k is selected from

Ring E or F is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1,2 heteroatoms selected from O, S, N;

R^k2is selected from CH₂、C＝O、S＝O、SO₂；

R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、CN、COOH、C_1-4Alkyl or C_1-4An alkoxy group;

R^k5is selected from C ═ O or

M₁Is selected from the group consisting of a bond, -CH₂-C (═ O) NH-or-C (═ O) CH₂NH-；

M₂Is selected from-NHC (═ O) -C_1-6Alkyl, 8-10 membered hetero-cyclic or-NHC (═ O) -C_3-6Cycloalkyl, said alkyl, hetero-fused ring or cycloalkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl, oxo or C_1-4Substituted by a substituent of alkoxy;

M₃is selected from-NH-or-O-;

R^k6is selected from C_1-6Alkyl, said alkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, C_1-6Alkyl or C_3-6Cycloalkyl, substituted with a substituent;

R^k7each independently selected from H, F, Cl, Br, I, OH, SH, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Alkylthio radical, C_1-6Alkyl formyloxy, said alkyl, alkoxy or alkylthio being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k8、R^k9each independently selected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k10selected from 5-6 membered heteroaryl, said heteroaryl optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, substituted with a substituent;

g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;

p1 or p2 are each independently selected from 0, 1,2,3 or 4.

The second embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, 4-7 membered heteromonocyclic ring, 5-10 membered heterobicyclic ring, 6-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered benzocycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl or 6-10 membered aryl, said aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic or heterobridged ring being optionally further substituted with 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH, Cl, Br, I, O₂、oxo、CF₃、COOH、CN、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4(ii) alkoxy, said heteromonocyclic, heterobicyclic, heterospirocyclic, or heterobridged ring containing 1,2,3, or 4 heteroatoms selected from O, S, N;

b is selected from B1-W1-B2-B3-B4-;

b1 is selected from phenyl or pyridyl further optionally substituted by 0, 1,2,3 or 4R^b1Substituted;

w1 is selected from-O-, -NHCO-, or-CONH-;

b2 is selected from phenyl or pyridyl further optionally substituted by 0, 1,2,3 or 4R^b2Substituted;

b3 is selected from substituted or unsubstituted imidazopyrimidines, pyrazolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, when substituted, optionally further substituted with 0, 1,2,3 or 4R^b3Substituted;

b4 is selected from cyclohexyl, cyclopentyl and cyclobutyl, which are further optionally substituted by 0, 1,2,3 or 4R^b4Substituted;

k is selected from

R^k2Is selected from CH₂、C＝O；

R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH or NH₂；

the other groups are as defined in the first embodiment.

The third embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from the group consisting of a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylocyclocyclohexyl, cyclopentylcyclohexyl, cyclohexylocyclocyclohexyl, cyclopropylcyclobutylcyclobutyl, cyclopropylocyclocyclopentyl, cyclopropylcyclohexylcyclohexyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylprofospiranyl, cyclopentylprofecolhexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, cyclopropyloazetidinyl, Cyclopropylazacyclohexylyl, cyclopropylazapiperidinyl, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylpiperidinyl, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclopentazacyclohexyl, cyclopentazacyclopentyl, cyclohexylazacyclobutyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, azetidinyl, azetidinoazetidinyl, azetidinyl, cyclopentyl, azetidinyl, cyclopentyl, cyclohexyl-and azetidinyl, Azacyclohexylpiperidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinylA group, a cyclohexylspiroazacyclohexylgroup, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclopentylpentyl group, an azetidinylspiroazacyclohexylgroup, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclohexylgroup, a cyclobutyl spiropiperidinyl group, a cyclopentylspiropiperidinyl group, a cyclohexylspiropiperidinyl group, an azetidinylspiropiperidinyl group, an azetidinylspiroazacylpiperidinyl group, an acid derivative thereof, a salt thereof, and a pharmaceutically acceptable salt thereof,

b is selected from

R^b1、R^b2、R^b3Or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、CF₃COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted by 0, 1,2,3 or 4 substituents selected from H, F, Cl, Br, I;

n1, n2, n3, n4 are each independently selected from 0, 1,2,3 or 4;

the other groups are defined as in the first and second embodiments.

The fourth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

L is selected from

Or L may be selected from

Or L may be selected from

The left side of the L is connected with the B, and the right side of the L is connected with the K;

b is selected from

R^b1、R^b2Each independently selected from H, F, Cl, Br, OH, NH₂、CN、CF₃Hydroxymethyl, methyl or methoxy;

k is selected from

The other groups are as defined in the first, second or third schemes.

The fifth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

B is selected from

At least 4 of Ak1, Ak2, Ak3, Ak4 and Ak5 are selected from bonds;

cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4-7 membered azamonocyclic ring, a 5-10 membered azabicyclic ring, a 7-10 membered heterobridged ring or a 6-12 membered nitrogen-containing heterospirocyclic ring, said heteromonocyclic, heterofused, heterobridged or heterospirocyclic ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, and mixtures thereof₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4(ii) alkoxy, said heteromonocyclic, heterobicyclic, heterobridged, or heterospirocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;

k is selected from

The other groups are as defined in the first embodiment.

The sixth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

Ak1、Ak2. Ak3, Ak4 and Ak5 are each independently selected from CH₂O, or a bond, and at least 4 of Ak1, Ak2, Ak3, Ak4, and Ak5 are selected from the group consisting of bonds;

cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, azetidinyl, azepinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentoazetidinyl, cyclohexyloazetidinyl, azetidinyl, azetidinoheteroazetidinyl, cyclohexyloazetidinyl, azetidinoazetidinyl, azetidinyl, azetidinoheteroazetidinyl, azetidinoazetidinyl, cyclopentoazetidinyl, azetidinyl, cyclopentaizacetyl, cyclopentaizazetidinyl, cyclopentaizacyloheteropiperidyl, cyclopentaizacylo-azacyclobutylazacycloteyl, cyclopentaizacylo-azacycloteyl, cyclopentaizacylo-azacyclotebucin, cyclopentaizacylo-azacyclo-pentyl, cyclopentaidyl, cyclopentaizacylo-azacyclo-hexyl, and piperidine, Azetidinyl, azacyclohexylazapiperidino, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexylspiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl, and the like, Cyclohexyl spiropiperidine, azetidinyl spiropiperidine, azepinyl spiropiperidine, azetidinyl spiropiperidine, and azetidinyl spiropiperidine,

B₅or B₆Each independently selected from substituted or unsubstituted phenyl or 6 membered heteroaryl, when substituted, optionally further substituted with 0 to 4R^b1(iii) substituted, said heteroaryl contains 1 to 3N atoms;

R^b5independently selected from H, F, Cl, Br, I, OH, CF₃、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

R^b6selected from H, C_1-4An alkyl group;

R^b7、R^b8each independently selected from H, F, Cl, Br, I, NH₂、CF₃、-C(＝O)NH₂、C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

m is selected from 0 or 1;

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

R^k1、R^k3or R^k4Each independently selected from H, CH₃F, Cl, Br, I, OH or NH₂；

M₂Is selected from-NHC (═ O) -methyl, -NHC (═ O) -ethyl, -NHC (═ O) -cyclopropyl, -NHC (═ O) -cyclobutyl, -NHC (═ O) -cyclopentyl or-NHC (═ O) -cyclohexyl, said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k6selected from methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl;

R^k7each independently selected from H, F, OH, SH, methyl, methoxy or-SCH₃；

R^k8、R^k9Each independently selected from H, methyl, ethyl, cyclopropyl or cyclobutyl;

p1 or p2 are each independently selected from 0, 1 or 2;

the other groups are defined as in the first and fifth schemes.

The seventh embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond,

b is selected from

K is selected from

The other groups are as defined in the first, fifth or sixth schemes.

The eighth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

L is selected from a bond,

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

the other groups are as defined in the first, fifth, sixth or seventh embodiment.

The ninth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

B is selected from

Or B is selected from

The other groups are as defined in the first, fifth, sixth, seventh or eighth schemes.

The tenth embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

K is selected from

The other groups are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments.

The eleventh embodiment of the present invention relates to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

K is selected from

Some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:

some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is selected from the group consisting of trifluoroacetate.

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparing a medicament for treating diseases related to BTK activity or expression.

The invention relates to application of the compound or stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparing a medicament for treating diseases related to inhibiting or degrading BTK.

The compound or the stereoisomer, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof can be used for treating tumors or autoimmune diseases.

The compound or the stereoisomer, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof are applied to tumors, wherein the tumors are selected from non-Hodgkin's lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma and B cell lymphoma, and the autoimmune diseases are selected from rheumatoid arthritis or psoriasis.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further replaced by one or more of their corresponding isotopesWherein the isotope of carbon comprises¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"halogen" means F, Cl, Br or I.

"halo-substituted" refers to F, Cl, Br, or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "halogen-substituted" is simply referred to as "halo".

"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups, as used herein, are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

"hydrocarbyl" refers to a substituted or unsubstituted, straight or branched chain, saturated or unsaturated group consisting of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent, or tetravalent.

"heteroalkyl" means that 1 or more (including but not limited to 2,3, 4,5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v-X(CH₂) v-H (v is an integer from 1 to 5, X is independently selected from a bond or a heteroatomHeteroatoms include, but are not limited to N, O or S, and at least 1X is selected from the heteroatom, and either N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.

"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of the alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

"Heteroalkylidene" means a substituted or unsubstituted alkylene group in which 1 or more (including but not limited to 2,3, 4,5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v-X(CH₂) v-, v is an integer from 1 to 5, each X is independently selected from the group consisting of a bond, N, O or S, and at least 1X is selected from the group consisting of N, O or S.

"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl as found herein, is as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl groups may be attached to a heteroatom or carbon atom, heterocycloalkyl groups may be attached to an aromatic ring or to a non-aromatic ring, heterocycloalkyl groups may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

"alkenyl" means a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group having at least 1, and typically 1,2 or 3 carbon double bonds, the backbone including, but not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

"alkynyl" refers to substituted or unsubstituted, straight and branched chain, monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, including, but not limited to, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, and examples of alkynyl include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"alkoxy" means a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"Carbocyclyl group"Or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system, to which the carbocyclic group may be attached, optionally monocyclic, bridged, or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, and mixtures thereof,

"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and contain 1 or more (including but not limited to 2,3, 4, or 5) heteroatoms selected from N, O or S, optionally substituted N, S of the heterocyclyl ring being oxidizable to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrinylPyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"spiro" or "spirocyclic" refers to a polycyclic group that shares a single atom (referred to as a spiro atom) between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2,3 or 4) double bonds, and optionally may contain 0 to 5 rings selected from N, O or S (═ O)_nA heteroatom of (a).

The "spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1,2,3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (═ O)_nOr O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly linked, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S (═ O)_nOr O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubane and adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent or tetravalent.

"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as referred to herein, is defined in accordance with the definition of spiro.

"carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. "carbocyclic ring", "fused carbocyclic ring group", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl", or "carbobridyclyl" as used herein, is defined in accordance with the definition of bridged ring.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein, is defined consistent with the definition of heterocycle.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The term "fused ring" as used herein refers to a "fused ring," fused ring group, "fused heterocyclic group," or "fused ring group," which is defined as being fused.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.

"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, a substituted naphthalene group, a substituted or substituted naphthalene group, a substituted benzene or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is located on the aryl ring.

"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains from 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (═ O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrryl, pyridyl, substituted pyridyl, substituted pyridyl, and the like,Pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include

Heteroaryl, as used herein, is defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.

The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiophene rings, pyrazolothiophene rings.

"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2,3, 4, or 5) substituents including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynesradical-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed.

"contains 1 to 5 heteroatoms selected from O, S, N" means containing 1,2,3, 4 or 5 heteroatoms selected from O, S, N.

"0 to X substituents selected from …" means substituted with 0, 1,2,3 … X substituents selected from …, X being selected from any integer between 1 and 10. If "substituted with 0 to 4 substituents selected from …" is intended to mean substituted with 0, 1,2,3, or 4 substituents selected from …. If "substituted with 0 to 5 substituents selected from …" is meant substituted with 0, 1,2,3, 4, or 5 substituents selected from …. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1,2,3 or 4 substituents selected from H or F.

The ring of X-Y element (X is selected from the integer less than or equal to Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes the ring of X +1, X +2, X +3, X +4 … Y element. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuteroides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"tautomer" refers to functional group isomers resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-enol isomers, and the like.

"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.

“IC₅₀"is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).

Detailed Description

To accomplish the objects of the present invention, the compounds "commercially available chemicals" used in the reactions described herein are prepared from standard commercial sources including Shanghai Aladdin Biotechnology GmbH, Shanghai Merlin Biotechnology GmbH, Sigma-Aldrich, Afahesa (China) Chemicals GmbH, echiei (Shanghai) chemical developments GmbH, Annagi chemistry, Shanghai Tantaceae technology GmbH, Corlon Chemicals, Bailinguo science GmbH, and the like, starting from commercially available chemicals and/or compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art.

References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.

Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.

The compounds of the present invention can also be synthesized by any of the following methods:

the first synthesis method comprises the following steps:

obtaining a corresponding general formula (A-2) by the nucleophilic substitution reaction or the coupling reaction of the general formula (A-1) and the general formula (Z-2), and obtaining a corresponding general formula (A-4) by the coupling reaction or the substitution reaction of the general formula (A-2) and the general formula (A-3);

and a second synthesis method comprises the following steps:

the general formula (Z-1) and the general formula (Z-2) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-3), and the general formula (Z-3) is subjected to protecting group removal to obtain a compound of a general formula (Z-3'); the general formula (Z-3') and the general formula (Z-4) are subjected to nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Ia);

the general formula (Z-3 ') and the general formula (Z-5) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-6), and the general formula (Z-6) is subjected to protecting group removal to obtain a compound of the general formula (Z-6'); the general formula (Z-6') and the general formula (Z-4) are subjected to nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Ib);

the general formula (Z-6 ') and the general formula (Z-7) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-8), and the general formula (Z-8) is subjected to protecting group removal to obtain a compound of the general formula (Z-8'); the general formula (Z-8') and the general formula (Z-4) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Ic);

the general formula (Z-8 ') and the general formula (Z-9) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-10), the general formula (Z-10) is subjected to protecting group removal to obtain a compound of the general formula (Z-10 '), and the general formula (Z-10 ') is subjected to nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Id);

R¹、R⁴、R⁶、R⁸each independently selected from (═ O), -CHO, F, Cl, Br, I, OTf, CH₂Cl、CH₂Br、CH₂I、CH₂OTf、CH₂OMs、CH₂OTs；

R²、R⁵、R⁷、R⁹Each independently selected from H, (═ O), -CHO, F, Cl, Br, I or an amino protecting group, preferably Boc;

R³、R¹⁰selected from the group consisting of independently H, NH₂、F、Cl、Br、I、OTf、OH；

X and R¹¹Each independently selected from F, Cl, Br, I, OTf, halogenated magnesium, B (OH)₂Borate, alkyl-substituted tin, zinc halide, copper halide, and the like.

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from compounds described in the commercial chemicals and/or chemical literature. "commercial chemicals" are obtained from regular commercial sources, and suppliers include: tatan science and technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical engineering, Shaoshao chemical technology, Nanjing Yashi, Yaogongkang and Bailingwei science and technology.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);

the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm;

the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.

SEM:

THP:

Boc: a tert-butoxycarbonyl group; ms:

TBS:

MTBE methyl tert-butyl ether; bn:

DIPEA: n, N-diisopropylethylamine; DMAc: n, N-dimethylacetamide; DMSO, DMSO: dimethyl sulfoxide; DCM: dichloromethane; cbz:

NMP: n-methyl pyrrolidone; tf: a trifluoromethanesulfonyl group; ts: a p-toluenesulfonyl group; TMS: trimethylsilyl; DME: ethylene glycol dimethyl ether; DCM: dichloromethane; DCE: 1, 2-dichloroethane; pd₂dba₃: tris (dibenzylidene) acetone dipalladium; john Phos: (2-biphenyl) di-tert-butylphosphine; THF: tetrahydrofuran; the DIAD: diisopropyl azodicarboxylate; CDI: n, N' -carbonyldiimidazole; MsCl: methanesulfonyl chloride; TFA: trifluoroacetic acid.

Examples

Example 1

5-amino-1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 1)

5-amino-1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: 4- (Methanesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (1b)

tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate

Tert-butyl 4-hydroxypiperidine-1-carboxylate 1a (5.00g, 24.84mmol) and triethylamine (3.77g, 37.26mmol) were dissolved in 30mL of dichloromethane, and methanesulfonyl chloride (3.41g, 29.81mmol) was added dropwise in an ice-water bath, and after completion of the addition, the mixture was naturally returned to room temperature and stirred for 1 hour. After the reaction was completed, 50mL of water was added for extraction. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:10) and concentrated to give the title compound as a yellow oil (1b) (6.5g, 93.66% yield).

The second step is that: (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) boronic acid (1d)

(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)boronic acid

The compound 5-fluoro-2-methoxybenzoic acid 1c (0.71g,4.10mmol) and 4-aminomethylphenylboronic acid hydrochloride (0.92g,4.92mmol), N-methylimidazole (0.84g,10.25mmol) were added to 15mL of dry DMF, TCFH (2.87g,10.25mmol) was added in portions under ice-water bath, and the mixture was allowed to naturally warm to room temperature and stirred for 1 hour. The reaction solution was quenched with water (50mL), extracted with EA ((20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PET: EA ═ 1:1) to give the objective compound 1d (0.94g, yield: 74.89%).

MS m/z＝304.1[M+H]⁺

The third step: 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1f)

5-amino-3-bromo-1H-pyrazole-4-carbonitrile

The compound 5-amino-1H-pyrazole-4-carbonitrile (1e) (1.0g,9.25mmol) was dissolved in 15mL of dry DMF, NBS (2.47g,13.88mmol) was added portionwise at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with water (50mL), extracted with EA ((20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PET: EA ═ 2:1) to give the objective compound (1f) (1.30g, yield: 75.15%).

MS m/z＝187.0,189.1[M+H]⁺

The fourth step: 4- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1g)

tert-butyl 4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate

The compound 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1f) (1.0g,5.35mmol), tert-butyl 4- (methanesulfonyloxy) piperidine-1-carboxylate (1b) (1.79g,6.42mmol) and cesium carbonate (2.61g,8.02mmol) were dissolved in 15mL of dry DMF and stirred at room temperature overnight. The reaction solution was quenched with water (50mL), extracted with EA ((20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PET: EA ═ 2:1) to obtain 1g (0.90g, yield: 45.46%) of the objective compound.

MS m/z＝370.1,372.2[M+H]⁺

The fifth step: 4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1H)

tert-butyl 4-(5-amino-4-cyano-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The compound tert-butyl 4- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) piperidine-1-carboxylate (1g) (0.50g,1.35mmol), (4- (5-fluoro-2-methoxybenzamide) methyl) phenyl) boronic acid (1d) (0.53g,1.76mmol), cesium carbonate (0.92g,2.82mmol), Pd (dppf) Cl₂(103.4mg,0.14mmol) was added to a mixed solvent of 10mL dioxane and water (v/v. sub.5: 1), and the mixture was replaced with nitrogen 3 times, heated to 110 ℃ and reacted for 3 hours. The reaction mixture was quenched with water (50mL), EA extracted ((20 mL. times.3), the combined organic phases were washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH)₃OH ═ 10:1) gave the title compound (1h) (0.42g, yield: 56.69%).

MS m/z＝549.1[M+1]⁺

And a sixth step: 5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (1i)

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide

The compound 4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (1H)) (100mg,0.18mmoL) was dissolved in 5mL of sulfuric acid (90%), heated to 100 ℃ and reacted for 1 hour, the reaction solution was cooled to room temperature, PH was adjusted to 10 in an ice-water bath, EA extraction ((20mL × 3), organic phases were combined, saturated brine washing (20mL × 3), drying over anhydrous sodium sulfate, filtration, solvent removal from the filtrate under reduced pressure, and column chromatography of the residue was performed (DCM: CH)₃OH ═ 10:1) to obtain the objective compound (1i) (0.06g, yield: 70.5%).

MS m/z＝467.2[M+H]⁺

The seventh step: 5-amino-1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 1)

Reacting the compound 5-amino-3- (4- [ (5-fluoro-2-methoxyphenyl) formamido]Methyl } phenyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxamide (1i) (60.0mg,0.13mmol), 2- (2, 6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (69.0mg, 0.25mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (49.0mg, 0.38mmol) was added, and after completion of the addition, the reaction was carried out at 90 ℃ for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, 10mL of water was added, the mixture was filtered, the filter cake was dissolved in 20mL of dichloromethane, the solution was washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: CH)₃OH ═ 10:1) gave the title compound 1 as a yellow solid (20.0mg, 23% yield).

MS m/z＝723.2[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.67(d,1H),7.60(dd,1H),7.51–7.44(m,4H),7.39(d,1H),7.29–7.20(m,2H),7.17–7.11(m,1H),5.05(dd,1H),4.65(s,2H),4.45–4.34(m,1H),4.24–4.15(m,2H),3.93(s,3H),3.23–3.11(m,2H),2.92–2.19(m,1H),2.78–2.67(m,2H),2.28–2.01(m,5H).

Example 2

5-amino-1- (1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 2)

5-amino-1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: n- [ (4- (5-amino-4-cyano-1- (piperidin-4-yl) -1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide (2a)

N-[(4-(5-amino-4-cyano-1-(piperidin-4-yl)-1H-pyrazol-3-yl)phenyl)methyl]-5-fluoro-2-methoxybenzamide

Tert-butyl 4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (1H) (0.55g,1.01mmoL) was dissolved in 20mL of HCl/dioxane, reacted at room temperature for 3 hours, and the reaction solution was directly concentrated to dryness to give a crude product of the objective compound (2a) (0.41g) which was used directly in the next reaction.

MS m/z＝449.2[M+H]⁺

The second step is that: 3- (4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (2b)

tert-butyl 3-(4-(5-amino-4-cyano-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)azetidine-1-carboxylate

Intermediate N- [ (4- (5-amino-4-cyano-1- (piperidin-4-yl) -1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide hydrochloride (2a) (0.40g, 0.824mmol) was dissolved in 20mL of N, N-dimethylacetamide, 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.565g, 3.30mmol), anhydrous magnesium sulfate 0.5g, acetic acid 0.5mL, stirred at 70 ℃ for 1H, sodium cyanoborohydride (335mg, 5.5mmol) was added, and the reaction was continued overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of ethyl acetate and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid (2b) (0.38g, 76.31% yield)

MS m/z＝604.2[M+1]⁺

The third step: 5-amino-1- (1- (azetidin-3-yl) piperidin-4-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (2c)

5-amino-1-(1-(azetidin-3-yl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

Tert-butyl 3- (4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) azetidine-1-carboxylate (2b) (0.08g, 0.13mmol) was dissolved in 5mL sulfuric acid (90%), heated to 100 ℃ for 1 hour, the reaction was cooled to room temperature, PH was adjusted to 10 in an ice water bath, EA extraction ((20mL × 3), organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM: CH3OH ═ 10:1) to give the target compound (2c) (0.05g, yield: 71.5%).

MS m/z＝522.2[M+H]⁺

The fourth step: 5-amino-1- (1- (1- (2- (2, 6-oxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 2)

The compound 5-amino-1- (1- (azetidin-3-yl) piperidin-4-yl) -3- (4- [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (2c) (50.0mg,0.10mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (69.0mg, 0.25mmol) was dissolved in 5mL of DMSO, N-diisopropylethylamine (49.0mg, 0.38mmol) was added, and after completion of the addition, reaction was carried out at 90 ℃ for 2 hours. After the reaction was completed, it was cooled to room temperature, 10mL of water was added, it was filtered, the filter cake was dissolved in 20mL of dichloromethane, it was then washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product obtained was concentrated under reduced pressure and sent to the liquid phase for preparation to obtain the title compound 2 as a yellow solid (10.0mg, yield 14%). preparation conditions: instrument and preparative column: the liquid phase was prepared using WATERS 2767, column format Xbridge C18,5 μm, 19mm x 250mm in internal diameter x length.

The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

Mobile phase system: acetonitrile/(containing 0.05% ammonia) water. Gradient elution: the acetonitrile content is 30-75%, and the elution time is 15 min.

MS m/z＝778.3[M+1]⁺

Example 3

5-amino-1- (1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 3)

5-amino-1-(1-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)azetidin-3-yl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: n- [ (4- (5-amino-1- (1- (azetidin-3-yl) piperidin-4-yl) -4-cyano-1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide (3a)

N-[(4-(5-amino-1-(1-(azetidin-3-yl)piperidin-4-yl)-4-cyano-1H-pyrazol-3-yl)phenyl)methyl]-5-fluoro-2-methoxybenzamide

The compound tert-butyl 3- (4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) azetidine-1-carboxylate (2b) (0.20g,0.33mmoL) was dissolved in 20mL HCl/dioxane, reacted at room temperature for 3 hours, and the reaction solution was directly concentrated to dryness to give a crude product of the objective compound (3a) (0.18g) which was used directly in the next reaction.

MS m/z＝504.2[M+H]⁺

The second step is that: tert-butyl 3- (3- (4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) azetidine-1-carboxylate (3b)

tert-butyl 3-(3-(4-(5-amino-4-cyano-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)azetidin-1-yl)azetidine-1-carboxylate

Intermediate N- [ (4- (5-amino-1- (1- (azetidin-3-yl) piperidin-4-yl) -4-cyano-1H-pyrazol-3-yl) phenyl) methyl ] -5-fluoro-2-methoxybenzamide (3a) (0.16g, 0.33mmol) was dissolved in 20mL of N, N-dimethylacetamide, tert-butyl 3-oxoazetidine-1-carboxylate (0.285g, 1.65mmol), anhydrous magnesium sulfate 0.5g, acetic acid 0.5mL was added, stirred at 70 ℃ for 1H, sodium cyanoborohydride (335mg, 5.5mmol) was added, and the reaction was continued overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of ethyl acetate and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid (3b) (0.08g, 36.86% yield)

MS m/z＝659.3[M+1]⁺

The third step: 5-amino-1- (1- (1- (azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (3c)

5-amino-1-(1-(1-(azetidin-3-yl)azetidin-3-yl)piperidin-4-yl)-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazole-4-carboxamide

The compound tert-butyl 3- (3- (4- (5-amino-4-cyano-3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide)]Methyl } phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) azetidine-1-carboxylate (3b) (0.08g, 0.12mmol) was dissolved in 5mL sulfuric acid (90%), heated to 100 ℃ and reacted for 1 hour, the reaction solution was cooled to room temperature, PH was adjusted to 10 in an ice water bath, EA extraction ((20mL × 3), organic phases were combined, washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the residue was separated by column chromatography (DCM: CH: DCM)₃OH ═ 10:1) to obtain the objective compound (3c) (0.03g, yield: 42.8%).

MS m/z＝577.4[M+H]⁺

The fourth step: 5-amino-1- (1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazole-4-carboxamide (Compound 3)

The compound 5-amino-1- (1- (1- (azetidin-3-yl) piperidin-4-yl) -3- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamide ] methyl } phenyl) -1H-pyrazole-4-carboxamide (3c) (30.0mg,0.05mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (69.0mg, 0.25mmol) was dissolved in 5mL of DMSO, N-diisopropylethylamine (49.0mg, 0.38mmol) was added, and after completion of the addition, the reaction was carried out at 90 ℃ for 2 hours. After the reaction was completed, it was cooled to room temperature, 10mL of water was added, the mixture was filtered, the filter cake was dissolved in 20mL of dichloromethane, the mixture was washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product obtained was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 3 as a yellow solid (5.0mg, yield 11.53%)

The preparation conditions are as follows: instrument and preparative column: the liquid phase was prepared using WATERS 2767, column format Xbridge C18,5 μm, 19mm x 250mm in internal diameter x length.

MS m/z＝417.2[M/2+1]⁺

Example 4:

5-amino-1- (1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azacyclobutane-3-yl) methyl) azetidin-3-yl) piperidin-4-yl) -3- (4- ((5-fluoro-2-methoxybenzoyl) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 4)

5-amino-1-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: tert-butyl 3- [ [3- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] methyl ] azetidine-1-carbonate (4a)

tert-butyl3-[[3-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]azetidin-1-yl]methyl]azetidine-1-carboxylate

Compound 3a (0.5g, 1mmol) was dissolved in 5mL of N, N-dimethylacetamide, 3-formylazetidine-1-carboxylic acid tert-butyl ester (370mg, 2.0mmol), anhydrous magnesium sulfate 0.5g, 1 drop of acetic acid, stirred at 70 ℃ for 1h, sodium triacetoxyborohydride (422mg, 2.0mmol) was added, and the reaction was continued for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 10mL of ethyl acetate and 10mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid 4a (250mg, 37.4% yield)

MS m/z＝673.3[M+1]⁺

The second step is that: 5-amino-1- [1- [1- (azetidin-3-ylmethyl) azetidin-3-yl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (4b)

5-amino-1-[1-[1-(azetidin-3-ylmethyl)azetidin-3-yl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

After completion of the reaction, the compound (4a) (250mg, 0.37mmol) was dissolved in 2.5mL of 90% sulfuric acid, heated to 90 ℃, stirred for 1 hour, adjusted to PH 8 to 9 with an aqueous ammonia solution at 0 ℃, extracted with dichloromethane (20mL × 4), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4b) as a yellow solid (200mg, 92%) which was used in the next reaction.

MS m/z＝591.3[M+1]⁺

The third step: 5-amino-1- (1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azacyclobutane-3-yl) methyl) azetidin-3-yl) piperidin-4-yl) -3- (4- ((5-fluoro-2-methoxybenzoyl) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 4)

Compound (4b) (100mg,0.15mmol), 2- (2, 6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to give the title compound 4 as a yellow solid (10mg, yield 7.0%).

MS m/z＝847.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.04(s,1H),8.81(t,1H),7.62(d,1H),7.51(dd,1H),7.48–7.38(m,4H),7.37–7.29(m,1H),7.18(dd,1H),6.76(d,1H),6.62(dd,1H),6.32(br.s,2H),5.04(dd,1H),4.54(d,2H),4.15–4.02(m,3H),3.89(s,3H),3.72–3.64(m,2H),3.54–3.38(m,2H),2.96–2.69(m 8H),2.62–2.53(m,2H),2.07–1.72(m,8H).

Example 5:

5-amino-1- [1- [ [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -4-piperidinyl ] methyl ] azetidin-3-yl ] -4-piperidinyl ] -3- [4- [ [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 5)

5-amino-1-[1-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl]azetidin-3-yl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: tert-butyl 4- [ [3- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] methyl ] piperidine-1-carbonate (compound 5a)

tert-butyl4-[[3-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]azetidin-1-yl]methyl]piperidine-1-carboxylate

Compound 4a (0.5g, 1.0mmol) was dissolved in 10mL of N, N-dimethylacetamide, and added1-Boc-4-piperazine Pyridinecarboxaldehyde(0.84g, 4.0mmol), anhydrous magnesium sulfate 0.5g, acetic acid 3 drops, stirring at 70 ℃ for 1h, adding sodium triacetoxyborohydride (0.84g, 4.0mmol), and continuing the reaction for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of ethyl acetate and 20mL of water. Drying the organic phase with anhydrous sodium sulfate to obtain crude productPurification by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1), and concentration gave the title compound as a yellow solid (5a) (0.25g, yield 35.9%)

MS m/z＝701.3[M+H]⁺

The second step is that: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- [1- (4-piperidinylmethyl) azepin-3-yl ] -4-piperidinyl ] pyrazole-4-carboxamide (5b)

5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-[1-(4-piperidylmethyl)azetidin-3-yl]-4-piperidyl]pyrazole-4-carboxamide

Tert-butyl 4- [ [3- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidin-1-yl ] methyl ] piperidine-1-carboxylate (5a) (250mg, 0.35mmol) was dissolved in 2.5mL of 90% sulfuric acid, warmed to 90 ℃, stirred for 1 hour, after completion of the reaction, after adjusting the PH to 8 to 9 with an aqueous ammonia solution at 0 ℃, the mixture was extracted with dichloromethane (20mL × 4), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5b) as a yellow solid (200mg, 90%) which was used in the next reaction.

MS m/z＝619.3[M+1]⁺

The third step: 5-amino-1- [1- [ [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -4-piperidinyl ] methyl ] azetidin-3-yl ] -4-piperidinyl ] -3- [4- [ [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 5)

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- [1- (4-piperidinylmethyl) azepin-3-yl ] -4-piperidinyl ] pyrazole-4-carboxamide (5b) (100mg,0.18mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after completion of the addition, the reaction was carried out at 90 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to give the title compound 5 as a yellow solid (5mg, yield 3.4%).

MS m/z＝875.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.05(s,1H),8.81(t,1H),7.64(d,1H),7.51(dd,1H),7.48–7.38(m,4H),7.37–7.27(m,2H),7.25–7.15(m,2H),6.32(br.s,2H),5.05(dd,1H),4.55(d,2H),4.17–3.96(m,3H),3.89(s,3H),3.60–3.37(m,2H),3.01–2.71(m,8H),2.63–2.53(m,2H),2.44–2.33(m,1H),2.05–1.53(m,11H),1.23–1.09(m,2H).

Example 6:

5-amino-1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 6)

5-amino-1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: 4- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] piperidine-1-carboxylic acid tert-butyl ester (compound 6a)

tert-butyl4-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]piperidine-1-carboxylate

Intermediate 2a (1.45g, 3.0mmol) was dissolved in 10mL of N, N-dimethylacetamide and added1-Boc-4-piperazine Pyridinones as inhibitors of HIV replication(1.2g, 6.0mmol), anhydrous magnesium sulfate 0.5g, acetic acid 3 drops, stirring at 70 ℃ for 1h, adding sodium triacetoxyborohydride (1.26g, 6.0mmol), and continuing the reaction for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of ethyl acetate and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid (6a) (1.45g, 76.7% yield)

MS m/z＝632.3[M+H]⁺

The second step is that: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazole-4-carboxamide (6b)

5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-1-[1-(4-piperidyl)-4-piperidyl]pyrazole-4-carboxamide

After completion of the reaction, the compound 6a (145mg, 0.23mmol) was dissolved in 2.5mL of 90% sulfuric acid, heated to 90 ℃, stirred for 1 hour, adjusted to PH 8 to 9 with an aqueous ammonia solution at 0 ℃, extracted with dichloromethane (20mL × 4), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (6b) as a yellow solid (145mg, 93%), which was used directly in the next reaction.

MS m/z＝550.3[M+1]⁺

The third step: 5-amino-1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 6)

Compound (6b) (100mg,0.18mmol), 2- (2, 6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to obtain the title compound 6as a yellow solid (5mg, yield 3.4%).

MS m/z＝806.3[M+1]⁺

Example 7:

5-amino-1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] azetidin-3-yl ] -4-piperidinyl ] -3- [4- [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 7)

5-amino-1-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: n- [ [4- [ 5-amino-4-cyano-1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazol-3-yl ] phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide (compound 7a)

N-[[4-[5-amino-4-cyano-1-[1-(4-piperidyl)-4-piperidyl]pyrazol-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

After the reaction was completed, the intermediate 6a (1.0g, 1.58mmol) was dissolved in 10mL of DCM, and 2mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure, dichloromethane 5m was added again, and l was adjusted to PH 8 to 9 with an aqueous ammonia solution at 0 ℃, extracted with dichloromethane (20mL × 4), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a crude yellow solid 7a (1.0g), which was used in the next reaction.

MS m/z＝532.3[M+H]⁺

The second step is that: tert-butyl 3- [4- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] azetidine-1-carboxylate (7b)

tert-butyl 3-[4-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]-1-piperidyl]azetidine-1-carboxylate

N- [ [4- [ 5-amino-4-cyano-1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazol-3-yl ] phenyl ] methyl ] -5-fluoro-2-methoxy-benzamide compound 7a (1.0g, 1.87mmol) was dissolved in 10mL of N, N-dimethylacetamide, tert-butyl 3-azetidine-1-carboxylate (0.85g, 5mmol), anhydrous magnesium sulfate 0.5g, 1 drop of acetic acid, stirred at 70 ℃ for 1h, sodium triacetoxyborohydride (1.05mg, 5mmol) was added, and the reaction was continued for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 10mL of ethyl acetate and 10mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid 7b (0.5g, 38.7% yield)

MS m/z＝687.3[M+1]⁺

The third step: 5-amino-1- [1- [1- (azetidin-3-yl) -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (7c)

5-amino-1-[1-[1-(azetidin-3-yl)-4-piperidyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

After completion of the reaction, the compound (7b) (0.5g, 0.72mmol) was dissolved in 2.5mL of 90% sulfuric acid, the temperature was raised to 90 ℃, and the mixture was stirred for 1 hour, and then the PH was adjusted to 8 to 9 with an aqueous ammonia solution at 0 ℃, and the mixture was extracted with dichloromethane (20mL × 4), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (7c) as a yellow solid (300mg, 70%) which was used in the next reaction.

MS m/z＝605.3[M+1]⁺

The fourth step: 5-amino-1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] azetidin-3-yl ] -4-piperidinyl ] -3- [4- [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 7)

Compound 7c (100mg,0.15mmol), 2- (2, 6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to obtain the title compound 7 as a yellow solid (10mg, yield 7.0%).

MS m/z＝861.3[M+1]⁺

Example 8:

5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-3-yl) methyl) - [1,4' -bipiperidin ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide

5-amino-1-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (8a)

tert-butyl 3-((4-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)azetidine-1-carboxylate

Compound (7a) (170mg,0.20mmol) was dissolved in 15mL of DCE, sodium carbonate (67mg, 0.80mmol) was added, and the mixture was stirred at room temperature for 30min, tert-butyl 3-formylazetidine-1-carboxylate (74mg,0.40mmol) was added, and after stirring at room temperature for 25 min, sodium triacetoxyborohydride (127mg, 0.60mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 20mL of an aqueous sodium bicarbonate solution, extracted with DCM (50mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-4:1) to give tert-butyl 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidin ] -1' -yl) methyl) azetidine-1-carboxylate (8a) (120mg, yield: 81.5%).

MS m/z＝701.4[M+1]⁺

The fourth step: 5-amino-1- (1'- (azetidin-3-ylmethyl) - [1,4' -bispiperidine ] -4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (8b)

5-amino-1-(1'-(azetidin-3-ylmethyl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

Mixing 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4' -bipiperidine]-1' -yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (8a) (120mg,0.17mmol) was dissolved in 2mL 90% H₂SO₄And the mixture is stirred for 1.5 hours at 90 ℃ in an external bath. Cooling, slowly pouring the system into sodium carbonate aqueous solution under ice water external bath, extracting with dichloromethane, drying with anhydrous sodium sulfate, and spin-drying to obtain 5-amino-1- (1'- (azetidine-3-ylmethyl) - [1,4' -bipiperidine]-4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (8b) (85mg, yield: 74.5%).

MS m/z＝619.4[M+1]⁺

The fifth step: 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-3-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 8)

5-amino-1- (1'- (azetidin-3-ylmethyl) - [1,4' -bispiperidine ] -4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (8b) (80mg,0.13mmol) was dissolved in 4 mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (54mg, 0.19mmol) were added, the reaction was stirred at 80 ℃ in an external bath for 5 hours, the reaction was cooled, 50mL of water was added, filtration was performed, the solid was collected, washed with water, dissolved in dichloromethane, dried over anhydrous sodium sulfate, after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-3-yl) methyl) - [1,4' -bipiperidin ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (compound 8) (40mg, yield: 35.2%).

MS m/z＝875.4[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.66–7.58(m,2H),7.55–7.43(m,4H),7.29–7.20(m,1H),7.15(dd,1H),6.78(d,1H),6.62(dd,1H),5.04(dd,1H),4.67(s,2H),4.23–4.05(m,3H),3.95(s,3H),3.78–3.67(m,2H),3.22–2.95(m,5H),2.91–2.60(m,5H),2.54–2.37(m,3H),2.27–2.03(m,5H),2.02–1.84(m,4H),1.71–1.54(m,2H).

Example 9:

5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) pyrrolidin-3-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 9)

5-amino-1-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-yl)methyl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-fluoro-2-methoxy benzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (9a)

tert-butyl 3-((4-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)pyrrolidine-1-carboxylate

Compound (7a) (170mg crude, 0.20mmol) was dissolved in 15mL DCE, sodium carbonate (67mg, 0.80mmol) was added, and the mixture was stirred at room temperature for 30min, tert-butyl 3-formylpyrrolidine-1-carboxylate (80mg,0.40mmol) was added, and after stirring at room temperature for 25 min, sodium triacetoxyborohydride (127mg, 0.60mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 20mL of an aqueous sodium hydrogencarbonate solution, followed by extraction with DCM (50mL × 3), washing of the organic phase with 50mL of water, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-4:1) to give tert-butyl 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidin ] -1' -yl) methyl) pyrrolidine-1-carboxylate (9a) (95mg, yield: 61.5%).

MS m/z＝715.4[M+1]⁺

The second step is that: 5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (pyrrolidin-3-ylmethyl) - [1,4' -bipiperidine ] -4-yl) -1H-pyrazole-4-carboxamide (9b)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1'-(pyrrolidin-3-ylmethyl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide

Mixing 3- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4' -bipiperidine]-1' -Yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (9a) (90mg,0.13mmol) was dissolved in 2mL of 90% H₂SO₄And the mixture is stirred for 1.5 hours at 90 ℃ in an external bath. Cooling, slowly pouring the system into sodium carbonate aqueous solution under ice water external bath, extracting with dichloromethane, drying with anhydrous sodium sulfate, and spin-drying to obtain 5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (pyrrolidine-3-ylmethyl) - [1,4' -bipiperidine]-4-yl) -1H-pyrazole-4-carboxamide (9b) (60mg, yield: 75.2%).

MS m/z＝633.4[M+1]⁺

The third step: 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) pyrrolidin-3-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 9)

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (pyrrolidin-3-ylmethyl) - [1,4' -bipiperidine ] -4-yl) -1H-pyrazole-4-carboxamide (9b) (60mg,0.10mmol) was dissolved in 4 mL DMSO, 0.5mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (40mg, 0.15mmol) were added, the reaction was stirred at 80 ℃ for 5 hours in an external bath, the reaction was cooled, 15mL water was added, filtration was carried out, the solid was collected, washed with water, the solid was dissolved with dichloromethane, dried over anhydrous sodium sulfate, after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) pyrrolidin-3-yl) methyl) - [1,4' -bipiperidin ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (compound 9) (25mg, yield: 29.0%).

MS m/z＝889.3[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.66–7.58(m,2H),7.54–7.45(m,4H),7.29–7.21(m,1H),7.19–7.13(m,1H),6.99–6.94(m,1H),6.80(dd,1H),5.04(dd,1H),4.67(s,2H),4.58–4.47(m,1H),4.18–4.06(m,1H),3.95(s,3H),3.69–3.38(m,4H),3.23–3.01(m,5H),2.92–2.60(m,4H),2.54–2.42(m,4H),2.28–2.04(m,5H),2.04–1.77(m,5H),1.72–1.58(m,2H).

Example 10:

5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 10)

5-amino-1-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidine ] -1' -yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (10a)

tert-butyl 4-((4-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)-[1,4'-bipiperidin]-1'-yl)methyl)piperidine-1-carboxylate

Compound (7a) (340mg of crude product, 0.40mmol) was dissolved in 25mL of DCE, and sodium hydrogencarbonate (135mg, 1.60mmol) was added thereto, followed by stirring at room temperature for 30min, tert-butyl 4-formylpiperidine-1-carboxylate (170mg,0.80mmol) was added thereto, followed by stirring at room temperature for 25 min, followed by addition of sodium triacetoxyborohydride (254mg, 1.20mmol) and stirring at room temperature overnight. To the reaction system was slowly added 20mL of an aqueous sodium hydrogencarbonate solution, followed by extraction with DCM (50mL × 3), washing of the organic phase with 50mL of water, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-4:1) to give tert-butyl 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4 '-bipiperidin ] -1' -yl) methyl) piperidine-1-carboxylate (10a) (190mg, yield: 62%).

MS m/z＝729.4[M+1]⁺

The second step is that: 5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (piperidin-4-ylmethyl) - [1,4' -bipiperidine ] -4-yl) -1H-pyrazole-4-carboxamide (10b)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1'-(piperidin-4-ylmethyl)-[1,4'-bipiperidin]-4-yl)-1H-pyrazole-4-carboxamide

Mixing 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) - [1,4' -bipiperidine]-1' -Yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (10a) (190mg,0.26mmol) was dissolved in 3mL 90% H₂SO₄And the mixture is stirred for 1.5 hours at 90 ℃ in an external bath. Cooling, slowly pouring the system into sodium carbonate aqueous solution under ice water bath, extracting with dichloromethane, drying with anhydrous sodium sulfate, and spin-drying to obtain 5-amino-3- (4- (((5-fluoro-2-methoxybenzyl)Amido) methyl) phenyl) -1- (1'- (piperidin-4-ylmethyl) - [1,4' -bipiperidine]-4-yl) -1H-pyrazole-4-carboxamide (10b) (140mg, yield: 83.2%).

MS m/z＝647.4[M+1]⁺

The third step: 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 10)

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (piperidin-4-ylmethyl) - [1,4' -bipiperidine ] -4-yl) -1H-pyrazole-4-carboxamide (10b) (70mg,0.11mmol) was dissolved in 4 mL of DMSO, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (50mg, 0.15mmol) were added, the reaction was stirred at 80 ℃ in an external bath for 5 hours, the reaction was cooled, 15mL of water was added, filtration was performed, the solid was collected, washed with water, the solid was dissolved with dichloromethane, dried over anhydrous sodium sulfate, after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (compound 10) (20mg, yield: 20.2%).

MS m/z＝903.4[M+1]⁺

Example 11:

5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) - [1,4' -bipiperidin ] -4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 11)

5-amino-1-(1'-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-[1,4'-bipiperidin]-4-yl)-3-(4-((5-fluoro-2-methoxybenz-amido)methyl)phenyl)-1H-pyrazole-4-carboxamide

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1'- (piperidin-4-ylmethyl) - [1,4' -bipiperidine ] -4-yl) -1H-pyrazole-4-carboxamide (10b) (70mg,0.11mmol) was dissolved in 4 mL of DMSO, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (50mg, 0.15mmol) were added, the reaction was stirred at 80 ℃ in an external bath for 5 hours, the reaction was cooled, 15mL of water was added, filtration was performed, the solid was collected, washed with water, the solid was dissolved with dichloromethane, dried over anhydrous sodium sulfate, after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give 5-amino-1- (1'- ((1- (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) - [1,4' -bipiperidine ] -4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (compound 11) (25mg, yield: 24.6%).

MS m/z＝921.3[M+1]⁺

Example 12:

5-amino-1- [1- [2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -2-azaspiro [3.5] non-7-yl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 12)

5-amino-1-[1-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2-azaspiro[3.5]nonan-7-yl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: tert-butyl 7- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] -2-azaspiro [3.5] nonane-2-carbonate (12a)

tert-butyl 7-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]-2-azaspiro[3.5]nonane-2-carboxylate

Intermediate 2a (145mg, 0.3mmol) was dissolved in 5mL of N, N-dimethylacetamide, and tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-carboxylate (239mg, 1.0mmol), anhydrous magnesium sulfate 0.5g, 1 drop of acetic acid was added, stirred at 70 ℃ for 1h, and sodium triacetoxyborohydride (211mg, 1.0mmol) was added, and the reaction was continued for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 10mL of ethyl acetate and 10mL of water. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1), and concentrated to give the title compound as a yellow solid (12a) (100mg, yield 46.7%)

MS m/z＝672.3[M+H]⁺

The second step is that: 5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazole-4-carboxamide (12b)

Tert-butyl 7- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] -2-azaspiro [3.5] nonane-2-carbonate (12a) (100mg,0.15mmol) was dissolved in 2.5mL of 90% sulfuric acid, the temperature was raised to 90 ℃, stirring was performed for 1 hour, after completion of the reaction, the PH was adjusted to 8 to 9 with an aqueous ammonia solution at 0 ℃, dichloromethane was used for extraction (20mL × 4), the mixture was washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (12b) as a yellow solid (100mg, 89%) which was used directly in the next reaction.

MS m/z＝590.3[M+1]⁺

The third step: 5-amino-1- [1- [2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -2-azaspiro [3.5] non-7-yl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 12)

5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] -1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazole-4-carboxamide (12b) (100mg,0.15mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) was dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after the addition, the reaction was carried out at 90 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to give the title compound 12 as a yellow solid (10mg, yield 7.0%).

MS m/z＝846.3[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.67–7.46(m,6H),7.29–7.10(m,2H),6.84–6.77(m,1H),6.69–6.60(m,1H),5.05(dd,1H),4.71–4.62(m,2H),4.51–4.37(m,1H),3.96(s,3H),3.88–3.66(m,6H),3.44–3.16(m,3H),2.93–2.63(m,3H),2.47–2.04(m,9H),1.82–1.57(m,4H).

Example 13:

1- [1- [ (3aR,6aS) -2- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindol-5-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrol-5-yl ] -4-piperidyl ] -5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 13)

1-[1-[(3aR,6aS)-2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-4-piperidyl]-5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: tert-butyl (3aR,6aS) -5- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenty [ c ] pyrrole-2-carbonate (Compound 13a)

tert-butyl(3aR,6aS)-5-[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate

Intermediate 2a (145mg, 0.3mmol) was dissolved in 5mL of N, N-dimethylacetamide, and (3aR,6aS) -5-octahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (225mg, 1.0mmol), anhydrous magnesium sulfate 0.5g, 1 drop of acetic acid, stirred at 70 ℃ for 1H, sodium triacetoxyborohydride (211mg, 1.0mmol) was added, and the reaction was continued for 1H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 10mL of ethyl acetate and 10mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid 13a (100mg, 50.8% yield)

MS m/z＝658.3[M+H]⁺

The second step is that: 1- [1- [ (3aR,6aS) -1,2,3,3a, 4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] -4-piperidinyl ] -5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (13b)

1-[1-[(3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-4-piperidyl]-5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Tert-butyl (3aR,6aS) -5- [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrole-2-carbonate (compound 13a) (100mg,0.15mmol) was dissolved in 2.5mL of 90% sulfuric acid, the temperature was raised to 90 ℃, stirring was performed for 1 hour, after completion of the reaction, the pH was adjusted to 8 to 9 with an aqueous ammonia solution at 0 ℃, dichloromethane was extracted (20 mL. times.4), washed once with saturated brine (20 mL. times.1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (13b) aS a yellow crude solid (87mg), directly used for the next reaction.

MS m/z＝576.3[M+1]⁺

The third step: 1- [1- [ (3aR,6aS) -2- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindol-5-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrol-5-yl ] -4-piperidyl ] -5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 13)

1- [1- [ (3aR,6aS) -1,2,3,3a, 4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] -4-piperidinyl ] -5-amino-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (13b) (100mg,0.15mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after the addition, the reaction was carried out at 90 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to give the title compound 13 as a yellow solid (10mg, yield 7.0%).

MS m/z＝832.3[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.70–7.41(m,6H),7.29–7.20(m,1H),7.19–7.11(m,1H),7.09–7.01(m,1H),6.95–6.86(m,1H),5.05(dd,1H),4.66(s,2H),4.49–4.37(m,1H),3.95(m,3H),3.85–3.64(m,3H),3.61–3.45(m,4H),3.24–3.10(m,2H),3.04–2.91(m,2H),2.91–2.54(m,5H),2.46–2.17(m,4H),2.15–2.05(m,1H),1.79–1.62(m,2H).

Example 14:

5-amino-1- [1- [ [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] azetidin-3-yl ] methyl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 14)

5-amino-1-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

The first step is as follows: tert-butyl 3- [ [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] methyl ] azetidine-1-carbonate (compound 14a)

tert-butyl3-[[4-[5-amino-4-cyano-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazol-1-yl]-1-piperidyl]methyl]azetidine-1-carboxylate

Intermediate 2a (145mg, 0.3mmol) was dissolved in 5mL of N, N-dimethylacetamide, 3-formylazetidine-1-carboxylic acid tert-butyl ester (185mg, 1.0mmol), anhydrous magnesium sulfate 0.5g, 1 drop of acetic acid, stirred at 70 ℃ for 1h, sodium triacetoxyborohydride (211mg, 1.0mmol) was added, and the reaction was continued for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 10mL of ethyl acetate and 10mL of water. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) and concentrated to give the title compound as a yellow solid 14a (100mg, 54.1% yield)

MS m/z＝618.3[M+H]⁺

The second step is that: 5-amino-1- [1- (azetidin-3-ylmethyl) -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (14b)

5-amino-1-[1-(azetidin-3-ylmethyl)-4-piperidyl]-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

Tert-butyl 3- [ [4- [ 5-amino-4-cyano-3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazol-1-yl ] -1-piperidinyl ] methyl ] azetidine-1-carbonate (compound 14a) (100mg, 0.19mmol) was dissolved in 2.5mL 90% sulfuric acid, the temperature was raised to 90 ℃, stirred for 1 hour, after completion of the reaction, the PH was adjusted to 8 to 9 with an aqueous ammonia solution at 0 ℃, extracted with dichloromethane (20mL × 4), washed once with a saturated saline solution (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (14b) as a crude yellow solid (100mg) which was used directly in the next reaction.

MS m/z＝536.2[M+1]⁺

The third step: 5-amino-1- [1- [ [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] azetidin-3-yl ] methyl ] -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (Compound 14)

5-amino-1- [1- (azetidin-3-ylmethyl) -4-piperidinyl ] -3- [4- [ [ (5-fluoro-2-methoxy-benzoyl) amino ] methyl ] phenyl ] pyrazole-4-carboxamide (14b) (100mg,0.15mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (124mg, 0.42mmol) was dissolved in 5mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after completion of the addition, reaction was carried out at 90 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, 10mL of water was added, and the filtrate was filtered, and the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and subjected to column chromatography (DCM: MeOH ═ 20:1) to give the title compound 14 as a yellow solid (10mg, yield 7.0%).

MS m/z＝792.3[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ7.69–7.45(m,6H),7.29–7.20(m,1H),7.19–7.11(m,1H),6.86–6.77(m,1H),6.71–6.62(m,1H),5.05(dd,1H),4.66(s,2H),4.53–4.40(m,1H),4.34–4.21(m,2H),3.95(s,3H),3.91–3.83(m,2H),3.79–3.69(m,1H),3.66–3.57(m,2H),3.39–3.33(m,1H),3.28–3.15(m,1H),2.91–2.63(m,4H),2.50–2.33(m,2H),2.31–2.19(m,2H),2.16–2.05(m,1H).

Example 15:

5-amino-1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 15)

5-amino-1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

The first step is as follows: tert-butyl 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (15a)

tert-butyl 4-((4-(5-amino-4-cyano-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate

Compound (2a) (0.67g,1.5mmol) was dissolved in 20mL of DCE, and tert-butyl 4-formylpiperidine-1-carboxylate (0.64g,3.0mmol) was added. After stirring at room temperature for 10min, sodium triacetoxyborohydride (0.7g, 3.3mmol) was added thereto, and the reaction was stirred at room temperature for 12 h. To the reaction solution, 50mL of a saturated sodium bicarbonate solution was slowly dropped, 30mL of dichloromethane was extracted, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (15a) (0.5g, yield: 52%).

LC-MS m/z＝646.3[M+1]⁺

The second step is that: 5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (piperidin-4-ylmethyl) piperidin-4-yl) -1H-pyrazole-4-carboxamide (15b)

5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide

Tert-butyl 4- ((4- (5-amino-4-cyano-3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) piperidine-1-carboxylate (15a) (0.5g,0.78mmol) was dissolved in 10mL sulfuric acid (W% ═ 90%), and stirred at 90 ℃ for 1H. After cooling to room temperature, 30mL of purified water was added to dilute the solution, the pH of the system was adjusted to about 10.0 with sodium carbonate solid, the solution was extracted with 60mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude 5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (piperidin-4-ylmethyl) piperidin-4-yl) -1H-pyrazole-4-carboxamide (15b) (0.34g, yield: 77%) which was directly subjected to the next reaction.

MS m/z＝564.3[M+1]⁺

The third step: 5-amino-1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 15)

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (piperidin-4-ylmethyl) piperidin-4-yl) -1H-pyrazole-4-carboxamide (15b) (0.2g,0.35mmol) was dissolved in 10mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.2g, 0.7mmol) were added, the reaction mixture was stirred at 90 ℃ for 5 hours while being externally bathed, cooled, diluted with 50mL of ethyl acetate, washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v): 20:1), to give 5-amino-1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (15) (0.15g, yield: 52%)

MS m/z＝820.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.06(br.s,1H),8.82(t,1H),7.64(d,1H),7.55–7.38(m,5H),7.37–7.27(m,2H),7.26–7.15(m,2H),6.33(br.s,2H),5.06(dd,1H),4.55(d,2H),4.15–4.06(m,1H),4.06–3.97(m,2H),3.90(s,3H),3.01–2.89(m,5H),2.63–2.53(m,2H),2.21–2.12(m,2H),2.09–1.92(m,5H),1.85–1.73(m,5H),1.21–1.08(m,2H).

Example 16:

5-amino-1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide

5-amino-1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1H-pyrazole-4-carboxamide

5-amino-3- (4- (((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1- (1- (piperidin-4-ylmethyl) piperidin-4-yl) -1H-pyrazole-4-carboxamide (15b) (0.2g,0.35mmol) was dissolved in 10mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione (0.2g, 0.7mmol) were added, the reaction mixture was stirred at 90 ℃ for 5 hours while being externally bathed, and the reaction mixture was cooled, diluted with 50mL of ethyl acetate, washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v): 20:1), to give 5-amino-1- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -3- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-4-carboxamide (Compound 16) (0.14g, yield: 47%)

MS m/z＝838.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆δ11.09(s,1H),8.82(t,1H),7.68(d,1H),7.55–7.29(m,7H),7.18(dd,1H),6.33(s,2H),5.09(dd,1H),4.55(d,2H),4.18–4.06(m,1H),3.89(s,3H),3.65–3.54(m,2H),3.00–2.81(m,5H),2.65–2.53(m,2H),2.25–2.17(m,2H),2.09–1.93(m,5H),1.88–1.75(m,5H),1.34–1.20(m,2H).

Example 17:

5- (4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 17)

5-(4-((4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The first step is as follows: 4-Methylbenzenesulfonic acid 4-oxocyclohexyl ester (17b)

4-oxocyclohexyl 4-methylbenzenesulfonate

4-Hydroxycyclohex-1-one (17a) (10g,87.61mmol) was dissolved in 120mL of dichloromethane, pyridine (10.4g, 131.5mmol) was added, p-toluenesulfonyl chloride (18.4g,96.52mmol) was added slowly in portions, and after the addition was complete, stirring was carried out at room temperature for 16 h. To the reaction mixture was added 300mL of methylene chloride, and the organic phase was washed successively with 0.5mol/L hydrochloric acid solution (100mL), 100mL of saturated sodium bicarbonate solution and 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-oxocyclohexyl 4-methylbenzenesulfonate (17b) (15g, yield: 64%).

The second step is that: 4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c)

4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexan-1-one

3- (4-Phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (9.1g, 30.00mmol) was dissolved in 120mL of DMF, potassium carbonate (12.43g, 90.00mmol) was added, the temperature of the reaction was raised to 70 ℃, 4-oxocyclohexyl 4-methylbenzenesulfonate (17b) (15.0g,55.9mmol) was added slowly in portions, and after the addition, the reaction was stirred at 70 ℃ for 4H. The reaction mixture was cooled to room temperature, 200mL of water was added, and the mixture was extracted with 200mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 25:1-15:1), to give 4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c) (3.0g, yield: 25%).

LCMS m/z＝400.2[M+1]⁺

The third step: 4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazine-1-carboxylic acid tert-butyl ester (17d)

tert-butyl 4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate

4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c) (200mg,0.50mmol) was dissolved in 15ml of DCE, tert-butyl piperazine-1-carboxylate (186mg,1.00mmol) was added, stirring was carried out at room temperature for 30min, sodium triacetoxyborohydride (212mg,1.00mmol) was added, and stirring was carried out at room temperature for 16H. To the reaction solution, 30mL of an aqueous sodium bicarbonate solution was slowly added, extraction was performed with 100mL of dichloromethane, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazine-1-carboxylate (17d) (210mg, yield: 74%).

LCMS m/z＝570.3[M+1]⁺

The fourth step: trifluoroacetic acid salt of 3- (4-phenoxyphenyl) -1- (4- (piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17e)

3-(4-phenoxyphenyl)-1-(4-(piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazine-1-carboxylate (17d) (200mg,0.35mmol) was dissolved in 15mL of dichloromethane, 8mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude product of 3- (4-phenoxyphenyl) -1- (4- (piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17e) as the trifluoroacetate salt (0.25 g).

LCMS m/z＝470.3[M+1]⁺

The fifth step: 4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (17f)

tert-butyl 4-((4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

The trifluoroacetate salt (0.12g) of the above crude 3- (4-phenoxyphenyl) -1- (4- (piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17e) was dissolved in 15mL of DCE, solid sodium bicarbonate (60mg, 0.71mmol) was added, and the mixture was stirred at room temperature for 20min, tert-butyl 4-formylpiperidine-1-carboxylate (73mg,0.34mmol) was added, and the mixture was stirred at room temperature for 30min, sodium triacetoxyborohydride (72mg, 0.34mmol) was added, and the mixture was stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with dichloromethane (30mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidine-1-carboxylate (17f) (100mg, two-step yield from compound 17 d: 89%).

LCMS m/z＝667.4[M+1]⁺

And a sixth step: trifluoroacetic acid salt of 3- (4-phenoxyphenyl) -1- (4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17g)

3-(4-phenoxyphenyl)-1-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidine-1-carboxylate (17f) (100mg,0.15mmol) was dissolved in 10mL DCM and 5mL trifluoroacetic acid was added and stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude product of 3- (4-phenoxyphenyl) -1- (4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17g) as the trifluoroacetate salt (0.15 g).

LCMS m/z＝567.3[M+1]⁺

The seventh step: 5- (4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 17)

The above crude 3- (4-phenoxyphenyl) -1- (4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17g) as trifluoroacetate (0.15g) was dissolved in 5mL of DMSO, solid sodium bicarbonate (61mg, 0.73mmol) was added and stirred at room temperature for 10min, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (60mg, 0.22mmol) were added and the reaction was stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 50mL of water was added, and the filtrate was filtered, and the filter cake was collected, washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5- (4- ((4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 17) (70mg, two-step yield from compound 17 f: 57%).

¹H NMR(400MHz,CDCl₃)δ8.63(br.s,1H),8.38(s,1H),7.70–7.61(m,3H),7.43–7.35(m,2H),7.29–7.26(m,1H),7.21–7.12(m,3H),7.12–7.00(m,3H),5.58(br.s,2H),5.02–4.87(m,2H),4.00–3.88(m,2H),3.02–2.92(m,2H),2.92–2.63(m,7H),2.63–2.51(m,2H),2.51–2.39(m,2H),2.31–2.08(m,6H),1.95–1.77(m,6H),1.67–1.52(m,2H),1.36–1.22(m,3H).

LCMS m/z＝823.4[M+1]⁺

Example 18:

trifluoroacetate salt of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 18)

5-(3-(4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate

The first step is as follows: 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (18a)

tert-butyl 3-(4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)azetidine-1-carboxylate

The trifluoroacetate salt (460mg) of the above crude 3- (4-phenoxyphenyl) -1- (4- (piperazin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (17e) is dissolved in 25mL of DCE, solid sodium bicarbonate (240mg, 2.86mmol) is added, stirring is carried out at room temperature for 20min, tert-butyl 3-oxaazetidine-1-carboxylate (240mg,1.40mmol) is added, stirring is carried out at room temperature for 30min, sodium triacetoxyborohydride (297mg, 1.40mmol) is added, and stirring is carried out at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with dichloromethane (30mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidine-1-carboxylate (18a) (400mg, two-step yield from compound 17 d: > 99%).

LCMS m/z＝625.4[M+1]⁺

The second step is that: trifluoroacetic acid salt of 1- (4- (4- (azetidin-3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (18b)

1-(4-(4-(azetidin-3-yl)piperazin-1-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidine-1-carboxylate (18a) (200mg,0.32mmol) was dissolved in 10mL DCM and 5mL trifluoroacetic acid was added and stirred at rt for 2H. The reaction system was concentrated under reduced pressure to give a crude 1- (4- (4- (azetidin-3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (18b) as the trifluoroacetate salt (260 mg).

LCMS m/z＝525.3[M+1]⁺

The third step: trifluoroacetate salt of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 18)

The above crude trifluoroacetate salt (260mg) of 1- (4- (4- (azetidin-3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (18b) was dissolved in 10mL of DMSO, solid sodium bicarbonate (121mg, 1.44mmol) was added and stirred at room temperature for 10min, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (120mg, 0.43mmol) were added and the reaction stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 20mL of water was added, the mixture was filtered, the filter cake was collected, the filter cake was washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give a trifluoroacetate salt (75mg) of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 18).

¹H NMR(400MHz,CDCl₃)δ9.27(br.s,1H),8.42–8.36(m,1H),7.69–7.60(m,3H),7.43–7.34(m,2H),7.21–7.03(m,5H),6.81–6.75(m,1H),6.56–6.48(m,1H),5.70(br.s,2H),4.99–4.70(m,2H),4.16–4.04(m,2H),3.95–3.84(m,2H),3.49–3.35(m,1H),2.95–2.78(m,2H),2.78–2.65(m,4H),2.65–2.50(m,3H),2.50–2.35(m,2H),2.26–2.08(m,4H),2.02–1.66(m,5H),1.66–1.50(m,1H).

LCMS m/z＝781.3[M+1]⁺

Example 18-1:

5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 18)

5-(3-(4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The trifluoroacetate salt (85mg) of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 18) was dissolved in 50mL of dichloromethane and 5mL of methanol, washed with saturated aqueous sodium bicarbonate solution (30 mL. times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, 10mL of petroleum ether and 2mL of ethyl acetate were added to the residue, stirred for 0.5H, filtered, and the filter cake was dried under vacuum to give 5- (3- (4- (4-amino-3-) (5- (4-amino-3-) (compound 18) 4-Phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 18) (60 mg).

¹H NMR(400MHz,CDCl₃)δ9.12–8.90(m,1H),8.42–8.34(m,1H),7.69–7.60(m,3H),7.43–7.34(m,2H),7.22–7.02(m,5H),6.81–6.75(m,1H),6.56–6.48(m,1H),5.64(br.s,2H),4.99–4.70(m,2H),4.16–4.04(m,2H),3.95–3.85(m,2H),3.50–3.35(m,1H),2.95–2.78(m,2H),2.78–2.63(m,4H),2.63–2.50(m,3H),2.50–2.35(m,2H),2.28–2.05(m,5H),1.95–1.45(m,5H).

LCMS m/z＝781.3[M+1]⁺

Example 19:

trifluoroacetic acid salt of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 19)

5-(3-(4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)-[1,3'-biazetidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate

The first step is as follows: 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylic acid tert-butyl ester (19a)

tert-butyl 3-(4-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)-[1,3'-biazetidine]-1'-carboxylate

The trifluoroacetate salt (260mg) of the above crude 1- (4- (4- (azetidin-3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (18b) was dissolved in 25mL of DCE, solid sodium bicarbonate (135mg, 1.61mmol) was added and stirred at room temperature for 20min, tert-butyl 3-oxoazetidine-1-carboxylate (110mg,0.64mmol) was added and stirred at room temperature for 30min, sodium triacetoxyborohydride (136mg, 0.64mmol) was added and stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated aqueous sodium bicarbonate solution was slowly added, extraction was performed with dichloromethane (30mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1-8:1) to give tert-butyl 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylate (19a) (110mg, two-step yield from compound 18 a: 51%).

LCMS m/z＝680.4[M+1]⁺

The second step is that: trifluoroacetate salt of 1- (4- (4- ([1,3' -diaza-but ] -3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (19b)

1-(4-(4-([1,3'-biazetidin]-3-yl)piperazin-1-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -carboxylate (19a) (100mg,0.15mmol) was dissolved in 10mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude 1- (4- (4- ([1,3' -bisazetidin ] -3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (19b) as the trifluoroacetate salt (140 mg).

LCMS m/z＝580.3[M+1]⁺

The third step: trifluoroacetic acid salt of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 19)

The trifluoroacetate salt (140mg) of the crude 1- (4- (4- ([1,3' -diazepin ] -3-yl) piperazin-1-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (19b) described above is dissolved in 10mL of DMSO, solid sodium bicarbonate (74mg, 0.88mmol) is added, stirring is carried out at room temperature for 10min, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis is described in WO2017197056) (60mg, 0.22mmol) are added, and the reaction is stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 20mL of water was added, the mixture was filtered, the filter cake was collected, the filter cake was washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give a trifluoroacetate salt (40mg) of 5- (3- (4- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperazin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 19).

¹H NMR(400MHz,CDCl₃)δ8.94(br.s,1H),8.38(s,1H),7.70–7.60(m,3H),7.43–7.35(m,2H),7.21–7.05(m,5H),6.77(d,1H),6.50(dd,1H),5.60(br.s,2H),5.01–4.87(m,2H),4.07–3.98(m,2H),3.88–3.81(m,2H),3.71–3.62(m,1H),3.55–3.47(m,2H),3.16–3.01(m,3H),2.92–2.65(m,5H),2.56–2.36(m,6H),2.26–2.08(m,3H),1.95–1.77(m,5H),1.77–1.62(m,2H).

LCMS m/z＝836.4[M+1]⁺

Example 20:

trifluoroacetate salt of 5- (4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 20)

5-(4-((1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate

The first step is as follows: 4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (20a)

tert-butyl 4-((1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c) (200mg,0.50mmol) was dissolved in 15mL of DCE, acetic acid (0.25mL,4.375mmol) and tert-butyl 4- (piperidin-4-ylmethyl) piperazine-1-carboxylate (284mg,1.00mmol) were added (see WO2020051564 for synthesis), stirred at room temperature for 30min, sodium triacetoxyborohydride (212mg,1.00mmol) was added, and stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with 100mL of dichloromethane, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give tert-butyl 4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (20a) (170mg, yield: 51%).

LCMS m/z＝667.4[M+1]⁺

The second step is that: trifluoroacetic acid salt of 3- (4-phenoxyphenyl) -1- (4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (20b)

3-(4-phenoxyphenyl)-1-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (20a) (150mg,0.22mmol) was dissolved in 8mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude product of 3- (4-phenoxyphenyl) -1- (4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (20b) as the trifluoroacetate salt (0.22 g).

LCMS m/z＝567.4[M+1]⁺

The third step: trifluoroacetate salt of 5- (4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 20)

The above crude trifluoroacetate salt of 3- (4-phenoxyphenyl) -1- (4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) cyclohexyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (20b) (0.22g) was dissolved in 5mL of DMSO, solid sodium bicarbonate (95mg, 1.13mmol) was added and stirred at room temperature for 10min, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (93mg, 0.34mmol) were added and the reaction was stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 20mL of water was added, the filtrate was collected, the filter cake was washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) after concentration under reduced pressure to give a trifluoroacetate salt (100mg) of 5- (4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 20).

¹H NMR(400MHz,CDCl₃)δ8.39(s,1H),7.72–7.60(m,3H),7.43–7.34(m,2H),7.30–7.26(m,1H),7.20–7.11(m,3H),7.11–7.01(m,3H),5.70(br.s,2H),5.03–4.68(m,2H),3.47–3.37(m,4H),3.23–2.94(m,2H),2.93–2.66(m,3H),2.60–2.50(m,4H),2.50–2.38(m,2H),2.38–2.08(m,9H),2.05–1.93(m,1H),1.93–1.68(m,5H),1.68–1.48(m,2H).

LCMS m/z＝823.4[M+1]⁺

Example 20-1:

5- (4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 20)

5-(4-((1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The trifluoroacetate salt (60mg) of 5- (4- ((1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 20) was dissolved in 50mL of dichloromethane and 5mL of methanol, washed with a saturated aqueous sodium bicarbonate solution (30 mL. times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was added with 10mL of petroleum ether and 2mL of ethyl acetate, stirred for 0.5H, filtered, and the filter cake was dried under vacuum to give 5- (4- ((1- (4- (4-amino-3- (4-Phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 20) (40 mg).

¹H NMR(400MHz,CDCl₃)δ8.39(s,1H),7.72–7.60(m,3H),7.43–7.34(m,2H),7.30–7.26(m,1H),7.20–7.11(m,3H),7.11–7.01(m,3H),5.71(br.s,2H),5.03–4.68(m,2H),3.47–3.35(m,4H),3.17–2.92(m,2H),2.92–2.64(m,3H),2.60–2.50(m,4H),2.50–2.35(m,2H),2.38–1.96(m,10H),1.92–1.65(m,5H),1.65–1.45(m,2H).

LCMS m/z＝823.4[M+1]⁺

Example 21:

5- (3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 21)

5-(3-(7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2,7-diazaspiro[3.5]nonan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The first step is as follows: 7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (21a)

tert-butyl 7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c) (150mg,0.38mmol) was dissolved in 15mL of DCE, acetic acid (0.25mL,4.375mmol) and tert-butyl 2, 7-diazaspiro [3.5] non-2-carboxylate (171mg,0.76mmol) were added, stirred at room temperature for 30min, sodium triacetoxyborohydride (160mg,0.75mmol) was added, and stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with 100mL of dichloromethane, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (21a) (70mg, yield: 30%).

LCMS m/z＝610.3[M+1]⁺

The second step is that: trifluoroacetate salt of 1- (4- (2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21b)

1-(4-(2,7-diazaspiro[3.5]nonan-7-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (21a) (70mg,0.11mmol) was dissolved in 8mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude 1- (4- (2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21b) as the trifluoroacetate salt (0.12 g).

LCMS m/z＝510.3[M+1]⁺

The third step: 3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidine-1-carboxylic acid tert-butyl ester (21c)

tert-butyl 3-(7-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-2,7-diazaspiro[3.5]nonan-2-yl)azetidine-1-carboxylate

The trifluoroacetate salt (0.12g) of the above crude 1- (4- (2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21b) was dissolved in 15mL of DCE, solid sodium bicarbonate (48mg, 0.57mmol) was added and stirred at room temperature for 20min, tert-butyl 3-oxoazetidine-1-carboxylate (40mg,0.23mmol) was added and stirred at room temperature for 30min, sodium triacetoxyborohydride (50mg, 0.24mmol) was added and stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with dichloromethane (30mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidine-1-carboxylate (21c) (35mg, two-step yield from compound 21 a: 48%).

LCMS m/z＝665.4[M+1]⁺

The fourth step: 1- (4- (2- (azetidin-3-yl) -2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21d) trifluoroacetate

1-(4-(2-(azetidin-3-yl)-2,7-diazaspiro[3.5]nonan-7-yl)cyclohexyl)-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidine-1-carboxylate (21c) (35mg,0.05mmol) was dissolved in 10mL DCM, and 5mL trifluoroacetic acid was added and stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give crude 1- (4- (2- (azetidin-3-yl) -2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21d) trifluoroacetate (60 mg).

LCMS m/z＝565.3[M+1]⁺

The fifth step: 5- (3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 21)

The crude 1- (4- (2- (azetidin-3-yl) -2, 7-diazaspiro [3.5] non-7-yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (21d) trifluoroacetate (60mg) was dissolved in 5mL of DMSO, solid sodium bicarbonate (21mg, 0.25mmol) was added and stirred at room temperature for 10min, 0.5mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (21mg, 0.08mmol) were added and the reaction stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 20mL of water was added, the mixture was filtered, the filter cake was collected, the filter cake was washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure to be purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5- (3- (7- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) -2, 7-diazaspiro [3.5] non-2-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (compound 21) (15mg, two-step yield from compound 21 c: 37%).

¹H NMR(400MHz,CDCl₃)δ8.49(br.s,1H),8.38(s,1H),7.68–7.60(m,3H),7.43–7.34(m,2H),7.21–7.04(m,5H),6.79–6.74(m,1H),6.54–6.47(m,1H),5.52(br.s,2H),5.13–4.68(m,2H),4.07–3.98(m,2H),3.86–3.77(m,2H),3.72–3.61(m,1H),3.13–3.04(m,4H),2.95–2.65(m,4H),2.65–2.37(m,5H),2.26–2.08(m,4H),1.97–1.54(m,7H).

LCMS m/z＝821.3[M+1]⁺

Example 22:

5- (3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 22)

5-(3-(5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The first step is as follows: 5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (22a)

tert-butyl 5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohex-1-one (17c) (150mg,0.38mmol) was dissolved in 15mL of DCE, acetic acid (0.25mL,4.375mmol) and tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (160mg,0.75mmol) were added, stirring at room temperature for 30min, sodium triacetoxyborohydride (160mg,0.75mmol) was added, and stirring at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with 100mL of dichloromethane, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (22a) (120mg, yield: 53%).

LCMS m/z＝596.3[M+1]⁺

The second step is that: trifluoroacetate salt of 1- (4- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxy-phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22b)

1-(4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)cyclohexyl)-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (22a) (120mg,0.20mmol) was dissolved in 8mL DCM and 3mL trifluoroacetic acid was added. Stirred at room temperature for 2 h. The reaction system was concentrated under reduced pressure to give a crude 1- (4- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxy-phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22b) as the trifluoroacetate salt (145 mg).

LCMS m/z＝496.3[M+1]⁺

The third step: 3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidine-1-carboxylic acid tert-butyl ester (22c)

tert-butyl 3-(5-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)azetidine-1-carboxylate

The trifluoroacetate salt (145mg) of the above crude 1- (4- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxy-phenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22b) was dissolved in 15mL DCE, solid sodium bicarbonate (85mg, 1.00mmol) was added and stirred at room temperature for 20min, tert-butyl 3-oxoazetidine-1-carboxylate (68mg,0.40mmol) was added and stirred at room temperature for 30min, sodium triacetoxyborohydride (85mg, 0.40mmol) was added and stirred at room temperature for 16H. To the reaction solution, 30mL of a saturated sodium bicarbonate solution was slowly added, extraction was performed with dichloromethane (30mL × 3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to give tert-butyl 3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidine-1-carboxylate (22c) (110mg, two-step yield from compound 22 a: 85%).

LCMS m/z＝651.4[M+1]⁺

The fourth step: trifluoroacetic acid salt of 1- (4- (5- (azetidin-3-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22d)

1-(4-(5-(azetidin-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate

Tert-butyl 3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidine-1-carboxylate (22c) (100mg,0.15mmol) was dissolved in 10mL DCM and 5mL trifluoroacetic acid was added and stirred at room temperature for 2H. The reaction system was concentrated under reduced pressure to give a crude 1- (4- (5- (azetidin-3-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22d) as the trifluoroacetate salt (130 mg).

LCMS m/z＝551.3[M+1]⁺

The fifth step: 5- (3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 22)

The trifluoroacetate salt (130mg) of the crude 1- (4- (5- (azetidin-3-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) cyclohexyl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (22d) was dissolved in 5mL DMSO, solid sodium bicarbonate (63mg, 0.75mmol) was added, stirring was carried out at room temperature for 10min, 0.5mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (synthesis see WO2017197056) (64mg, 0.23mmol) were added and the reaction was stirred at 80 ℃ for 5H. The reaction mixture was cooled to room temperature, 20mL of water was added, and the mixture was filtered, and the filter cake was collected, washed with 10mL of water, the solid was dissolved in 100mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give 5- (3- (5- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 22) (70mg, two-step yield from compound 22 c: 58%).

¹H NMR(400MHz,CDCl₃)δ9.24(br.s,1H),8.39(s,1H),7.69(d,2H),7.60(d,1H),7.31(t,2H),7.17–7.06(m,3H),7.04–6.92(m,2H),6.72(d,1H),6.47–6.39(m,1H),5.70(br.s,2H),4.97–4.78(m,2H),4.07–3.97(m,2H),3.94–3.84(m,2H),3.56–3.46(m,1H),3.00–2.64(m,6H),2.62–2.41(m,5H),2.40–2.20(m,2H),2.16–2.05(m,2H),2.04–1.85(m,4H),1.85–1.74(m,2H),1.74–1.55(m,2H).

LCMS m/z＝807.3[M+1]⁺

Test example

1. Cell proliferation inhibition assay

The Mino culture medium is RPMI1640+ 10% FBS, and is cultured at 37 deg.C and 5% CO₂An incubator. Cells were plated in 96-well plates. Wherein, the Mino cells are 5000 cells/well, and each well is 90 mu L. Each well was dosed with 10 μ L of compound at different concentrations. Each concentration was set to 3 more wells, the last column was DMSO vehicle control, at 37 ℃, 5% CO₂The culture was continued under the conditions for 72 hours. After 72 hours, 100. mu.L of detection reagent (Ce) was added to each wellll visual Assay, Promega, G7573), mixed for 2 minutes, incubated at room temperature for 10 minutes, and the fluorescence signal value was measured with a microplate reader (PHERAstar FSX). Using origin9.2 software, the IC of compounds to inhibit cell proliferation was calculated₅₀The value, and the inhibition Max inhi% at the highest concentration of compound was calculated according to formula (1).

Max inhi.％＝(1-T_{72 administration of drugs}/T_{72 vehicle}) X 100% of formula (1).

IC for inhibiting Mino cell proliferation₅₀The results are shown in Table 1.

TABLE 1 IC for inhibition of Mino cell proliferation₅₀Value of

Serial number	Compound numbering	IC₅₀(nM)
			1	Compound 8	73
2	Compound 12	412
			3	Compound 17	186
4	Trifluoroacetic acid salt of Compound 18	21
			5	Trifluoroacetic acid salt of Compound 19	80
6	Trifluoroacetic acid salt of Compound 20	111
			7	Compound 21	147
8	Compound 22	286

And (4) conclusion: the compound synthesized by the technology has a certain inhibition effect on the proliferation of Mino cells (mantle cell lymphoma cells). Specific values of activity are shown in Table 1.

2. In vitro BTK C481S kinase assay

Kinase BTK C481S (Carna, Cat.No. 08-547) was prepared into 2.5X kinase solution, substrates FAM-P2(GL Biochem, Cat.No.112394) and ATP ((Sigma, Cat.No. A7699-1G) were prepared into 2.5X substrate solution, 5. mu.L of compounds with different concentrations were added to 384-well plates, 10. mu.L of 2.5X kinase solution was added, incubated at room temperature for 10 minutes, 10. mu.L of 2.5X substrate solution was added, after incubation at 28 ℃ for an appropriate time, 30. mu.L of stop solution was added to terminate the reaction, and the detection was performed using a Caliper EZ reader2 instrument, the inhibition calculation formula is shown in formula 2, where max is the DMSO control reading, min is the negative control reading, and conversion is the compound reading, and IC was calculated using XLIPT extended-in version5.4.0.8 software according to the inhibition value₅₀The value is obtained.

Inhibition ratio [% ], [ ([ max-conversion ]/[ max-min ] ]) [% ], and [ 100% ]

The results of the activity test are shown in table 2:

TABLE 2 IC of the Compounds of the invention against BTK C481S kinase in vitro₅₀(nM)

Compound (I)	BTK C481S IC₅₀(nM)
		Compound 1	17nM
Compound 6	21nM
		Compound 7	24nM
Compound 8	19nM
		Compound 13	23nM
Compound 14	28nM
		Compound 15	47nM
Compound 16	45nM

And (4) conclusion: the compound disclosed by the invention has good inhibitory activity on in vitro BTK C481S kinase.

3. Pharmacokinetic testing of rats

Purpose of the experiment: in this test, the test substance is administered to SD rats via single-dose vein and gavage, and the concentration of the test substance in the plasma of the rats is measured to evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the rats.

Test animals: male SD rats, about 200g, 6-8 weeks old, 6 per compound. Purchased from Woods laboratories Inc.

The test method comprises the following steps: on the day of the experiment, 6 SD rats were randomly grouped by body weight. The food is fasted for 12-14 h before administration for 1 day, and is fed for 4h after administration.

Doses are in free base.

Sampling

Before and after administration isoflurane anesthesia 0.1mL of blood was drawn from the orbit and placed in an EDTAK2 centrifuge tube. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.

Plasma time points were collected in groups G1& G2:

G1:0,5min,15min,30min,1,2,4,6,8,24h；

G2:0,15min,30min,1,2,4,6,8,24h.

all samples were stored at-80 ℃ before analytical testing. The samples were tested by HPLC-MS/MS.

Table 3 pharmacokinetic parameters of the compounds in rat plasma

Test compounds	Mode of administration	AUC_0-t(ng/ml·h)	F(％)
				Compound 18	i.g.(20mg/kg)	5698±750	19.6±2.6
Compound 20	i.g.(20mg/kg)	560±147	6.78±1.8

Injecting: compound was administered i.g. (gavage).

And (4) conclusion: the compound synthesized by the technology of the invention has certain oral bioavailability in rat bodies.

Claims

1. A compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

B-L-K (I)；

L is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;

ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH₂、O、-NR^b0-C ═ O, C ≡ C or a bond;

cy1, Cy2, Cy3 and Cy4 are each independently selected from 3 to 12 membered heterocyclic ring, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or bond, said heterocyclic, cycloalkyl or aryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、oxo、CF₃、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl, CN, COOH orC_1-4Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

b is selected from B1-W1-B2-B3-B4-or

When B is selected from B1-W1-B2-B3-B4-, Cy1, Cy2, Cy3 and Cy4 cannot be bonds at the same time;

when B is selected from B1-W1-B2-B3-B4-, Ak1, Ak2, Ak3, Ak4 or Ak5 is not a bond, the two can not be directly connected with each other;

b1 is selected from 6-membered heteroaromatic ring or phenyl further optionally substituted with 0 to 4R^b1(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;

w1 is selected from-O-, -S-, -NH-, -NHCO-or-CONH-;

b2 is selected from 6-membered heteroaromatic ring or phenyl optionally further optionally substituted with 0 to 4R^b2(iii) substituted, said heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N;

b3 is selected from 8-10 membered heterorings, optionally further optionally substituted with 0 to 4R^b3(iii) substituted, said heteroring contains 1 to 4 heteroatoms selected from O, S, N;

b4 is selected from the group consisting of 4-7 membered monocycloalkyl, 6-12 membered spirocycloalkyl, 5-10 membered benzocycloalkyl, and 7-10 membered bridged cycloalkyl, said monocycloalkyl, spirocycloalkyl, benzocycloalkyl, and bridged cycloalkyl groups optionally further optionally substituted with 0 to 4R^b4Substituted;

R^b0selected from H, C_1-4Alkyl, 3 to 12 membered cycloalkyl or 3 to 12 membered heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

R^b1、R^b2、R^b3or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CF₃、COOH、CONH₂、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said alkyl and alkoxy being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

m is selected from 0, 1 or 2;

k is selected from

Ring E or F is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;

R^k2is selected from CH₂、C＝O、S＝O、SO₂；

R^k5is selected from C ═ O or

M₂Is selected from-NHC (═ O) -C_1-6Alkyl, 8-10 membered hetero-cyclic or-NHC (═ O) -C_3-6Cycloalkyl, said alkyl, hetero-cyclo or cycloalkyl optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl, oxo or C_1-4Substituted by a substituent of alkoxy;

M₃is selected from-NH-or-O-;

R^k6is selected from C_1-6Alkyl, said alkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C_1-6Alkyl or C_3-6Cycloalkyl, substituted with a substituent;

R^k7each independently selected from H, F, Cl, Br, I, OH, SH, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Alkylthio radical, C_1-6Alkyl formyloxy, said alkyl, alkoxy or alkylthio being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k8、R^k9each independently selected from H, C_1-6Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k10selected from 5-6 membered heteroaryl, said heteroaryl optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, substituted with a substituent;

g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, CF₃、CN、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;

p1 or p2 are each independently selected from 0, 1,2,3 or 4.

2. A compound according to claim 1 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4-7 membered heteromonocyclic ring, a 5-10 membered heterobicyclic ring, a 6-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, a 4-7 membered monocycloalkyl, a 5-10 membered heterocycloalkyl, a 6-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl or a 6-10 membered aryl, all of whichThe aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic or heterobridged ring is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH₂、oxo、CF₃、COOH、CN、C_1-4Alkyl, hydroxy substituted C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

b is selected from B1-W1-B2-B3-B4-;

b1 is selected from phenyl or pyridyl further optionally substituted with 0 to 4R^b1Substituted;

w1 is selected from-O-, -NHCO-, or-CONH-;

b2 is selected from phenyl or pyridyl further optionally substituted with 0 to 4R^b2Substituted;

b3 is selected from substituted or unsubstituted imidazopyrimidines, pyrazolopyrimidines, imidazopyrazines, pyrazolopyrazines, imidazotetrahydropyrimidines, pyrazolotetrahydropyrimidines, when substituted, optionally further substituted with 0 to 4R^b3Substituted;

b4 is selected from cyclohexyl, cyclopentyl and cyclobutyl, said cyclohexyl, cyclopentyl and cyclobutyl being further optionally substituted by 0 to 4R^b4Substituted;

k is selected from

R^k2Is selected from CH₂Or C ═ O;

M₁Is selected from the group consisting of a bond, -CH₂-C(＝O) NH-or-C (═ O) CH₂NH-；

p1 or p2 are each independently selected from 0, 1,2,3 or 4.

3. A compound according to claim 2 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from substitutedOr one of the following unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexylcyclohexyl, cyclopropylcyclobutylcyclopentyl, cyclopropylcyclopentylyl, cyclopropylcyclohexylcyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylpirocyclopentyl, cyclopentylpirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, azetidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacylclocyclohexyl, Cyclopropylazapiperidinyl, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylazopiperidinyl, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclopentazacyclohexyl, cyclopentazacyclohexadinyl, cyclopentazacyclobutyl, cyclopentazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylazacyclobutylazetidinyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylboroazetidinyl, azetidinylcyclopentyl, azetidinylcyclohexyl, azetidinylcyclopentylgroup, azetidinopentylazacyclopentyl, azetidinohexylazacyclohexadecylohexylyl, azacyclopentadipiperidinyl, azetidinylcyclobutyl, azetidinohexylazacyclopentyl, azacyclohexazacyclopentadinyl, azacyclohexadipinyl, azetidinyl, azetidinylcohexylazacyclohexadinyl, azacyclohexadinyl, azacyclohexylpiperidinyl, azacyclohexadipinyl, azacyclohexadinyl, and the like, Cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclobutyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl, cyclopentyl spiroazetidinyl, cyclohexyl, cyclopentyl, cyclohexyl, cyclopentyl spiroazetidinyl, cyclohexyl, cyclopentyl, cyclohexyl, cyclopentyl spiroazetidinyl, cyclohexyl, or cyclohexyl,An azacyclopentyl spiroazacyclohexyl group, an azacyclohexyl spiroazetidinyl group, a cyclobutyl spiropiperidinyl group, a cyclopentyl spiropiperidinyl group, a cyclohexyl spiropiperidinyl group, an azetidinyl spiropiperidinyl group, an azacyclopentyl spiropiperidinyl group, an azacyclohexyl spiropiperidinyl group, an azacyclopentyl spiropiperidinyl group, an azacyclohexyl spiropiperidinyl group, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, a pharmaceutically,

When substituted, is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、oxo、CF₃、CN、C_1-4Alkyl, CF₃、CH₂OH, COOH or C_1-4Substituted by a substituent of alkoxy;

b is selected from

R^b1、R^b2、R^b3、R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、CF₃COOH, hydroxymethyl, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

n1, n2, n3 and n4 are respectively and independently selected from 0, 1,2,3 or 4.

4. A compound according to claim 3 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

L is selected from

Or L may be selected from

Or L may be selected from

Or L may be selected from

b is selected from

k is selected from

5. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

b is selected from

At least 4 of Ak1, Ak2, Ak3, Ak4 and Ak5 are selected from bonds;

k is selected from

6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH₂O, or a bond, and at least 4 of Ak1, Ak2, Ak3, Ak4, and Ak5 are selected from the group consisting of bonds;

cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, azetidinyl, azacyclopentyl, piperazinePyridine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutylazetidinyl, cyclobutylpipetidinyl, cyclopentaizetidinyl, cyclopentaietidactyl, cyclopentaietioazetidinyl, cyclopentaizaclidinyl, cyclopentaiclidinyl, cyclohexylazepinyl, cyclohexylazaclidinyl, azetidinyl, azetidinoazetidinyl, azetidinobutylazinyl, azetidinobutylazocycloazetidinyl, azetidinoazetidinyl, cyclopentaizacyclopentyl, azetidinohexyl, azetidinyl, azetidinoazetidinyl, cyclopentaizacyclobutylyl, cyclopentaizacylo-azacyclobutylyl, cyclopentaizacylohexyl, cyclopentaizacylpiperidine, azetidinyl, cyclopentaizacylobutyryl, cyclopentaizacylo-azacyclobutylyl, cyclopentaizacylohexyl, cyclopentaizacylohexylyl, cyclopentaizacylbutyl, and azetidinyl, Azetidinyl, azacyclohexylazapiperidyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclohexylspiropiperidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropiperidinyl, azetidinyl, and the like, An azacyclopentyl spiropiperidine, an azacyclohexyl spiropiperidine,

R^b6selected from H, C_1-4An alkyl group;

m is selected from 0 or 1;

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

M₂Selected from-NHC (═ O) -methyl, -NHC (═ O) -ethyl, -NHC (═ O) -cyclopropyl, -NHC (═ O)O) -cyclobutyl, -NHC (═ O) -cyclopentyl or-NHC (═ O) -cyclohexyl, said methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^k7each independently selected from H, F, OH, SH, methyl, methoxy or-SCH₃；

p1 or p2 are each independently selected from 0, 1 or 2.

7. The compound of claim 6, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

b is selected from

K is selected from

8. The compound of claim 7, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,

l is selected from a bond,

Wherein the left side is connected with B; or L is selected from

Wherein the left side is connected with B;

orL is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected to B.

9. A compound according to claim 1 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

B is selected from

Or B is selected from

10. The compound of claim 4 or 7, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

K is selected from

11. A compound according to claim 10 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

K is selected from

12. A compound or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:

13. a compound according to any one of claims 1 to 12, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is selected from trifluoroacetate salt.

14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

15. Use of a compound of any one of claims 1-13, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and the pharmaceutical composition of claim 14, for the manufacture of a medicament for the treatment of a disease associated with inhibition or degradation of BTK.

16. The use according to any one of claims 15, wherein the disease is selected from a tumor or an autoimmune disease.