CN113292536A

CN113292536A - Compound capable of degrading Bcr-Abl or PARP and preparation method and pharmaceutical application thereof

Info

Publication number: CN113292536A
Application number: CN202110107001.6A
Authority: CN
Inventors: 张晨; 何平; 叶飞; 李凯; 廖鹏飞; 宣兆利; 王健民; 李瑶; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2020-02-21
Filing date: 2021-01-27
Publication date: 2021-08-24

Abstract

The invention relates to a compound shown in a general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a stereoisomer, a deuterode, 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 Bcr-Abl or PARP related diseases such as tumors. B-K (Ia) B-Cy1-K (Ib) B-Cy1-Cy2-K (ic) B-Cy1-Cy2-Cy3-K (Id) B-Cy1-Cy2-Cy3-Cy4-K (ie).

Description

Compound capable of degrading Bcr-Abl or PARP and preparation method and pharmaceutical application thereof

Technical Field

The invention relates to a compound shown in a general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a stereoisomer, a deuterode, 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 Bcr-Abl or PARP related diseases such as tumors or autoimmune system diseases.

Background

Chronic Myelogenous Leukemia (CML) is a self-renewing hematopoietic stem cell malignant myeloproliferative disease, and about 90% of patients have detectable in peripheral blood cells an abnormal chromosome, the PH chromosome. The Bcr gene of chromosome 9 and the c-Abl gene of chromosome 22 form a new gene sequence Bcr-Abl (BreakPoint Cluster region-Abelson) fusion gene. The P210 protein encoded by the gene enhances the activity of tyrosine kinase, thereby generating the inhibition effect of apoptosis, which is closely related to the occurrence of chronic granulocytic leukemia. The first small molecule targeted antineoplastic agent was imatinib (imatinib), which is effective in inhibiting Bcr-Abl kinase, whereas imatinib is anew with the advent of different classes of mutant Bcr-Abl kinases. Second generation Bcr-Abl kinase inhibitors are mainly directed against imatinib resistant mutant Bcr-Abl and appear simultaneously as multi-target inhibitors for the treatment of chronic myeloid leukemia, but none of these have been effective against T315I mutant Bcr-Abl kinase. The third-generation Bcr-Abl kinase inhibitor mainly aims at T315I mutant Bcr-Abl kinase, and comprises single inhibition and synergistic action with other drugs, and meanwhile, the attempts to improve the selectivity of the drugs and reduce the occurrence of adverse reactions are also being made.

PARP is called poly-ADP-ribose polymerase, namely poly ADP ribose polymerase, and participates in a series of cellular processes including DNA repair, genome stability and the like; the protein family consists of 17 members, including PARP1, PARP2, and the like. PARP inhibitors result in failure of PARP proteins to break away from the site of DNA damage by binding to PARP1 or PARP2 catalytic sites. PARP bound to DNA can arrest DNA replication during DNA replication, further leading to BER limitations. At this point, cells trigger homologous recombination repair, and BRCA1, BRCA2 and other proteins called "BRCA-like" play an important role in homologous repeat repair. Thus, homologous recombination repair is not possible in BRCA mutated cancer cells. In addition, the function of PARP is inhibited, so that cancer cells can only carry out an error-prone DNA double-strand repair mode, and the cancer cells die.

PROTAC (protein targeting chimera) molecules are bifunctional compounds capable of simultaneously combining targeting proteins and E3 ubiquitin ligase, and the compounds can be recognized by proteasomes of cells to cause 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.

However, the application of Protac technology to Bcr-Abl kinase inhibitors has been reported in succession in the literature and patents (Angew. chem. int. Ed.2016,55,807-810; J.Med. chem.2019,62,9281-9298; WO 2017079267).

Therefore, there is a need to develop novel PROTAC drugs of Bcr-Abl kinase inhibitors or PARP inhibitors and E3 ubiquitin ligase for the treatment of Bcr-Abl or PARP related diseases.

Disclosure of Invention

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

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

The invention relates to a compound or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (Ia), (Ib), (Ic), (Id) or (Ie),

B-K (Ia)

B-Cy1-K (Ib)

B-Cy1-Cy2-K (Ic)

B-Cy1-Cy2-Cy3-K (Id)

B-Cy1-Cy2-Cy3-Cy4-K (Ie)

in certain embodiments, B is selected from

In certain embodiments, R^b1、R^b2、R^b3、R^b4Or R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、COOH、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, n1, n2, n3, n4 or n5 each independently selected from 0, 1,2,3 or 4;

in certain embodiments, R^b1、R^b2、R^b3、R^b4Or R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂COOH, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, n1, n2, n3, n4 or n5 each independently selected from 0, 1,2,3 or 4;

in certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

R^b1、R^b2Or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、COOH、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^b3Selected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, n1, n2 or n3 each independently selected from 0, 1,2,3 or 4;

in certain embodiments, B is selected from

R^b1、R^b2Or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂COOH, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, R^b3Selected from H, methyl or cyclopropyl, said methyl or cyclopropyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, n1, n2 or n3 each independently selected from 0, 1,2,3 or 4;

in certain embodiments, B is selected from

R^b3Selected from methyl, n1, n2 or n3 is selected from 0;

in certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, Cy1, Cy2, Cy3, Cy4 are each independently selected from 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 bicycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, or 6-10 membered aryl, said aryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospirocyclic, or heterobridged ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, Br, OH, COOH, CN, and optionally₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy 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;

in certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from 4-7 membered azamonocyclic, 5-10 membered azabicyclic, 6-12 membered azaspirocyclic, or 7-10 membered heterobridged ring, optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring, hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of substituted or unsubstituted: azetidinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentoazetidinyl, cyclopentaietiracetamPentylazacyclohexyl, cyclopentazapiperidine, cyclohexylazacyclobutyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylazacyclobutyl, azetidinylboazetidinyl, azetidinylbetazetidinyl, azetidinylcyclopentazetidinyl, azetidinopentylazacyclopentazacyclopentyl, azetidinoazetidinyl, azetidinopentylazacyclopentazacyclopentyl, azetidinocyclidinyl, cyclopentaspiralkyl, cyclohexylazacyclobutylt, cyclohexylmethyl, cyclohexylazacyclobutylt, cyclopentaspiralkyl, cyclohexylbutyl, cyclohexylmethyl, cyclohexyl spiroazetidinyl, cyclohexyl, and cyclohexyl, Cyclohexyl spiroazacyclopentyl, cyclohexyl spiroazacyclohexyl, azetidinyl spiroazacyclobutyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazacyclobutyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiroheterocycloalkyl, azetidinyl, and the,

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

in certain embodiments, each Cy1, Cy2, Cy3, Cy4 is independently selected from one of the following substituted or unsubstituted groups:

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

in certain embodiments, Cy1 in the compound of formula (Ib) is selected from the group consisting of

Wherein the left side is connected with B;

Wherein the left side is connected with B;

in certain embodiments, Cy1-Cy2 in the compounds of formula (Ic) is selected from the group consisting of

Wherein the left side is connected with B;

in certain embodiments, or the compound of formula (Ic) wherein Cy1-Cy2 is selected from the group consisting of

Wherein the left side is connected with B;

in certain embodiments, the Cy1-Cy2-Cy3 in the compound of formula (Id) is selected from

Wherein the left side is connected with B;

Wherein the left side is connected with B;

in certain embodiments, the Cy1-Cy2-Cy3-Cy4 in the compound of formula (Ie) is selected from

Wherein the left side is connected with B;

in certain embodiments, K is selected from

Each of rings E or F is independently selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N, R^k2Each independently 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_1-4Alkoxy radical, R^k5Is selected from C ═ O or

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

in certain embodiments, K is selected from

R^k2Each independently 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_1-4Alkoxy radical, R^k5Is selected from C ═ O or

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

in certain embodiments, 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 NH₂P1 or p2 are each independently selected from 0, 1 or 2;

in certain embodiments, K is selected from

In certain embodiments, K is selected from

In certain embodiments, K is selected from

As a first embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

R^b1、R^b2、R^b3、R^b4Or R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、COOH、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 B is selected from

R^b3Selected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I), n1, n2, or n3 each independently selected from 0, 1,2,3, or 4;

cy1, Cy2, Cy3, Cy4 are each independently selected from 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 bicycloalkyl, 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 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl radicalHydroxy-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;

k is selected from

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

R^k2each independently 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

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

n1, n2, n3, n4 or n5 are each independently selected from 0, 1,2,3 or 4.

As a second embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

n1, n2, n3, n4 or n5 are each independently selected from 0, 1,2,3 or 4;

the remaining definitions are the same as in the first embodiment of the present invention.

As a third embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

cy1, Cy2, Cy3 and Cy4 are each independently selected from 4-7 membered azamonocyclic ring, 5-10 membered azabicyclic ring, 6-12 membered azaspiro ring or 7-10 membered heterobridged ring, said heteromonocyclic, heterobicyclic, heterospiro or heterobridged ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy 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;

k is selected from

The remaining definitions are the same as in any of the first and second embodiments of the present invention.

As a fourth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, 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: azetidinyl, piperidine, morpholine, piperazine, cyclopropylazacyclobutylyl,Cyclopropylazacyclopentaimyl, cyclopropylazacyclohexylgroup, cyclopropylazapiperidine, cyclobutylazacyclobutyl, cyclobutylazacyclopentaimyl, cyclobutylazahexylgroup, cyclobutylpiperidine, cyclopentaizacyclobutyl, cyclopentaizacyclopentaizacyle, cyclopentaizacylpiperidine, cyclohexyloazacyclobutyl, cyclohexyloazacyclopentaizacyle, cyclohexyloazacyle, cyclohexylazacyclobutylazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl and azetidinyl, Azacyclohexylaminopiperidine, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclopentyl spiropiperidine, azetidinyl spiroazetidinyl,

b is selected from

R^b1、R^b2、R^b3、R^b4Or R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂COOH, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

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；

n1, n2, n3, n4 or n5 are each independently selected from 0, 1,2,3 or 4;

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

the other definitions are the same as any one of the first, second and third schemes of the invention.

As a fifth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, 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:

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

b is selected from

K is selected from

The other definitions are the same as any one of the first, second, third and fourth schemes of the invention.

As a sixth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

or Cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

cy1-Cy2 in the compound represented by the general formula (Ic) is selected from the group consisting of

Wherein the left side is connected with B;

or Cy1-Cy2 in the compound represented by the general formula (Ic) is selected from

Wherein the left side is connected with B;

the compound represented by the general formula (Id) wherein Cy1-Cy2-Cy3 is selected from the group consisting of

Wherein the left side is connected with B;

or Cy1-Cy2-Cy3 in the compound represented by the general formula (Id) is selected from

Wherein the left side is connected with B;

the Cy1-Cy2-Cy3-Cy4 in the compound represented by the general formula (Ie) is selected from

Wherein the left side is connected with B;

the other definitions are the same as any one of the first, second, third, fourth and fifth schemes of the invention.

As a seventh embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

k is selected from

The other definitions are the same as any one of the first, second, third, fourth, fifth and sixth schemes of the invention.

As an eighth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

k is selected from

The other definitions are the same as any one of the first, second, third, fourth, fifth, sixth and seventh schemes of the invention.

As a ninth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

Or B is selected from

The other definitions are the same as any one of the first, second, third, fourth, fifth, sixth, seventh and eighth schemes of the invention.

As a tenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As an eleventh embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As a twelfth embodiment of the present invention, a compound represented by the general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As a thirteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As an embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the compound being selected from one of the following structures:

some embodiments of the invention relate to compounds of the structure shown below or stereoisomers, deuterons, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,

as a fourteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

R^b1、R^b2Or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、COOH、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^b3selected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

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

As a fifteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,

cy1, Cy2, Cy3 and Cy4 are each independently selected from 4-7 membered azamonocyclic ring, 5-10 membered azabicyclic ring or 6-12 membered azaheterocyclic spiro ring, said azamonocyclic, heterocyclic or heterocyclic spiro ring being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy 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;

k is selected from

The remaining definitions are the same as in any of the first and fourteenth embodiments of the present invention.

As a sixteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, 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: azetidinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinylPyridine, cyclopentoazetidibuthyl, cyclopentoazetidityl, cyclopentoazetidinyl, cyclopentaptiperidine, cyclohexyloazetidinyl, azetidinylbutanyl, azetidinoazetidinyl, azetidinylboazetidinyl, azetidinopiperidinyl, azetidinonazetidinyl, azetidinyl, azetidinobutyl, azetidinonazetidinyl, azetidinonactetidinyl, azetidinocyclidinyl, cyclobutylspiroazetidinyl, cyclopentylpropetidinyl, cyclopentylpipetidinyl, cyclopentylpiperidyl, and the like, Cyclopentyl spiroazacyclohexyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine or azetidinyl spiropiperidine, when substituted, are optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH, N₂、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;

R^b1、R^b2or R^b4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂COOH, methyl or methoxy, said methyl or methoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b3selected from H, methyl or cyclopropyl, said methyl or cyclopropyl being optionally substitutedOne step is substituted by 0 to 4 substituents selected from H, F, Cl, Br, I;

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

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

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

the remaining definitions are the same as in any of the first, fourteenth and fifteenth embodiments of the present invention.

As a seventeenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

k is selected from

R^b3Is selected from methyl;

n1, n2 or n3 is selected from 0;

the remaining definitions are the same as in any of the first, fourteenth, fifteenth, sixteen embodiments of the present invention.

As an eighteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

Wherein the left side is connected with B;

Wherein the left side is connected with B;

the remaining definitions are the same as in any of the first, fourteenth, fifteenth, sixteenth, seventeenth embodiments of the present invention.

As a nineteenth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

k is selected from

The remaining definitions are the same as in any of the first, fourteenth, fifteenth, sixteenth, seventeenth and eighteenth embodiments of the present invention.

As a twentieth embodiment of the present invention, a compound represented by the general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

k is selected from

The remaining definitions are the same as in any of the first, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth or nineteenth embodiments of the present invention.

As a twenty-first embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,

b is selected from

The remaining definitions are the same as in any of the first, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteen, twenty embodiments of the present invention.

As a twenty-second embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As a twenty-third embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

As a twenty-fourth embodiment of the present invention, a compound represented by general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein,

b is selected from

some embodiments of the invention relate to a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the salt is selected from the group consisting of trifluoroacetate salts.

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

The invention relates to application of a compound shown in a general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, a cocrystal or a pharmaceutical composition of the compound in preparation of a medicament for treating diseases related to Bcr-Abl activity or expression.

The invention relates to application of a compound shown in a general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) or a stereoisomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, a eutectic or a pharmaceutical composition of the compound in preparation of a medicament for treating Bcr-Abl related diseases.

The invention relates to a compound of the invention or a stereoisomer, a deuterogen, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, a eutectic crystal or a pharmaceutical composition of the compound, wherein the disease is selected from tumors, preferably lung cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, gastric cancer, kidney cancer, ovarian cancer, hematopathy, lymphoma, myeloma, chronic granulocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, myeloproliferative diseases, invasive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protruberans or gastrointestinal stromal tumor.

The invention relates to application of a compound shown in a general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, a cocrystal or a pharmaceutical composition of the compound in preparation of a medicament for treating diseases related to PARP activity or expression.

The invention relates to application of a compound shown in a general formula (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, a cocrystal or a pharmaceutical composition of the compound in preparation of a medicament for treating diseases related to PARP inhibition or degradation.

The invention relates to an application of the compound or the stereoisomer, the deutero-isomer, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt, the eutectic crystal or the pharmaceutical composition, which is characterized in that the disease is selected from tumors, and the tumors are selected from ovarian cancer, fallopian tube cancer, peritoneal tumor, prostate cancer, pancreatic cancer, lung cancer or gastric cancer.

The first synthesis method comprises the following steps:

R¹、R⁴、R⁶、R⁸each independently selected from (═ O), -CHO, F, Cl, Br, I, OTf;

R²、R⁵、R⁷、R⁹each independently selected from H, (═ O), -CHO, F, Cl, Br, I or an amino protecting group, preferably Boc;

R³is selected from NH₂、F、Cl、Br、I、OTf、OH；

The general formula (Z-1) and the general formula (Z-4) are subjected to nucleophilic substitution reaction to obtain a corresponding general formula (Ia);

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), if the reaction site of the general formula (Z-3) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction with the general formula (Z-4) to obtain a corresponding general formula (Ib);

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), if the reaction site of the general formula (Z-6) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction with the general formula (Z-4) to obtain a corresponding general formula (Ic);

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), if the reaction site of the general formula (Z-8) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction with the general formula (Z-4) to obtain a corresponding general formula (Id);

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), if the reaction site of the general formula (Z-10) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction with the general formula (Z-4) to obtain a corresponding general formula (Ie);

and a second synthesis method comprises the following steps:

route 1:

route 2:

route 3:

route 4:

route 1: if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-11), wherein the general formula (Z-11) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a general formula (Ib);

route 2: if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-12), if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-12) to obtain a corresponding general formula (Z-13), and carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-13) and the general formula (Z-1) to obtain a general formula (Ic);

route 3: if the reaction site of the general formula (Z-7) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain the corresponding general formula (Z-14), if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-14) to obtain the corresponding general formula (Z-15), if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-15) to obtain a general formula (Z-16), and carrying out reductive amination, nucleophilic substitution reaction or coupling reaction on the general formula (Z-16) and the general formula (Z-1) to obtain a general formula (Id);

route 4: if the reaction site of the general formula (Z-9) has an amino protecting group, removing the amino protecting group, then reacting with the general formula (Z-4) through nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Z-17), if the reaction site of the general formula (Z-7) has an amino protecting group, removing the amino protecting group, then reacting with the general formula (Z-17) through reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Z-18), if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, then reacting with the general formula (Z-18) through reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the general formula (Z-19), if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, then reacting with the general formula (Z-19) through reductive amination, Nucleophilic substitution reaction or coupling reaction to obtain a general formula (Z-20), wherein the general formula (Z-20) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a general formula (Ie);

the definition of each substituent is the same as that of the synthesis method I.

The above-mentioned B-Cy1-R²In (Z-3), when B is selected from

When the method is used, the method can be used for synthesizing the compound by the following steps:

the first scheme is as follows:

R_x、R_y、R_zeach independently selected from F, Cl, Br, I, OTf, SOMe, SO₂Me, organic boronic acid (ester) groups (e.g. -B (OH)₂、-B(C_1-6Alkyl radical)₂Or

) Organotin group (e.g. -Sn (C)_1-6Alkyl radical)₃) Organozinc groups (e.g.: -ZnCl, -ZnBr or, -ZnI);

R_mselected from H or a protecting group, preferably THP;

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

scheme II:

the general formula (Y-1) and the general formula (Z-2) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Y-3), and the general formula (Y-3) is subjected to nucleophilic substitution reaction or coupling reaction with the general formula (Z-2) to obtain the corresponding general formula (Z-3).

The third scheme is as follows:

R_nselected from H or a protecting group, preferably THP;

the general formula (Y-1) and the general formula (Y-5) are subjected to nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Y-7), and the general formula (Y-7) is subjected to nucleophilic substitution reaction or coupling reaction with the general formula (Y-8) to obtain a corresponding general formula (Z-3).

And the scheme is as follows:

nucleophilic substitution reaction or coupling reaction with the general formula (Y-8) to obtain the corresponding general formula (Y-9), and nucleophilic substitution reaction or coupling reaction between the general formula (Y-9) and the general formula (Y-6) to obtain the corresponding general formula (Z-3).

Unless stated to the contrary, the terms used in the specification and claims of this application 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 substituted with one or more of their corresponding isotopes, where isotopes of carbon include¹²C、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" means F, Cl, Br or I-substituted, 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, 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.

"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, each X is independently selected from a bond or a heteroatom, a heteroatom including but not limited to N, O or S, and at least 1X is selected from a heteroatom, and either N or S in a 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 radical may 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, and the backbone includes from 2 to 10 carbon atoms, including but not limited to from 2 to 6 carbon atoms in the backbone and from 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, 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" or "carbocycle" 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, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is 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,

"carbocyclic ringThe radical "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, benzopyrolyl, 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 oneValence, 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 ring containing any two atoms not directly connectedPolycyclic groups, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom containing groups (including but not limited to N, S (═ O) n or O, where 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, 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-alkynyl-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 mixtures thereofSelection of 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.

"substituted with 0 to X substituents" means substituted with 0, 1,2, 3.. X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1,2,3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1,2,3, 4, or 5 substituents. 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.

X-Y membered rings (X is selected from integers less than Y greater than 3 and Y is selected from any integer between 4 and 12) include X +1, X +2, X +3, X +4. 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.).

“DC₅₀"refers to the dosage at which 50% of the protein is degraded.

Detailed Description

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.

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: 3-527-; 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 73 volumes.

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 structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6(ppm) of a monomerThe bit is 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.

Example 1

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 1)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: 4- [ 3-bromo-5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2-pyridinyl ] piperazine-1-carboxylic acid tert-butyl ester (1B)

tert-butyl 4-[3-bromo-5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-pyridyl]piperazine-1-carboxylate

5-bromo-6-chloro-N- [4- [ chloro (difluoro) methoxy ] phenyl ] pyridine-3-carboxamide (409mg, 1.00mmol), piperazine-1-carboxylic acid tert-butyl ester (204mg, 1.10mmol) were dissolved in 10mL of isopropanol, N-diisopropylethylamine (222mg, 1.72mmol) was added, and after the addition, reaction was carried out at 120 ℃ for 2 hours. After the reaction, cooled to room temperature, added water 50mL, then ethyl acetate (50mL x 2) extraction, organic phase collected, 5mL saturated sodium chloride washing, anhydrous sodium sulfate drying, vacuum concentration of the crude silica gel column purification, eluent: DCM-2% MeOH/DCM-5% MeOH/DCM to give compound 4- [ 3-bromo-5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2-pyridinyl ] piperazine-1-carboxylic acid tert-butyl ester (1B) as a brown solid (500mg, yield: 89%).

¹H NMR(400MHz,CDCl₃)δ8.68(d,1H),8.30(d,1H),8.06(s,1H),7.74–7.60(m,2H),7.24(d,2H),3.59(dd,4H),3.49–3.44(m,4H),1.48(s,9H).

LCMS m/z＝561.8[M+1]⁺

The second step is that: 4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl-3- (2-tetrahydropyran-2-ylpyrazol-3-yl) -2-pyridinyl ] piperazine-1-carboxylic acid (1C)

tert-butyl

4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(2-tetrahydropyran-2-ylpyrazol-3-yl)-2-pyridyl]piperazine-1-carboxylate

Tert-butyl 4- [ 3-bromo-5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2-pyridinyl ] piperazine-1-carboxylate (1B) (280mg, 0.50mmol) and 1-tetrahydropyran-2-yl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (172mg, 0.60mmol) were dissolved in a mixed solvent of 8mL of 1, 4-dioxane and 2mL of water, potassium carbonate (140mg, 1.01mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (37mg, 0.05mmol) were added, and the mixture was stirred at 100 ℃ for 2h under nitrogen protection. After the reaction is finished, cooling to room temperature, and concentrating under reduced pressure to obtain a crude product, purifying by a silica gel column, and eluting: DCM-0% MeOH/DCM-4% MeOH/DCM. The compound 4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl-3- (2-tetrahydropyran-2-ylpyrazol-3-yl) -2-pyridinyl ] piperazine-1-carboxylic acid (1C) was obtained as a brown solid (259mg, yield: 82%).

LCMS m/z＝633.1[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-piperazin-1-yl-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl-3- (2-tetrahydropyran-2-ylpyrazol-3-yl) -2-pyridinyl ] piperazine-1-carboxylic acid (1C) (200mg, 0.45mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to be used directly in the next step. N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (120mg, 85%) was obtained as a yellow oil.

LCMS m/z＝448.8[M+1]+

The fourth step N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 1)

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (120mg, 0.26mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL 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 the reaction was completed, it was cooled to room temperature, 10mL of water was added, and the mixture 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 concentrated under reduced pressure to obtain a crude product, which was prepared by a liquid phase, and concentrated to obtain N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (compound 1) as a yellow solid (25mg, yield 13%).

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.

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.

¹H NMR(400MHz,DMSO-d₆)δ13.08(s,1H),11.06(s,1H),10.42(s,1H),8.79(d,1H),8.38(s,1H),7.93–7.83(m,3H),7.69(d,1H),7.37–7.22(m,4H),6.75(s,1H),5.07(dd,1H),3.63–3.49(m,4H),3.43–3.32(m,4H),2.95–2.82(m,1H),2.65–2.51(m,2H),2.06–1.98(m,1H).

LCMS m/z＝705.1[M+1]⁺

Example 2

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 2)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: 3- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] azetidine-1-carboxylic acid (2A)

tert-butyl 3-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]azetidine-1-carboxylate

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (242mg, 0.556mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, 1-Boc-3-azetidinone (285mg, 1.66mmol) and anhydrous zinc chloride (406mg, 2.98mmol) were added, stirring was performed at 55 ℃ for 1H, sodium cyanoborohydride (140mg, 2.24mmol) was added, and the reaction was continued for 8H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride 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 3- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] azetidine-1-carboxylic acid (2A) as an yellowish solid (120mg, 40% yield).

LCMS m/z＝604.0[M+1]⁺

The second step is that: 6- [4- (azetidin-3-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (2B)

6-[4-(azetidin-3-yl)piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

3- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] azetidine-1-carboxylic acid (2A) (120mg,0.20mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH 8 was adjusted with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to be used directly in the next step, 6- [4- (azetidin-3-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (2B), yellow oil (100mg, yield 100%).

LCMS m/z＝503.9[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 2)

6- [4- (azetidin-3-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (2B) (100mg, 0.20mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluorodihydroisoindole-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMMSO, N-diisopropylethylamine (60mg, 0.46mmol) 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, and the mixture 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 to obtain N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (compound 2) as a yellow solid (20mg, yield 13%).

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

¹H NMR(400MHz,DMSO-d₆)δ13.04(s,1H),11.00(s,1H),10.39(s,1H),8.76(d,1H),8.33(s,1H),7.92–7.79(m,3H),7.65(d,1H),7.35(d,2H),6.79(d,1H),6.71–6.63(m,2H),5.05(dd,1H),4.15–4.06(m,2H),3.93–3.82(m,2H),3.42–3.36(m,1H),3.26–3.17(m,4H),2.93–2.83(m,1H),2.69–2.53(m,2H),2.48–2.36(m,4H),2.06–1.97(m,1H).

LCMS m/z＝760.1[M+1]⁺

Example 3

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5 ] -yl ] azetidin-3-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 3)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: tert-butyl 3- [3- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- ] (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-vinyl ] azetidin-1-yl ] azetidine-1-carboxylic acid ester (3A)

tert-butyl 3-[3-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]azetidin-1-yl]azetidine-1-carboxylate

6- [4- (azetidin-3-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (2B) (250mg, 0.50mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, 1-Boc-3-azetidinone (285mg, 1.66mmol), anhydrous zinc chloride (406mg, 2.98mmol) were added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (140mg, 2.24mmol) was added, and the reaction was continued for 8H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride 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 compound (3A) as a yellow solid (150mg, yield 46%).

LCMS m/z＝659.1[M+1]⁺

The second step is that: 6- [4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (3B)

6-[4-[1-(azetidin-3-yl)azetidin-3-yl]piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Tert-butyl 3- [3- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- ] (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] azetidin-1-yl ] azetidine-1-carboxylic acid ester (3A) (105mg, 0.16mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added and reacted at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (3B) as a yellow oil (80mg, yield 89%), which was used in the next step without further purification.

LCMS m/z＝559.0[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5 ] -yl ] azetidin-3-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 3)

6- [4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (3B) (80mg, 0.14mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (60mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (60mg, 0.46mmol) was added, and after 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, and the mixture 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, prepared through a liquid phase, and concentrated to give Compound 3as a yellow solid (8mg, yield 6.9%).

¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),11.04(s,1H),10.39(s,1H),8.75(d,1H),8.33(s,1H),7.92–7.80(d,3H),7.63(d,1H),7.34(d,2H),6.78(d,1H),6.70–6.61(m,2H),5.04(dd,1H),4.08–3.99(m,2H),3.85–3.75(m,2H),3.64–3.58(m,1H),3.41–3.34(m,2H),3.23–3.13(m,4H),2.98–2.82(m,4H),2.69–2.53(m,2H),2.39–2.27(m,4H),2.05–1.95(d,1H).

LCMS m/z＝815.2[M+1]⁺

Example 4

6- [4- [1- [1- [1- [2- (1-adamantyl) acetyl ] azetidin-3-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) ] methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 4)

6-[4-[1-[1-[2-(1-adamantyl)acetyl]azetidin-3-yl]azetidin-3-yl]piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: 6- [4- [1- [1- [1- [2- (1-adamantyl) acetyl ] azetidin-3-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) ] methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 4)

6- [4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (3B) (80mg, 0.14mmol), adamantane acetic acid (27mg, 0.14mmol) was dissolved in 2mL DMF, N-methylimidazole (44mg, 0.34mmol), tetramethyl chlorourea hexafluorophosphate (39mg, 0.14mmol) was added, and then reacted at 25 ℃ for 2 hours. After the reaction, 10mL of water was added, filtration was carried out, 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 purified by silica gel column by concentration under reduced pressure, eluent: DCM-2% MeOH/DCM-5% MeOH/DCM to give crude product prepared over liquid phase and concentrated to give compound 5 as a white solid (20mg, 19%).

The preparation conditions are as follows: a. instrument and preparative column: the liquid phase was prepared using GILSON GX-281, column number SunFire C18,5 μm, inner diameter × length 30mm × 150mm was prepared.

b. 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.

c. Mobile phase system: acetonitrile/water (0.05% ammonium acetate), gradient elution.

¹H NMR(400MHz,CDCl₃)δ8.88–8.68(m,2H),8.27(d,1H),7.77(d,2H),7.65(d,1H),7.23(d,2H),6.64(s,1H),4.15–4.03(m,1H),4.03–3.91(m,2H),3.79–3.72(m,1H),3.53–3.41(m,3H),3.38–3.25(m,4H),3.21–3.06(m,2H),2.56–2.38(m,4H),1.98–1.88(m,3H),1.87–1.66(m,7H),1.64–1.53(m,8H).

LCMS m/z＝735.3[M+1]⁺

Example 5

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] -4-piperidinyl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 5)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: tert-butyl 4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] piperidine-1-carboxylic acid (5A)

tert-butyl 4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]piperidine-1-carboxylate

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (448mg, 1mmol) was dissolved in 10mL of N, N-dimethylacetamide, N-Boc-piperidone (239mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) was added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give compound (5A) as a yellow solid (240mg, 38% yield).

LCMS m/z＝632.1[M+1]⁺

The second step is that: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- (4-piperidinyl) piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (5B)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-(4-piperidyl)piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Tert-butyl 4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] piperidine-1-carboxylic acid (5A) (140mg, 0.22mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added to react at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (5B) as a yellow oil (115mg, yield 98%) which was used in the next step without further purification.

LCMS m/z＝532.0[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] -4-piperidinyl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 5)

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- (4-piperidinyl) piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (5B) (140mg, 0.22mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluorodihydroisoindole-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.92mmol) 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, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 8 as a yellow solid (30mg, yield 14%).

¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),11.05(s,1H),10.38(s,1H),8.75(s,1H),8.31(s,1H),7.88(d,2H),7.81(s,1H),7.65(d,1H),7.38–7.29(m,3H),7.24(dd,1H),6.66(s,1H),5.06(dd,1H),4.06(d,2H),3.24–3.12(m,4H),3.04–2.93(m,2H),2.92–2.84(m,1H),2.63–2.51(m,7H),2.07–1.98(m,1H),1.89–1.80(m,2H),1.53–1.39(m,2H).

LCMS m/z＝788.2[M+1]⁺

Example 6

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5 ] -yl ] azetidin-3-yl ] -4-piperidinyl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 6)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: 3- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1- [ yl ] -1-piperidinyl ] azetidine-1-carboxylate (6A)

tert-butyl 3-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]-1-piperidyl]azetidine-1-carboxylate

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- (4-piperidinyl) piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (5B) (260mg, 0.49mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (205mg, 1.2mmol) and anhydrous zinc chloride (545mg, 4mmol) were added, stirring was performed at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give compound (6A) as a yellow solid (200mg, yield 60%).

LCMS m/z＝687.2[M+1]⁺

The second step is that: 6- [4- [1- (azetidin-3-yl) -4-piperidinyl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (6B)

6-[4-[1-(azetidin-3-yl)-4-piperidyl]piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

3- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1- [ yl ] -1-piperidinyl ] azetidine-1-carboxylic acid ester (6A) (200mg, 0.29mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added and reacted at room temperature for 8H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (6B) as a yellow oil (150mg, 88%) which was used in the next step without further purification.

LCMS m/z＝587.1[M+1]+

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5 ] -yl ] azetidin-3-yl ] -4-piperidinyl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 6)

6- [4- [1- (azetidin-3-yl) -4-piperidinyl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (6B) (120mg,0.20mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after 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, the mixture was filtered, the filter cake was dissolved in 20mL of dichloromethane, and then washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product obtained was concentrated under reduced pressure to prepare a liquid phase, which was concentrated to obtain Compound 6as a yellow solid (25mg, yield 15%).

¹H NMR(400MHz,CDCl₃)δ10.59(s,1H),8.83(d,1H),8.70(s,1H),8.30(d,1H),7.71(d,2H),7.65–7.59(m,2H),7.12(d,2H),6.76–6.72(m,2H),6.51(dd,1H),4.97(dd,1H),4.13–4.07(m,2H),3.89–3.81(m,2H),3.38–3.27(m,4H),2.97–2.87(m,3H),2.84–2.72(m,2H),2.69–2.61(m,3H),2.45–2.35(m,1H),2.20–2.13(m,1H),1.97–1.83(m,4H),1.66–1.56(d,4H).

LCMS m/z＝843.3[M+1]⁺

Example 7

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [7- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -7-azaspiro [3.5] nonyl-2-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 7)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[4-[7-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]piperazin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: tert-butyl 2- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] -7-azaspiro [3.5] nonane-7-carboxylate (7A)

tert-butyl 2-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (400mg, 0.89mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (286mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, stirring was performed at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give compound (7A) as a yellow solid (220mg, yield 37%).

LCMS m/z＝672.2[M+1]+

The second step is that: 6- [4- (7-Azaspiro [3.5] nonyl-2-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-ylpyridine-3-carboxamide (7B)

6-[4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Tert-butyl 2- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] -7-azaspiro [3.5] nonane-7-carboxylate (7A) (170mg, 0.25mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (7B) as a yellow oil (130mg, 90%) which was used directly in the next step.

LCMS m/z＝572.0[M+1]+

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [4- [7- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -7-azaspiro [3.5] nonyl-2-yl ] piperazin-1-yl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 7)

6- [4- (7-Azaspiro [3.5] nonyl-2-yl) piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-ylpyridine-3-carboxamide (7B) (130mg, 0.22mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, reaction was carried out at 90 ℃ for 2 hours after completion of the addition, after completion of the reaction, cooling to room temperature, adding 10mL of water, filtering, dissolving the cake with 20mL of dichloromethane, washing with 5mL of saturated sodium chloride, drying over anhydrous sodium sulfate, the crude product was concentrated under reduced pressure, prepared via the liquid phase, and concentrated to give compound 9 as a yellow solid (22mg, 12% yield).

¹H NMR(400MHz,CDCl₃)δ10.02(s,1H),8.81(d,1H),8.49(s,1H),8.29(d,1H),7.75–7.58(m,4H),7.25–7.22(m,2H),7.13(d,2H),7.03(dd,1H),6.73(d,1H),4.97(dd,1H),3.47–3.26(m,6H),2.97–2.72(m,4H),2.51–2.35(m,3H),2.18–2.02(m,3H),1.78–1.53(m,9H).

LCMS m/z＝828.3[M+1]⁺

Example 8

6- [4- [ (3aS,6aR) -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 ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 8)

6-[4-[(3aS,6aR)-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]piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows: tert-butyl (3aS,6aR) -5- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrole-2-carboxylate (8A)

tert-butyl(3aS,6aR)-5-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-3-(1H-pyrazol-5-yl)-2-pyridyl]piperazin-1-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6-piperazin-1-yl-5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (1D) (400mg, 0.89mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, and tert-butyl (3aR,6aS) -5-oxohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (270mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) and stirred at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) was added and the reaction was continued for 8H. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1 to 5:1) to give compound (8A) (200mg, yield 49%) as a yellow solid.

LCMS m/z＝658.1[M+1]+

The second step is that: 6- [4- [ (3aS,6aR) -1,2,3,3a,4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (8B)

6-[4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]piperazin-1-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Tert-butyl (3aS,6aR) -5- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -3- (1H-pyrazol-5-yl) -2-pyridinyl ] piperazin-1-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrole-2-carboxylate (8A) (150mg, 0.23mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out overnight at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (8B) as a yellow oil (110mg, 86%) which was used in the next reaction.

LCMS m/z＝558.0[M+1]⁺

The third step: 6- [4- [ (3aS,6aR) -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 ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 8)

6- [4- [ (3aS,6aR) -1,2,3,3a,4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] piperazin-1-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (8B) (100mg, 0.18mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindol-1, 3-dione (62mg, 0.21mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after 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, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 8 as a yellow solid (25mg, yield 17%).

¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),11.03(s,1H),10.38(s,1H),8.74(d,1H),8.30(s,1H),7.91–7.75(m,3H),7.63(d,1H),7.34(d,2H),6.94(d,1H),6.85(dd,1H),6.65(s,1H),5.08–5.01(m,1H),3.60–3.53(m,2H),3.38–3.34(m,2H),3.20–3.12(m,4H),2.93–2.82(m,2H),2.81–2.73(m,2H),2.66–2.54(m,3H),2.48–2.43(m,3H),2.19–2.09(m,2H),2.04–1.96(m,1H),1.39–1.30(m,2H).

LCMS m/z＝814.2[M+1]⁺

Example 9

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindol-5-yl ] -4-piperidyl ] pyrazol-4-yl ] -6- [ ((3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 9)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: 4- [4- [5- [5- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -2- [ ((3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] piperidine-1-carboxylic acid (9B)

tert-butyl 4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate

5-bromo-N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ ((3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (5.0g, 10.8mmol), tert-butyl 4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl ] piperidine-1-carboxylate (4.89g, 13.0mmol), potassium carbonate (2.99g, 21.6mmol) and a catalyst 10% [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex are respectively added into a dioxane/water mixed solvent, heated at 100 ℃ for 4H, reacted with 100mL of ethyl acetate, washing with 100mL of purified water; dried over anhydrous sodium sulfate, concentrated to dryness, and column chromatographed to give the compound 4- [4- [5- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -2- [ ((3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] piperidine-1-carboxylic acid (5.3g, 77% yield).

¹H NMR(400MHz,CDCl₃)δ8.64(s,1H),8.22(s,1H),7.88(s,1H),7.72(d,2H),7.53(d,2H),7.23(d,2H),4.47(s,1H),4.26(d,3H),3.65–3.56(m,1H),3.48(d,1H),3.33(t,2H),2.90(t,2H),2.14(d,2H),2.02–1.85(m,4H),1.49(s,9H).

LCMS m/z＝633.3[M+1]⁺

The second step is that: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -5- [1- (4-piperidinyl) pyrazol-4-yl ] pyridine-3-carboxamide (9C)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-[1-(4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide

4- [4- [5- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] tert-butyl ] -2- [ ((3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] piperidine-1-carboxylic acid (5.3g, 8.37mmol) was dissolved in 50mL dichloromethane, 10mL trifluoroacetic acid was added, reaction was carried out at room temperature for 2h, the solvent and trifluoroacetic acid were removed under reduced pressure, 200mL dichloromethane was added, PH was adjusted to 8-9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extraction was carried out 2 times with dichloromethane (100mL × 2), washing was carried out once with a saturated saline solution (100mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step, as a gray solid (2.2g, yield 49%).

LCMS m/z＝533.2[M+1]+

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindol-5-yl ] -4-piperidyl ] pyrazol-4-yl ] -6- [ ((3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 9)

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -5- [1- (4-piperidinyl) pyrazol-4-yl ] pyridine-3-carboxamide (9C) (120mg, 0.225mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (74.6mg, 0.270mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (145mg, 1.13mmol) 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, 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 to give Compound 9 as a yellow solid (40mg, yield 23%).

¹H NMR(400MHz,CD₃OD)δ8.66(d,1H),7.99(d,1H),7.85(s,1H),7.81–7.73(m,1H),7.70(d,1H),7.64(s,1H),7.42(d,1H),7.30(dd,1H),7.26(d,1H),5.07(dd,1H),4.54(s,1H),4.58–4.49(m,1H),4.39–4.34(m,1H),4.24–4.16(m,2H),3.61–3.52(m,1H),3.48(dd,1H),3.27–3.15(m,3H),2.92–2.65(m,3H),2.32–2.08(m,5H),2.01–1.83(m,2H).

LCMS m/z＝789.2[M+1]⁺

Example 10

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azepin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 10)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl 3- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azepanol-1-ester (10A)

tert-butyl 3-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]azetidine-1-carboxylate

Compound 9C (300mg, 0.56mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (205mg, 1.2mmol) and anhydrous zinc chloride (545mg, 4mmol) were added, stirred at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 10A, which was purified by column chromatography (DCM: MeOH ═ 10:1) to give compound 10A as a yellow solid (60mg, 15.45% yield).

LCMS m/z＝688.2[M+1]⁺

The second step is that: 5- [1- [1- (azetidinyl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (10B)

5-[1-[1-(azetidin-3-yl)-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

Tert-butyl 3- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azepin-1-ester (10A) (60mg, 0.087mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added and reacted at room temperature overnight. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (10B) as a yellow oil (50mg, without further purification) which was used in the next step. .

LCMS m/z＝588.2[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azepin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 10)

5- [1- [1- (azetidinyl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (10B) (50mg,0.085mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after 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, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 10 as a yellow solid (15mg, 20.3% yield in two steps).

¹H NMR(400MHz,CD₃OD):δ8.62(d,1H),8.17(d,1H),7.92(s,1H),7.78(d,2H),7.75–7.67(m,2H),7.28(d,2H),6.98(d,1H),6.82(dd,1H),5.08(dd,1H),4.74–4.62(m,1H),4.50–4.40(m,3H),4.40–4.27(m,3H),3.86–3.73(m,2H),3.65–3.56(m,1H),3.53(dd,1H),3.46–3.38(m,1H),3.30–3.20(m,2H),2.65(s,3H),2.92–2.65(m,4H),2.53–2.37(m,4H),2.16–1.91(m,3H).

LCMS m/z＝844.2[M+1]⁺

Example 11

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoxazolin-5-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 11)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl 4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] piperidine-1-carboxylate (11A)

tert-butyl 4-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]piperidine-1-carboxylate

Compound 9C (200mg, 0.375mmol) was dissolved in 8mL of N, N-dimethylacetamide, 1-Boc-4-piperidone (200mg, 1.0mmol), anhydrous magnesium sulfate 0.5g, 3 drops of acetic acid were added, stirred at 70 ℃ for 1h, sodium cyanoborohydride (140mg, 2.24mmol) 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 compound 11A as a yellow solid (11A) (200mg, 74% yield).

LCMS m/z＝716.2[M+1]⁺

The second step is that: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -5- [1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazol-4-yl ] pyridine-3-carboxamide (11B)

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-[1-[1-(4-piperidyl)-4-piperidyl]pyrazol-4-yl]pyridine-3-carboxamide

Tert-butyl 4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] piperidine-1-carboxylate (11A) (200mg, 0.279mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound (11B) (200mg), which was used in the next step without further purification.

LCMS m/z＝616.2[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoxazolin-5-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 11)

Crude N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] -5- [1- [1- (4-piperidinyl) -4-piperidinyl ] pyrazol-4-yl ] pyridine-3-carboxamide (11B) (200mg), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (93mg, 0.33mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (60mg, 0.46mmol) 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, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 11 as a yellow solid (20mg, 7.6% yield in two steps).

¹H NMR(400MHz,CD₃OD)δ8.67(d,1H),7.99(d,1H),7.82(s,1H),7.77(d,2H),7.67(d,1H),7.63(s,1H),7.37(d,1H),7.27–7.22(m,3H),5.06(dd,1H),4.40–4.33(m,1H),4.33–4.21(m,1H),4.09(d,2H),3.60–3.51(m,1H),3.51–3.44(m,1H),3.26–3.16(m,3H),3.07–2.97(m,2H),2.92–2.65(m,4H),2.60–2.50(m,2H),2.26–2.02(m,7H),2.02–1.92(m,2H),1.92–1.83(m,1H),1.74–1.61(d,2H).

LCMS m/z＝872.3[M+1]⁺

Example 12

5- [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 ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 3)

5-[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]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl (3aR,6aS) -5- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenty [ c ] pyrrole-2-carboxylate (12A)

tert-butyl(3aR,6aS)-5-[4-[4-[5-[[4[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate

Intermediate 9C (300mg, 0.563mmol) was dissolved in 8mL of N, N-dimethylacetamide, tert-butyl 5-oxo-1, 3,3a,4, 6,6 a-hexahydrocyclopenta [ C ] pyrrole-2-carboxylate (225mg, 1.0mmol), anhydrous magnesium sulfate 0.5g, 3 drops of acetic acid, stirred at 70 ℃ for 1h, sodium cyanoborohydride (140mg, 2.24mmol) 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 compound 12A as a yellow solid (12A) (250mg, 60.75% yield).

LCMS m/z＝742.2[M+1]⁺

The second step is that: 5- [1- [1- [ (3aR,6aS) -1,2,3,3a,4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (12B)

5-[1-[1-[(3aR,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

Tert-butyl (3aR,6aS) -5- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenty [ c ] pyrrole-2-carboxylate (12A) (250mg, 0.337mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added and reacted at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (12B) as a yellow oil (250mg), which was used in the next step without further purification.

LCMS m/z＝642.3[M+1]⁺

The third step: 5- [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 ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 12)

5- [1- [1- [ (3aR,6aS) -1,2,3,3a,4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (12B) (250mg), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (93mg, 0.33mmol) dissolved in 2mL of DMSO, n, N-diisopropylethylamine (60mg, 0.46mmol) was added thereto, and the reaction was carried out at 90 ℃ for 2 hours after the addition was completed. After the reaction was completed, it was cooled to room temperature, 10mL of water was added, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 12 as a yellow solid (20mg, yield in two steps 5.7%).

¹H NMR(400MHz,CD₃OD)δ8.61(d,1H),8.17(d,1H),7.90(s,1H),7.81–7.76(m,2H),7.73–7.64(m,2H),7.28(d,2H),7.07(d,1H),6.92(dd,1H),5.06(dd,1H),4.67–4.55(m,1H),4.47–4.39(m,1H),3.88–3.68(m,3H),3.66–3.48(d,7H),3.46–3.38(m,1H),3.28–3.20(m,2H),3.04–2.94(m,2H),2.91–2.68(m,3H),2.67–2.53(m,2H),2.49–2.32(m,4H),2.16–1.91(m,4H),1.83–1.71(m,2H).

LCMS m/z＝898.3[M+1]⁺

Example 13

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [7- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -7-azaspiro [3.5] non-2-yl ] -4-piperidyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 13)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[7-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl 2- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] -7-azaspiro [3.5] nonane-7-carboxylate (13A)

tert-butyl 2-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]-7-azaspiro[3.5]nonane-7-carboxylate

Intermediate 9C (300mg, 0.563mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, and tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (286mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, and the mixture was stirred at 55 ℃ for 1h, followed by addition of sodium cyanoborohydride (188mg, 3mmol), and the reaction was continued overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with 50mL of methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the compound (13A) as a yellow solid (60mg, yield 14%).

LCMS m/z＝756.3[M+1]+

The second step is that: 5- [1- [1- (7-azaspiro [3.5] non-2-yl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (13B)

5-[1-[1-(7-azaspiro[3.5]nonan-2-yl)-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

Tert-butyl 2- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] -7-azaspiro [3.5] nonane-7-carboxylate (13A) (60mg, 0.079mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was allowed to proceed overnight at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (13B) as a yellow oil (60mg), which was used in the next step as it was.

LCMS m/z＝656.3[M+1]+

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [7- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -7-azaspiro [3.5] non-2-yl ] -4-piperidyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 13)

5- [1- [1- (7-Azaspiro [3.5] non-2-yl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (4B) (60mg, 0.079mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL 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 the reaction was completed, it was cooled to room temperature, 10mL of water was added, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 13 as a yellow solid (2.36mg, yield 1.6%).

¹H NMR(400MHz,CD₃OD)δ8.67(d,1H),7.99(d,1H),7.83(s,1H),7.77(d,2H),7.68–7.60(m,2H),7.34(d,1H),7.26(d,2H),7.21(dd,1H),5.05(dd,1H),4.41–4.26(m,2H),3.61–3.45(m,4H),3.45–3.38(m,2H),3.36–3.32(m,1H),3.23–3.11(m,3H),3.08–2.98(m,1H),2.92–2.64(m,3H),2.27–2.06(m,8H),2.04–1.85(m,4H),1.84–1.67(m,5H).

LCMS m/z＝912.3[M+1]⁺

Example 14

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] nonanidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 14)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl 3- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azelate-1-ester (14A)

tert-butyl 3-[4-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]-1-piperidyl]azetidine-1-carboxylate

Compound (11B) (615mg, 1.0mmol) was dissolved in 8mL of N, N-dimethylacetamide, 1-Boc-azetidinone (342mg, 2.0mmol), anhydrous magnesium sulfate 0.5g, 3 drops of acetic acid, stirred at 70 ℃ for 1h, sodium cyanoborohydride (140mg, 2.24mmol) 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 compound 14A as a yellow solid (14A) (300mg, 39% yield).

LCMS m/z＝771.3[M+1]+

The second step is that: 5- [1- [1- [1- (azepin-3-yl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (14B)

5-[1-[1-[1-(azetidin-3-yl)-4-piperidyl]-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

Tert-butyl 3- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azelate-1-ester (14A) (300mg, 0.389mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added and reacted at room temperature overnight. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extraction was performed 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (14B) as a yellow solid (200mg), which was used in the next reaction.

LCMS m/z＝671.3[M+1]⁺

The third step: 2- (2, 6-dioxopiperidin-3-yl) -5- ((3aR, 6aS) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) isoindoline-1, 3-dione (Compound 14)

2-(2,6-dioxopiperidin-3-yl)-5-((3aR,6aS)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)hexahydrocyclo penta[c]pyrrol-2(1H)-yl)isoindoline-1,3-dione

5- [1- [1- [1- (azepin-3-yl) -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (14B) (200mg, 0.23mmol), 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 the reaction was completed, it was cooled to room temperature, 10mL of water was added, and the mixture 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 to prepare a liquid phase, and was concentrated to obtain Compound 14 as a yellow solid (18mg, yield 10.6%).

¹H NMR(400MHz,CD₃OD)δ8.67(d,1H),7.99(d,1H),7.82(s,1H),7.77(d,2H),7.65–7.63(m,2H),7.26(d,2H),6.84(d,1H),6.68(dd,1H),5.05(dd,1H),4.40–4.34(m,1H),4.33–4.21(m,1H),4.21–4.13(m,2H),3.93–3.86(m,2H),3.61–3.50(m,1H),3.49–3.44(m,1H),3.43–3.36(m,1H),3.26–3.16(m,3H),3.09–3.00(m,2H),2.91–2.50(m,7H),2.27–2.07(m,5H),2.05–1.92(m,5H),1.92–1.83(m,1H),1.75–1.58(d,2H).

LCMS m/z＝927.3[M+1]⁺

Example 15

5- [1- [1- [1- [1- [2- (1-adamantyl) acetyl ] azaidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 15)

5-[1-[1-[1-[1-[2-(1-adamantyl)acetyl]azetidin-3-yl]-4-piperidyl]-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: 5- [1- [1- [1- [1- [2- (1-adamantyl) acetyl ] azaidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 15)

Compound (14B) (80mg, 0.119mmol) was dissolved in 3mL of N, N-dimethylformamide, and 1-adamantane acetic acid (23mg, 0.119mmol), N, N, N ', N' -tetramethylformamidine hexafluorophosphate (33.32mg, 0.119mmol), N-methylimidazole (19mg, 0.238mmol) were added and stirred at room temperature for 1h, followed by extraction 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), concentrated to give the crude product, prepared over the liquid phase, and concentrated to give compound 15 as a white solid (20mg, 19.97% yield).

¹H NMR(400MHz,CD₃OD)δ8.67(d,1H),7.99(d,1H),7.82(s,1H),7.77(d,2H),7.62(s,1H),7.26(d,2H),4.40–4.34(m,1H),4.30–4.20(m,2H),4.07–3.97(m,2H),3.83–3.76(m,1H),3.61–3.51(m,1H),3.50–3.44(m,1H),3.22–3.10(m,4H),3.01–2.91(m,2H),2.57–2.44(m,3H),2.24–2.05(m,4H),1.99–1.85(m,9H),1.79–1.71(m,3H),1.71–1.59(m,10H).

LCMS m/z＝847.4[M+1]⁺

Example 16

N- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] nonanidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 16)

N-[4-[chloro(difluoro)methoxy]phenyl]-5-[1-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]-4-piperidyl]pyrazol-4-yl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

The first step is as follows: tert-butyl 3- [3- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azepin-1-yl ] azaside-1-carboxylate (16A)

tert-butyl 3-[3-[4-[4-[5-[[4-[chloro(difluoro)methoxy]phenyl]carbamoyl]-2-[(3R)-3-hydroxypyrrolidin-1-yl]-3-pyridyl]pyrazol-1-yl]-1-piperidyl]azetidin-1-yl]azetidine-1-carboxylate

Compound (10B) (260mg, 0.442mmol) was dissolved in 8mLN, N-dimethylacetamide, 1-Boc-azetidinone (342mg, 2.0mmol), anhydrous magnesium sulfate 0.5g, 3 drops of acetic acid, stirred at 70 ℃ for 1h, sodium cyanoborohydride (140mg, 2.24mmol) 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 compound 16A as a yellow solid (210mg, 64% yield).

LCMS m/z＝743.3[M+1]+

The second step is that: 5- [1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (16B)

5-[1-[1-[1-(azetidin-3-yl)azetidin-3-yl]-4-piperidyl]pyrazol-4-yl]-N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridine-3-carboxamide

Tert-butyl 3- [3- [4- [4- [4- [5- [ [4- [ chloro (difluoro) methoxy ] phenyl ] carbamoyl ] -2- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-pyridinyl ] pyrazol-1-yl ] -1-piperidinyl ] azepin-1-yl ] azaside-1-carboxylate (16A) (210mg, 0.283mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was allowed to proceed overnight at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extraction was performed 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (16B) as a yellow solid (200mg), which was used in the next reaction.

LCMS m/z＝643.2[M+1]⁺

The third step: n- [4- [ chloro (difluoro) methoxy ] phenyl ] -5- [1- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] nonanidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (Compound 16)

5- [1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] pyrazol-4-yl ] -N- [4- [ chloro (difluoro) methoxy ] phenyl ] -6- [ (3R) -3-hydroxypyrrolidin-1-yl ] pyridine-3-carboxamide (7B) (200mg), 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 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, and the mixture 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 obtained was concentrated under reduced pressure, prepared by a liquid phase, and concentrated to give Compound 16 as a yellow solid (35mg, yield in two steps 13.9%).

¹H NMR(400MHz,CD₃OD)δ8.67(d,1H),7.99(d,1H),7.83(s,1H),7.77(d,2H),7.68–7.62(m,2H),7.26(d,2H),6.86(d,1H),6.70(dd,1H),5.05(dd,1H),4.40–4.25(m,2H),4.21–4.12(m,2H),4.00–3.94(m,2H),3.93–3.84(m,1H),3.82–3.61(m,3H),3.61–3.39(m,4H),3.26–3.16(m,2H),3.11–3.00(m,2H),2.92–2.66(m,3H),2.32–2.06(m,7H),2.00–1.84(m,2H).

LCMS m/z＝899.3[M+1]⁺

Example 17

N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) piperazin-1-yl) azetidin-1-yl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 17)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)azetidin-1-yl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows:

5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxyazetidin-1-yl) pyridine-3-carboxamide (17A)

5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)pyridine-3-carboxamide

Compound (1A) (5g, 12.19mmol), azetidine-3-ol hydrochloride (1.46g, 13.41mmol) were dissolved in 100mL of isopropanol, N-diisopropylethylamine (3.14g, 24.38mmol) was added, and the reaction was carried out at 140 ℃ for 3 hours. After cooling to room temperature, water (100mL) was added, followed by extraction with ethyl acetate (100mL × 2), the organic phase was washed with saturated sodium chloride (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with an eluent (dichloromethane/methanol (v/v) ═ 50:1-15:1) to give compound 17A as a pale yellow solid (17A) (4.6g, yield 84.40%).

LCMS m/z＝448.1[M+1]⁺

The second step is that:

n- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxyazetidin-1-yl) -5- (1- (oxocyclohexan-2-yl) -1H-pyrazol-5-yl) pyridine-3-carboxamide (17B)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-(1-(oxepan-2-yl)-1H-pyrazol-5-yl)pyridine-3-carboxamide

Compound 17A (4.6g, 10.29mmol) and 1- (oxocyclohexan-2-yl) -5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (4.29g, 15.43mmol) were dissolved in a mixed solvent of 30mL of toluene and 4mL of water, potassium phosphate (4.36g, 20.58mmol), palladium tetrakistriphenylphosphine (1.18g, 1.03mmol) were added, and the mixture was stirred at 110 ℃ for 3H under nitrogen. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with an eluent (dichloromethane/methanol (v/v) ═ 30:1-15:1) to give compound 17B as a white solid (17B) (4.2g, yield 78.65%).

LCMS m/z＝520.3[M+1]⁺

The third step:

n- (4- (chlorodifluoromethoxy) phenyl) -5- (1- (oxocyclohex-2-yl) -1H-pyrazol-5-yl) -6- (3-oxoazetidin-1-yl) pyridine-3-carboxamide (17C)

N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(oxepan-2-yl)-1H-pyrazol-5-yl)-6-(3-oxoazetidin-1-yl)pyridine-3-carboxamide

Compound 17B (4.2g, 8.09mmol) was dissolved in 30mL of dichloromethane, dessimutan oxidant (5.14g, 12.1mmol) was added, stirred at room temperature for 16h, concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography on silica gel with eluent (dichloromethane/methanol (v/v) ═ 30:1-15:1) to give compound 17C as a white solid (17C) (3.3g, yield 78.94%).

LCMS m/z＝518.1[M+1]⁺

The fourth step:

tert-butyl 4- (1- (5- [ (4- (chlorodifluoromethoxy) phenyl) carbamoyl ] -3- (1- (oxocyclohex-2-yl) -1H-pyrazol-5-yl) pyridin-2-yl) azetidin-3-yl) piperazine-1-carboxylate (17D)

tert-butyl

4-(1-(5-[(4-(chlorodifluoromethoxy)phenyl)carbamoyl]-3-(1-(oxepan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)azetidin-3-yl)piperazine-1-carboxylate

Compound 17C (400mg, 0.77mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-piperazine (287mg, 1.54mmol), anhydrous zinc chloride (421mg, 3.10mmol) were added, stirring was performed at 55 ℃ for 1h, sodium cyanoborohydride (243mg, 3.86mmol) was added, and the reaction was continued for 16 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to give an eluent (dichloromethane/methanol (v/v) ═ 20:1 to 15:1) to give compound 17D as a pale yellow solid (250mg, yield 47.08%).

LCMS m/z＝688.2[M+1]⁺

The fifth step

N- (4- (chlorodifluoromethoxy) phenyl) -5- (1- (oxocyclohexan-2-yl) -1H-pyrazol-5-yl) -6- (3- (piperazin-1-yl) azetidin-1-yl) pyridine-3-carboxamide (17E)

N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(oxepan-2-yl)-1H-pyrazol-5-yl)-6-(3-(piperazin-1-yl)azetidin-1-yl)pyridine-3-carboxamide

Compound 17D (250mg, 0.36mmol) was dissolved in 5mL of dichloromethane, 0.5mL of trifluoroacetic acid was added, after addition was completed, the reaction was allowed to react at room temperature for 3h, and the reaction solvent was removed by concentration under reduced pressure, and the residue was 17E and used directly in the next step as a brown liquid (170mg, 92.89% yield).

LCMS m/z＝504.1[M+1]⁺

And a sixth step:

Compound 17E (170mg, 0.34mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (186mg, 0.68mmol) were dissolved in 5mL of DMSO, N-diisopropylethylamine (130mg, 1.02mmol) was added, and the reaction was carried out at 100 ℃ for 3 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved with 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to prepare a liquid phase, and concentrated to obtain compound 17(31mg, yield 12.1%).

LCMS m/z＝760.2[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ8.75(d,1H),8.09(d,1H),7.80–7.71(d,3H),7.67(d,1H),7.35(d,1H),7.29–7.18(d,3H),6.51(d,1H),5.05(dd,1H),4.03–3.90(s,2H),3.83–3.73(m,2H),3.50–3.41(m,4H),3.26–3.17(m,1H),2.91–2.63(m,3H),2.58–2.44(m,4H),2.14–2.05(m,1H).

Example 18

N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 18)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)piperazin-1-yl)azetidin-1-yl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows:

tert-butyl 3- (4- (1- (5- [ (4- (chlorodifluoromethoxy) phenyl) carbamoyl ] -3- (1H-pyrazol-5-yl) pyridin-2-yl) azetidin-3-yl) piperazin-1-yl) azetidin-1-carboxylic acid ester (18A)

tert-butyl

3-(4-(1-(5-[(4-(chlorodifluoromethoxy)phenyl)carbamoyl]-3-(1H-pyrazol-5-yl)pyridin-2-yl)azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate

Compound 17E (600mg, 1.19mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (306mg, 1.79mmol) and anhydrous zinc chloride (650mg, 4.77mmol) were added, and the mixture was stirred at 55 ℃ for 1h, followed by addition of sodium cyanoborohydride (224mg, 3.57mmol) and further reaction for 16 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 30mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to give compound 18A as a white solid (310mg, yield 39.54%) as an eluent (dichloromethane/methanol (v/v) ═ 30:1-15: 1).

LCMS m/z＝659.1[M+1]⁺

The second step is that:

6- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxylic acid amine (18B)

6-(3-(4-(azetidin-3-yl)piperazin-1-yl)azetidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Compound 18A (310mg, 0.47mmol) was dissolved in 8mL of dichloromethane, 0.8mL of trifluoroacetic acid was added, after addition, the reaction was carried out at room temperature for 3h, the reaction solvent was removed by concentration under reduced pressure, and the residue was 18B and used directly in the next step as a brown liquid (260mg, yield 99.23%)

LCMS m/z＝558.1[M+1]⁺

The third step:

Compound 18B (260mg, 0.46mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (257mg, 0.92mmol) were dissolved in 8mL of DMSO, N-diisopropylethylamine (120mg, 0.92mmol) was added, and the reaction was carried out at 100 ℃ for 3 hours after the addition. After cooling to room temperature, 10mL of water was added, filtration was performed, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to prepare a liquid phase, and was concentrated to obtain Compound 18(44mg, 11.60% yield in two steps).

LCMS m/z＝815.1[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ8.73(d,1H),8.08(d,1H),7.80–7.70(m,3H),7.63(d,1H),7.26(d,2H),6.82(d,1H),6.66(dd,1H),6.49(d,1H),5.04(dd,1H),4.17–4.09(m,2H),3.96–3.85(m,4H),3.77–3.70(m,2H),3.43–3.36(m,1H),3.23–3.15(m,1H),2.87–2.66(m,3H),2.60–2.33(m,8H),2.11–2.05(m,1H).

Example 19

N- (4- (Chlorodifluoromethoxy) phenyl) -6- (7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 19)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows:

tert-butyl 2- (3-bromo-5- [ (4- (chlorodifluoromethoxy) phenyl) carbamoyl ] pyridin-2-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (19A)

tert-butyl

2-(3-bromo-5-[(4-(chlorodifluoromethoxy)phenyl)carbamoyl]pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Compound (1A) (5g, 12.19mmol), tert-butyl 2, 7-diazaspiro [3.5] nonane-7-carboxylate (3.03g, 13.41mmol) were dissolved in 100mL of isopropanol, N-diisopropylethylamine (3.14g, 24.38mmol) was added, and the reaction was carried out at 140 ℃ for 3 hours after the completion of the addition. After cooling to room temperature, water (100mL) was added, followed by extraction with ethyl acetate (100mL × 2), the organic phase was collected, washed once with saturated sodium chloride (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using an eluent (dichloromethane/methanol (v/v) ═ 50:1-15:1) to give compound 19A as a white solid (4.2g, yield 57.45%).

LCMS m/z＝601.3[M+1]⁺

The second step is that:

tert-butyl 2- (5- [ (4- (chlorodifluoromethoxy) phenyl) carbamoyl ] -3- (1- (oxohexan-2-yl) -1H-pyrazol-5-yl) pyridin-2-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (19B)

tert-butyl

2-(5-[(4-(chlorodifluoromethoxy)phenyl)carbamoyl]-3-(1-(oxepan-2-yl)-1H-pyrazol-5-yl)pyridin-2-y l)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Compound 19A (4.2g, 7.00mmol) and 1- (oxocyclohexan-2-yl) -5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.92g, 10.5mmol) were dissolved in a mixed solvent of 30mL of toluene and 4mL of water, potassium phosphate (2.97g, 14.00mmol), palladium tetratriphenylphosphine (808mg, 0.70mmol) were added, and the mixture was stirred at 110 ℃ for 3H under nitrogen. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with an eluent (dichloromethane/methanol (v/v) ═ 30:1-15:1) to give compound 19B as a white solid (2.9g, yield 61.70%).

LCMS m/z＝673.1[M+1]⁺

The third step

N- (4- (Chlorodifluoromethoxy) phenyl) -6- (2, 7-diazaspiro [3.5] nonan-2-yl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (19C)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-5-(1H-pyrazol-5-yl)py ridine-3-carboxamide

Compound 19B (2g, 2.97mmol) was dissolved in 8mL of dichloromethane, 1.5mL of trifluoroacetic acid was added, after addition was completed, the reaction was allowed to react at room temperature for 3h, and the reaction solvent was removed by concentration under reduced pressure, and the residue was 19C and used directly in the next step as a brown liquid (1.4g, 96.55% yield).

LCMS m/z＝489.1[M+1]⁺

The fourth step:

Compound 19C (400mg, 0.82mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (339mg, 1.23mmol) were dissolved in 8mL of DMSO, N-diisopropylethylamine (211mg, 1.64mmol) was added, and the reaction was carried out at 100 ℃ for 3 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved with 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to prepare a liquid phase, which was concentrated to obtain compound 19(55mg, yield 9.01%).

LCMS m/z＝745.1[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ8.74(d,1H),8.07(d,1H),7.82–7.70(m,3H),7.65(d,1H),7.37–7.17(m,4H),6.50(d,1H),5.05(dd,1H),3.73–3.63(m,4H),3.47–3.38(m,4H),2.93–2.63(m,3H),2.14–2.05(m,1H),1.90–1.80(m,4H).

Example 20

N- (4- (chlorodifluoromethoxy) phenyl) -6- (7- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) azetidin-3-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (Compound 20)

N-(4-(chlorodifluoromethoxy)phenyl)-6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)azetidin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

The first step is as follows:

tert-butyl 3- (2- (5- [ (4- (chlorodifluoromethoxy) phenyl) carbamoyl ] -3- (1H-pyrazol-5-yl) pyridin-2-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) azetidine-1-carboxylate (20A)

tert-butyl

3-(2-(5-[(4-(chlorodifluoromethoxy)phenyl)carbamoyl]-3-(1H-pyrazol-5-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)azetidine-1-carboxylate

Compound 19C (600mg, 1.23mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (420mg, 2.46mmol) and anhydrous zinc chloride (670mg, 4.92mmol) were added, stirring was carried out at 55 ℃ for 1h, sodium cyanoborohydride (309mg, 4.92mmol) was added, and the reaction was continued for 16 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 30mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with an eluent (dichloromethane/methanol (v/v) ═ 30:1-15:1) to give compound 20A as a white solid (325mg, yield 41.13%).

LCMS m/z＝644.1[M+1]+

The second step is that:

6- (7- (azetidin-3-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) pyridine-3-carboxamide (20B)

6-(7-(azetidin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Compound 20A (325mg, 0.50mmol) was dissolved in 8mL of dichloromethane, 1mL of trifluoroacetic acid was added, after addition was completed, the reaction was allowed to react at room temperature for 3h, and the reaction solvent was removed by concentration under reduced pressure to give 20B as a residue which was used directly in the next step as a brown liquid (0.27g, 98.54% yield).

LCMS m/z＝544.1[M+1]⁺

The third step:

Compound 20B (270mg, 0.50mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (274mg, 1.00mmol) were dissolved in 8mL of DMSO, N-diisopropylethylamine (128mg, 1.00mmol) was added, and the reaction was carried out at 100 ℃ for 3 hours after the addition. After cooling to room temperature, 10mL of water was added, filtration was performed, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to prepare a liquid phase, which was concentrated to obtain Compound 20(20mg, yield 5.03%).

LCMS m/z＝800.2[M+1]⁺

Example 21

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 21)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

The first step is as follows: 4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] tert-butyl-2-amino ] -2-methyl-pyrimidin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester (21B)

N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-pyrimidin-4-yl)amino]thiazole-5-carboxamide

N- (2-chloro-6-methyl-phenyl) -2- [ ((6-chloro-2-methyl-pyrimidin-4-yl) amino ] thiazole-5-carboxamide (394mg, 1.00mmol), piperazine-1-carboxylic acid tert-butyl ester (204mg, 1.10mmol) were dissolved in 10mL of DMF, N-diisopropylethylamine (222mg, 1.72mmol) was added, after which time it was reacted at 120 ℃ for 2 hours, cooled to room temperature, water was added to 150mL, and the suspension was filtered with suction to give the filter cake as the title compound (21B), a brown solid (500mg, yield: 82%).

LCMS m/z＝544.1[M+1]⁺

The second step is that: n- (2-chloro-6-methyl-phenyl) -2- [ (2-methyl-6-piperazin-1-yl-pyrimidin-4-yl) amino ] thiazole-5-carboxamide (21C)

N-(2-chloro-6-methyl-phenyl)-2-[(2-methyl-6-piperazin-1-yl-pyrimidin-4-yl)amino]thiazole-5-carboxamide

Compound (21B) (200mg, 0.45mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added to react at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21C) as a brown solid (160mg, 98%).

LCMS m/z＝444.0[M+1]⁺

The third step N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 21)

N- (2-chloro-6-methyl-phenyl) -2- [ (2-methyl-6-piperazin-1-yl-pyrimidin-4-yl) amino ] thiazole-5-carboxamide (21C) (120mg, 0.27mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (93mg, 0.33mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after completion of addition, reaction was carried out at 90 ℃ for 2 hours. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure to afford the title compound 21(38mg, 20% yield) as a liquid phase. 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.

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

LCMS m/z＝700.2[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.47(br.s,1H),11.06(br.s,1H),9.86(s,1H),8.22(s,1H),7.72(d,1H),7.45–7.33(m,2H),7.32–7.21(m,3H),6.09(s,1H),5.08(dd,1H),3.80–3.59(m,7H),2.95–2.82(m,1H),2.64–2.52(m,4H),2.46–2.42(m,2H),2.24(s,3H),2.09–2.97(m,1H).

Example 22

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] azetidin-3-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (compound 22)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

The first step is as follows: tert-butyl 3- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methyl-pyrimidin-4-yl ] piperazin-1-yl ] azetidine-1-carboxylic acid salt (22A)

tert-butyl

3-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]azetidine-1-carboxylate

Compound (21C) (440mg, 1.0mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (285mg, 1.66mmol) and anhydrous zinc chloride (406mg, 2.98mmol) were added, and the mixture was stirred at 55 ℃ for 1h, followed by addition of sodium cyanoborohydride (140mg, 2.24mmol) and further reaction for 8 h. Cooled to room temperature and extracted with 50mL of dichloromethane 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 (22A) as an earth yellow solid (250mg, 42% yield).

LCMS m/z＝599.2[M+1]⁺

The second step is that: 2- [ [6- [4- (azetidin-3-yl) piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (22B)

2-[[6-[4-(azetidin-3-yl)piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

Compound (22A) (300mg, 0.50mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the cullin compound (22B) which was used directly in the next step as a yellow oil (100mg, yield 100%).

LCMS m/z＝499.0[M+1]⁺

The third step: n- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] azetidin-3-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (compound 22)

Compound (22B) (100mg, 0.20mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (60mg, 0.46mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure to afford the title compound 22 as a yellow solid (30mg, 20% yield).

LCMS m/z＝755.2[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.41(br.s,1H),11.07(br.s,1H),9.85(s,1H),8.22(s,1H),7.66(d,1H),7.45–7.36(m,1H),7.32–7.22(m,2H),6.81(d,1H),6.67(dd,1H),6.08(s,1H),5.06(dd,1H),4.18–4.09(m,2H),3.97–3.87(m,2H),3.64–3.50(m,4H),3.44–3.36(m,2H),2.94–2.81(m,1H),2.63–2.54(m,2H),2.50–2.43(m,3H),2.42(s,3H),2.24(s,3H),2.06–1.96(m,1H).

Example 23

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl ] azetidin-3-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 23)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

The first step is as follows: tert-butyl 3- [3- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methyl-pyrimidin-4-yl ] piperazin-1-yl ] azetidin-1-carboxylic acid ester (23A)

tert-butyl

3-[3-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]azetidin-1-yl]azetidine-1-carboxylate

Compound (22B) (250mg, 0.50mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (285mg, 1.66mmol) and anhydrous zinc chloride (406mg, 2.98mmol) were added, and the mixture was stirred at 55 ℃ for 1h, followed by addition of sodium cyanoborohydride (140mg, 2.24mmol) and further reaction for 8 h. Cooled to room temperature and extracted with 50mL of dichloromethane 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 (23A) (180mg, 54% yield)

LCMS m/z＝654.2[M+1]⁺

The second step is that: 2- [ [6- [4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (23B)

2-[[6-[4-[1-(azetidin-3-yl)azetidin-3-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

Compound (23A) (105mg, 0.16mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added to react at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (23B) as a yellow oil (80mg, yield 89%) which was used in the next step without further purification.

LCMS m/z＝554.1[M+1]⁺

The third step: n- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl ] azetidin-3-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 23)

Compound (23B) (80mg, 0.14mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (60mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (60mg, 0.46mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the completion of the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure to afford the title compound 23 as a yellow solid (24mg, 21% yield).

LCMS m/z＝810.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.44(br.s,1H),11.05(br.s,1H),9.85(s,1H),8.21(s,1H),7.64(d,1H),7.42–7.36(m,1H),7.33–7.21(m,2H),6.79(d,1H),6.66(dd,1H),6.06(s,1H),5.05(dd,1H),4.09–4.00(m,2H),3.85–3.76(m,2H),3.67–3.60(m,1H),3.59–3.46(m,4H),3.43–3.37(m,2H),3.04–2.82(m,4H),2.63–2.53(m,2H),2.40(s,3H),2.38–2.28(m,4H),2.24(s,3H),2.05–1.96(m,1H).

Example 24

2- [ [6- [4- [ (3aS,6aR) -2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrol-5-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (Compound 24)

2-[[6-[4-[(3aS,6aR)-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]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

The first step is as follows: tert-butyl (3aS,6aR) -5- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methylpyrimidin-4-yl ] piperazin-1-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrole-2-carboxylate (24A)

tert-butyl

(3aS,6aR)-5-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate

Compound (21C) (400mg, 0.89mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, and tert-butyl (3aR,6aS) -5-oxohexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylate (270mg, 1.2mmol) and anhydrous zinc chloride (545mg, 4mmol) were added, stirred at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8H. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1 to 5:1) to give the title compound (24A) (200mg, yield 49%) as a yellow solid.

LCMS m/z＝653.2[M+1]⁺

The second step is that: 2- [ [6- [4- [ (3aS,6aR) -1,2,3,3a,4,5,6,6 a-octahydrocyclopenta [ c ] pyrrol-5-yl ] piperazin-1-yl ] -2-methylpyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (24B)

2-[[6-[4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

Compound (24A) (150mg, 0.23mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added to react at room temperature overnight. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the pH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (24B) as a yellow oil (110mg, 86%) which was used directly in the next reaction.

LCMS m/z＝553.1[M+1]⁺

The third step: 2- [ [6- [4- [ (3aS,6aR) -2- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindol-5-yl ] -3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta [ c ] pyrrol-5-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (Compound 24)

Compound (24B) (100mg, 0.18mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.21mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and the liquid phase was transferred to preparation to afford the title compound 24 as a yellow solid (25mg, 17% yield).

LCMS m/z＝809.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.45(br.s,1H),11.05(br.s,1H),9.85(s,1H),8.21(s,1H),7.64(d,1H),7.43–7.36(m,1H),7.32–7.22(m,2H),6.98–6.93(m,1H),6.86(dd,1H),6.04(s,1H),5.05(dd,1H),3.63–3.44(m,6H),3.39–3.33(m,2H),2.95–2.82(m,1H),2.82–2.72(m,2H),2.72–2.53(m,3H),2.49–2.43(m,4H),2.40(s,3H),2.24(s,3H),2.21–2.12(m,2H),2.05–1.96(m,1H),1.45–1.33(m,2H).

Example 25

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] -4-piperidinyl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (compound 25)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

The first step is as follows: tert-butyl 4- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methyl-pyrimidin-4-yl ] piperazin-1-yl ] piperidine-1-carboxylic acid (25A)

tert-butyl

4-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]piperidine-1-carboxylate

Compound 21C (440mg, 1.0mmol) was dissolved in 10mL of N, N-dimethylacetamide, N-Boc-piperidone (239mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) was added, stirring was carried out at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the title compound as a yellow solid (25A) (240mg, 38% yield).

LCMS m/z＝627.2[M+1]⁺

The second step is that: n- (2-chloro-6-methyl-phenyl) -2- [ [ 2-methyl-6- [4- (4-piperidinyl) piperazin-1-yl ] pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (25B)

N-(2-chloro-6-methyl-phenyl)-2-[[2-methyl-6-[4-(4-piperidyl)piperazin-1-yl]pyrimidin-4-yl]amino]thiazole-5-carboxamide

Compound 25A (140mg, 0.22mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (25B) as a yellow oil (115mg, yield 98%) which was used in the next step without further purification.

LCMS m/z＝527.1[M+1]⁺

The third step: n- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] -4-piperidinyl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (compound 25)

Compound 25B (140mg, 0.27mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (93mg, 0.33mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.92mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 25(30mg, 14% yield).

LCMS m/z＝783.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.38(br.s,1H),11.05(br.s,1H),9.85(s,1H),8.21(s,1H),7.65(d,1H),7.44–7.17(m,5H),6.05(s,1H),5.06(dd,1H),4.15–4.03(m,2H),3.59–3.43(m,4H),3.06–2.80(m,3H),2.63–2.53(m,6H),2.66–2.54(m,2H),2.40(s,3H),2.24(s,3H),2.07–1.97(m,1H),1.93–1.80(m,3H),1.56–1.41(m,2H).

Example 26

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] piperazin-1-yl ] -2-methylpyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 26)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

The first step is as follows: tert-butyl 3- [4- [4- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methylpyrimidin-4-yl ] piperazin-1-yl ] -1-piperidinyl ] azetidine-1-carboxylate (26A)

tert-butyl

3-[4-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]-1-piperidyl]azetidine-1-carboxylate

Compound 25B (260mg, 0.49mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, and 1-Boc-3-azetidinone (205mg, 1.2mmol) and anhydrous zinc chloride (545mg, 4mmol) were added, stirred at 55 ℃ for 1h, and sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued overnight. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1 to 5:1) to give the title compound (26A) as a yellow solid (200mg, yield 60%).

LCMS m/z＝682.3[M+1]⁺

The second step is that: 2- [ [6- [4- [1- (azetidin-3-yl) -4-piperidinyl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (26B)

2-[[6-[4-[1-(azetidin-3-yl)-4-piperidyl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

Compound 26A (200mg, 0.29mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (26B) as a yellow oil (150mg, 88%) which was used in the next step without further purification.

LCMS m/z＝582.2[M+1]⁺

The third step: n- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] piperazin-1-yl ] -2-methylpyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 26)

Compound 26B (120mg,0.20mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 26(20mg, 12% yield).

LCMS m/z＝838.4[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.43(br.s,1H),11.05(br.s,1H),9.85(s,1H),8.21(s,1H),7.64(d,1H),7.42–7.37(m,1H),7.31–7.22(m,2H),6.78(d,1H),6.65(d,1H),6.04(s,1H),5.04(dd,1H),4.15–4.05(m,2H),3.87–3.78(m,2H),3.57–3.44(m,4H),2.94–2.82(m,3H),2.62–2.52(m,7H),2.40(s,3H),2.30–2.29(m,4H),2.05–1.97(m,1H),1.91–1.74(m,4H),1.50–

1.37(m,2H).

Example 27

N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [7- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] -7-azaspiro [3.5] nonyl-2-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (Compound 27) N- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [7- [2- (2, 6-dioxy-3-piperidyl) -1, 3-dioxy-isoindolin-5-yl ] -7-azaspiro [3.5] nonan-2-yl Piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide

The first step is as follows: tert-butyl 2- [4- [6- [ [5- [ (2-chloro-6-methyl-phenyl) carbamoyl ] thiazol-2-yl ] amino ] -2-methyl-pyrimidin-4-yl ] piperazin-1-yl ] -7-azaspiro [3.5] nonane-7-carboxylate (27A)

tert-butyl

2-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

Compound 21C (400mg, 0.90mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (286mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, stirring was performed at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the title compound (27A) as a yellow solid (220mg, 37% yield).

LCMS m/z＝667.3[M+1]⁺

The second step is that: 2- [ [ [6- [4- (7-azaspiro [3.5] non-2-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] -N- (2-chloro-6-methyl-phenyl) thiazole-5-carboxamide (27B)

2-[[6-[4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]-N-(2-chloro-6-methyl-phenyl)thiazole-5-carboxamide

Compound 27A (170mg, 0.25mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (27B) as a yellow oil (130mg, 90%) which was used in the next step as it was.

LCMS m/z＝567.2[M+1]⁺

The third step: n- (2-chloro-6-methyl-phenyl) -2- [ [6- [4- [7- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5 ] -yl ] -7-azaspiro [3.5] nonyl-2-yl ] piperazin-1-yl ] -2-methyl-pyrimidin-4-yl ] amino ] thiazole-5-carboxamide (compound 27)

N-(2-chloro-6-methyl-phenyl)-2-[[6-[4-[7-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]piperazin-1-yl]-2-methyl-pyrimidin-4-yl]amino]thiazole-5-carboxamide

Compound 27B (130mg, 0.22mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 27(22mg, 12% yield).

LCMS m/z＝823.4[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.44(br.s,1H),11.06(br.s,1H),9.86(s,1H),8.22(s,1H),7.65(d,1H),7.45–7.37(m,1H),7.34–7.20(m,4H),6.07(s,1H),5.06(dd,1H),3.60–3.44(m,6H),3.44–3.37(m,2H),2.96–2.82(m,1H),2.80–2.69(m,1H),2.66–2.54(m,2H),2.41(s,3H),2.37–2.28(m,4H),2.25(s,3H),2.08–1.96(m,3H),1.72–1.54(m,6H).

Example 28

4- (((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile (Compound 28)

4-((2,4-dichloro-5-methoxyphenyl)amino)-7-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3-carbonitrile

The first step is as follows: 4- (3- ((3-cyano-4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinolin-7-yl) oxy) propyl) piperazine-1-carboxylic acid tert-butyl ester (28B)

tert-butyl

4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazine-1-carboxylate

7- (3-Chloropropoxy) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile (465mg, 1.00mmol), tert-butyl piperazine-1-carboxylate (28A) (204mg, 1.10mmol) were dissolved in 10mL of DMF, and N, N-diisopropylethylamine (222mg, 1.72mmol) was added, followed by reaction at 120 ℃ for 2 hours. After cooling to room temperature, 100mL of water was added, and the suspension was filtered with suction to give the title compound (28B) as a filter cake as a brown solid (500mg, yield: 81%).

LCMS m/z＝616.2[M+1]⁺

The second step is that: 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxy-7- (3- (piperazin-1-yl) propoxy) quinoline-3-carbonitrile (28C)

4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(piperazin-1-yl)propoxy)quinoline-3-carbonitrile

Compound 28B (500mg, 0.81mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (28C) as a brown solid (420mg, 81%).

LCMS m/z＝516.2[M+1]⁺

The third step 4- (((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile (Compound 28)

Compound 28C (120mg, 0.23mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (93mg, 0.33mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 28(38mg, 20% yield).

LCMS m/z＝772.2[M+1]⁺

¹H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.60(s,1H),8.40(s,1H),7.83(s,1H),7.76–7.65(m,2H),7.40–7.22(m,4H),5.07(dd,1H),4.28–4.20(m,2H),3.95(s,3H),3.86(s,3H),3.52–3.42(m,4H),2.94–2.82(m,1H),2.63–2.52(m,8H),2.08–1.96(m,3H).

Example 29

4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- (7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindol-5-yl) -7-azaspiro [3.5] nonan-2-yl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile (Compound 29)

4-((2,4-dichloro-5-methoxyphenyl)amino)-7-(3-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3-carbonitrile

The first step is as follows: 2- (4- (3- ((3-cyano-4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinolin-7-yl) oxy) propyl) piperazin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylic acid salt (29A)

tert-butyl

2-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

Compound 28C (400mg, 0.80mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (286mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, stirring was performed at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) was added, and the reaction was continued for 8 h. Cooled to room temperature and extracted with 50mL of dichloromethane and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the title compound (29A) as a yellow solid (220mg, 37% yield).

LCMS m/z＝739.3[M+1]⁺

The second step is that: 7- (3- (4- (7-azaspiro [3.5] non-2-yl) piperazin-1-yl) propoxy) -4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxyquinoline-3-carbonitrile (29B)

7-(3-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)propoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile

Compound 29A (170mg, 0.23mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 8 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, pH was adjusted to 8 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (29B) as a yellow oil (130mg, 89%) which was used in the next step.

LCMS m/z＝639.3[M+1]+

The third step: 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- (7- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindol-5-yl) -7-azaspiro [3.5] nonan-2-yl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile (Compound 29)

Compound 29B (130mg, 0.20mmol), 2- (2,6-dioxo-3-piperidyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and the reaction was carried out at 90 ℃ for 2 hours after the addition. Cooled to room temperature, water 10mL was added, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 29(22mg, 12% yield).

LCMS m/z＝895.4[M+1]⁺

Example 30

2- [4- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindol-5-yl ] -4-piperidinyl ] phenyl ] indazole-7-carboxamide (Compound 30)

2-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]phenyl]indazole-7-carboxamide

The first step is as follows: 4- [4- [ (E) - (3-methoxycarbonyl-2-nitro-phenyl) methyleneamino ] phenyl ] piperidine-1-carboxylic acid tert-butyl ester (30B)

tert-butyl 4-[4-[(E)-(3-methoxycarbonyl-2-nitro-phenyl)methyleneamino]phenyl]piperidine-1-carboxylate

Methyl 3-formyl-2-nitrobenzoate (30A) (10.00g, 47.81mmol),1-Boc-4- (4-aminophenyl) piperidine (13.88g, 50.20mmol) was dissolved in 240mL ethanol (0.2N) and heated to reflux for 2 h. After the reaction was complete, most of the ethanol was removed under reduced pressure, a large amount of solid precipitated, and the solid was filtered to give the product (30B) as a yellow solid (21.35g, 95.52%)

¹H NMR(400MHz,CDCl₃)δ8.52(dd,1H),8.38(s,1H),8.11(dd,1H),7.68(t,1H),7.28–7.21(m,2H),7.21–7.16(m,2H),4.26–4.23(m,2H),3.94(d,3H),2.81(t,2H),2.69-2.65(m,1H),1.84(d,2H),1.64-1.60(m,2H),1.48(s,9H).

The second step is that: 2- [4- (1-tert-Butoxycarbonyl-4-piperidinyl) phenyl ] indazole-7-carboxylic acid methyl ester (30C)

methyl 2-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]indazole-7-carboxylate

Tert-butyl 4- [4- [ (E) - (3-methoxycarbonyl-2-nitro-phenyl) methyleneamino ] phenyl ] piperidine-1-carboxylate (30B) (15.00g, 32.09mmol) was dissolved in 105mL of DMF, and sodium azide (2.19g, 33.69mmol) was added and the mixture was heated to 90 ℃ for reaction for 48 h. Cooled to room temperature, 150mL of ethyl acetate was added, and the mixture was washed with 100mL of water 2 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography using EA/PE-1/10 as an eluent. Obtained (17C) as a yellow solid (5.8g, 42%)

¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),8.14(dd,1H),7.95(dd,1H),7.90(d,2H),7.36(d,2H),7.19(dd,1H),4.28(d,2H),4.05(s,3H),2.87-2.80(m,2H),2.78-2.70(m,1H),1.87(d,2H),1.68-1.64(m,2H),1.49(s,9H).

LM-MS:m/z＝436.3[M+1]⁺

The third step: 4- [4- (7-carbamoylindazol-2-yl) phenyl ] piperidine-1-carboxylic acid tert-butyl ester (30D)

tert-butyl 4-[4-(7-carbamoylindazol-2-yl)phenyl]piperidine-1-carboxylate

The starting methyl 2- [4- (1-tert-butoxycarbonyl-4-piperidinyl) phenyl ] indazole-7-carboxylate (30C) (8.2g, 18.8mmol) was dissolved in 40mL of methanolic ammonia (7N), and the mixture was heated to 60 ℃ in a closed system and reacted overnight. The reaction was directly concentrated to dryness to give the product (30D) as a pale yellow solid (5.6g, 70.7%)

¹H NMR(400MHz,DMSO-d₆)δ9.27(s,1H),8.57(d,1H),8.10–8.04(m,3H),8.01(dd,1H),7.85(d,1H),7.50(d,2H),7.27(dd,1H),4.11(d,2H),2.94–2.70(m,3H),1.81(d,2H),1.57-1.53(m,2H),1.45(s,9H).

LM-MS:m/z＝421.3[M+1]⁺

The fourth step: 2- [4- (4-piperidyl) phenyl ] indole-7-carboxamide

2- [4- (4-piperidinyl) phenyl ] indazole-7-carboxamide (30E)

Tert-butyl 4- [4- (7-carbamoylindazol-2-yl) phenyl ] piperidine-1-carboxylate (30D) (5.6g, 13.3mmol) was dissolved in 30mL of dichloromethane, 10mL of trifluoroacetic acid was added, the reaction was carried out at room temperature for 2 hours, after completion of the reaction, the solvent and trifluoroacetic acid were removed under reduced pressure, 50mL of dichloromethane was added to dissolve the residue, the PH was adjusted to 8-9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, the mixture was extracted 2 times (50mL × 2) with dichloromethane, washed once with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (30E) (3.6g, 84.4%).

The fifth step: 2- [4- [1- [2- (2, 6-dioxol-3-piperidyl) -1, 3-dioxol-isoindolin-5-yl ] -4-piperidyl ] phenyl ] indole-7-carboxamide

2- [4- (4-piperidinyl) phenyl ] indazole-7-carboxamide (30E) (110mg, 0.343mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (114mg, 0.412mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (222mg, 1.72mmol) was added, and after the addition, the reaction was carried out at 90 ℃ for 2 hours. After the reaction is finished, cooling to room temperature, adding 10mL of water, filtering, dissolving a filter cake by 20mL of dichloromethane, washing by 5mL of saturated sodium chloride, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, purifying by a silica gel column, and eluting: DCM-2% MeOH/DCM-5% MeOH/DCM to give crude product which was then prepared as a liquid phase to give compound 30 as a yellow solid (90mg, 45%).

¹H NMR(400MHz,DMSO-d₆)δ10.98(s,1H),9.28(s,1H),8.56(d,1H),8.10–8.04(m,3H),8.04–7.98(m,1H),7.85(d,1H),7.69(d,1H),7.52(d,2H),7.40(d,1H),7.32(dd,1H),7.27(dd,1H),5.08(dd,1H),4.23(d,2H),3.17-3.05(m,2H),3.02-2.83(m,2H),2.64-2.52(m,2H),2.08-1.98(m,1H),1.98-1.90(d,2H),1.83-1.69(d,2H).

LCMS m/z＝577.3[M+1]⁺

Example 31

2- [4- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1], 3-dioxoisoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] phenyl ] indazole-7-carboxamide (Compound 31)

2-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]-4-piperidyl]phenyl]indazole-7-carboxamide

The first step is as follows:

tert-butyl 3-[4-[4-(7-carbamoylindazol-2-yl)phenyl]-1-piperidyl]azetidine-1-carboxylate

3- [4- [4- (4- (7-carbamoylindazol-2-yl) phenyl ] -1-piperidinyl ] azetidine-1-carboxylic acid tert-butyl ester (31A)

The starting material, 2- [4- (4-piperidinyl) phenyl ] indazole-7-carboxamide (30E) (320mg, 1mmol), was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, 1-Boc-3-azetidinone (205mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) was added, stirred at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. Used directly in the next step. (31A) Yellow solid (300mg, 63.2% yield).

LCMS m/z＝476.3[M+1]+

The second step is that: 2- [4- [1- (azetidin-3-yl) -4-piperidyl ] phenyl ] indole-7-carboxamide

2- [4- [1- (azetidin-3-yl) -4-piperidinyl ] phenyl ] indazole-7-carboxamide (31B)

Tert-butyl 3- [4- [4- (4- (7-carbamoylindazol-2-yl) phenyl ] -1-piperidinyl ] azetidine-1-carboxylate (31A) (300mg, 0.631mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was allowed to react at room temperature overnight, the solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step (31B) as a yellow oil (69mg, 29%).

The third step:

The starting material 2- [4- [1- (azetidin-3-yl) -4-piperidinyl ] phenyl ] indazole-7-carboxamide (31B) (60mg, 0.11mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) was dissolved in 2mL 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, filtered, the filter cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound as a yellow solid (20mg, yield 17%).

¹H NMR(400MHz,DMSO-d₆):δ11.04(s,1H),9.27(s,1H),8.57(d,1H),8.10–8.04(m,3H),8.01(dd,1H),7.85(d,1H),7.66(d,1H),7.51(d,2H),7.26(dd,1H),6.81(d,1H),6.68(dd,1H),5.06(dd,1H),4.16-4.12(m,2H),3.90-3.86(m,2H),3.42-3.38(m,1H),2.99-2.94(m,2H),2.94-2.82(m,1H),2.72-2.53(m,3H),2.07-1.95(m,3H),1.90-1.80(m,2H),1.79-1.65(m,2H).

LCMS m/z＝632.3[M+1]⁺

Example 32

2- [4- [1- [1- [1- [2- (2, 6-dioxo-3-piperidinyl) -1] -3-dioxoisoindolin-5-yl ] azetidin-3-yl ] -4-piperidinyl ] phenyl ] indazole-7-carboxamide (Compound 32)

2-[4-[1-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]-4-piperidyl]phenyl]indazole-7-carboxamide

The first step is as follows: tert-butyl 3- [3- [4- [4- (7-carbamoylazol-2-yl) phenyl ] -1-piperidyl ] azetidin-1-yl ] azetidine-1-carboxylate

3- [3- [4- [4- (4-carbamoylindazol-2-yl) phenyl ] tert-butyl ] azetidin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (32A)

2- [4- [1- (azetidin-3-yl) -4-piperidinyl ] phenyl ] indazole-7-carboxamide (31B) (140mg, 0.373mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, 1-Boc-3-azetidinone (766mg, 0.447mmol) and anhydrous zinc chloride (203mg, 1.49mmol) were added, stirred at 55 ℃ for 1h, sodium cyanoborohydride (70.3mg, 1.12mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid (32A) (70mg, 35% yield) which was used directly in the next step. .

The second step is that: 2- [4- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidyl ] phenyl ] indole-7-carboxamide

2- [4- [1- [1- (1-azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] phenyl ] indazole-7-carboxamide (32B)

Tert-butyl 3- [3- [4- [4- (4-carbamoylindazol-2-yl) phenyl ] tert-butyl ] azetidin-1-yl ] azetidine-1-carboxylate (32A) (70mg, 0.13mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added and reacted at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to be used as a yellow oil (40mg, yield 70%) in the next step (32B).

The third step: 2- [4- [1- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] azetidin-3-yl ] azetidin-3-yl ] -4-piperidyl ] phenyl ] indole-7-carboxamide

The starting material 2- [4- [1- [1- (1-azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] phenyl ] indazole-7-carboxamide (32B) (40mg, 0.093mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (31mg, 0.11mmol) was dissolved in 2ml dmso, N-diisopropylethylamine (60mg, 0.46mmol) was added, and after 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 was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound as a yellow solid (10mg, 16% yield).

¹H NMR(400MHz,CD₃OD)δ8.99(s,1H),8.17(d,1H),8.06(d,2H),8.03(dd,1H),7.67(d,1H),7.53(d,2H),7.30-7.25(m,1H),6.87(d,1H),6.72(dd,1H),5.08-5.03(m,1H),4.22-4.18(m,2H),4.03-3.96(m,4H),3.82-3.80(m,2H),3.55(d,2H),3.01-2.91(m,3H),2.86-2.81(m,1H),2.78-2.68(m,3H),2.22-2.16(d,2H),2.12-2.02(m,4H).

LCMS m/z＝687.3[M+1]⁺

Example 33

2- [4- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] -4-piperidyl ] phenyl ] indazole-7-carboxamide (Compound 33)

2-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]-4-piperidyl]phenyl]indazole-7-carboxamide

The first step is as follows: tert-butyl 4- [4- [4- (7-carbomoiylindazol-2-yl) phenyl ] -1-piperidyl ] piperidine-1-carboxylate

4- [4- [4- [4- (7-carbamoylindazol-2-yl) phenyl ] -1-piperidinyl ] piperidine-1-carboxylic acid tert-butyl ester (33A)

2- [4- (4-piperidinyl) phenyl ] indazole-7-carboxamide (30E) (320mg, 1mmol) was dissolved in 10mL of N, N-dimethylacetamide, N-Boc-piperidone (239mg, 1.2mmol) and anhydrous zinc chloride (545mg, 4mmol) were added, stirred at 55 ℃ for 1h, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give yellow solid (33A) (120mg, 24% yield) which was used directly in the next step.

The second step is that: 2- [4- [1- (4-piperidyl) -4-piperidyl ] phenyl ] indole-7-carboxamide (33B)

2- [4- [1- (4-piperidinyl) -4-piperidinyl ] phenyl ] indazole-7-carboxamide

Tert-butyl 4- [4- [4- (7-carbamoylindazol-2-yl) phenyl ] -1-piperidinyl ] piperidine-1-carboxylate (33A) (120mg, 0.238mmol) was dissolved in 5mL of dichloromethane, and 2mL of trifluoroacetic acid was added and reacted at room temperature for 2 h. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to be used as a yellow oil (80mg, yield 83%) in the next step (33B).

The third step: 2- [4- [1- [1- [2- (2,6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -4-piperidyl ] -4-piperidyl ] phenyl ] indole-7-carboxamide

2- [4- [1- (4-piperidinyl) -4-piperidinyl ] phenyl ] indazole-7-carboxamide (33B) (80mg, 0.20mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (66mg, 0.24mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (130mg, 1mmol) 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, 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 was concentrated under reduced pressure and sent to the liquid phase for preparation to give compound 33 as a yellow solid (5mg, yield 4%).

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

¹H NMR(400MHz,CD₃OD)δ8.99(s,1H),8.17(d,1H),8.07(d,2H),8.03(d,1H),7.73(d,,1H),7.53(d,2H),7.44(d,1H),7.33-7.26(m,2H),5.10-5.08(m,1H),4.27(d,2H),3.75(d,2H),3.29–3.21(m,2H),3.16–3.06(m,3H),2.91–2.82(m,2H),2.79–2.75(m,1H),2.74–2.70(m,1H),2.30-2.27(m,4H),2.10-2.02(m,3H),1.92-1.88(m,2H).

LCMS m/z＝660.3[M+1]⁺

Example 34

2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-aza [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) isoindoline-1, 3-dione (Compound 34)

2-(2,6-dioxopiperidin-3-yl)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)isoindoline-1,3-dione

8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-ef ] [2] benzazepin-6-one (34A) (120mg, 0.372mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (114mg, 0.412mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (222mg, 1.72mmol) was added, and after the addition, reaction was carried out at 90 ℃ for 2 hours. After the reaction is finished, cooling to room temperature, adding 10mL of water, filtering, dissolving a filter cake by 20mL of dichloromethane, washing by 5mL of saturated sodium chloride, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, purifying by a silica gel column, and eluting: DCM-2% MeOH/DCM-5% MeOH/DCM to give crude product which was then prepared as a liquid phase to give compound 34 as a yellow solid (100mg, 46%).

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),11.04(s,1H),8.21(t,1H),7.67(d,1H),7.60(d,2H),7.42(dd,1H),7.35(d,2H),7.30(dd,1H),7.13(d,1H),7.06(dd,1H),5.04(dd,1H),4.88(s,2H),3.41–3.35(m,2H),3.28(s,3H),3.05–2.99(m,2H),2.92–2.81(m,1H),2.62–2.51(m,2H),2.05–1.95(m,1H).

LCMS m/z＝580.2[M+1]⁺

Example 35

2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-aza [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) azetidin-1-yl) isoindoline-1, 3-dione (Compound 35)

2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)azetidin-1-yl)isoindoline-1,3-dione

The first step is as follows: tert-butyl 3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) azetidine-1-carboxylate (35A)

tert-butyl 3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)azetidine-1-carboxylate

The starting material, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-ef ] [2] benzazepin-6-one (34A) (240mg, 0.743mmol), was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, 1-Boc-3-azetidinone (205mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude title compound (35A) as a yellow solid (220mg, 61.9% yield) which was used in the next step without further purification.

LCMS m/z＝479.3[M+1]⁺

The second step is that: 2- (4- ((azetidin-3-yl (methyl) amino) methyl) phenyl) -8-fluoro-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-6-one (35B)

2-(4-((azetidin-3-yl(methyl)amino)methyl)phenyl)-8-fluoro-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl 3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) azetidine-1-carboxylate (35A) (200mg, 0.421mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was allowed to proceed overnight at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (35B) as a yellow oil (60mg, 24%) which was used in the next step without further purification.

LCMS m/z＝379.3[M+1]+

The third step: 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-aza [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) azetidin-1-yl) isoindoline-1, 3-dione (Compound 35)

2- (4- ((azetidin-3-yl (methyl) amino) methyl) phenyl) -8-fluoro-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-6-one (35B) (60mg,0.16mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL 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, 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 was concentrated under reduced pressure and then sent to the liquid phase for preparation to give the title compound 35 as a yellow solid (25mg, 21% yield).

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

¹H NMR(400MHz,DMSO-d₆) NMR (400MHz, crude product from DMSO, br.s,1H),8.22(t,1H),7.66(d,1H),7.61(d,2H),7.48(d,2H),7.42(dd,1H),7.32(dd,1H),6.82(d,1H),6.68(dd,1H),5.06(dd,1H),4.17(t,2H), 3.96-3.89 (m,2H),3.63(t,57(m,1H),3.54(s,2H), 3.44-3.35 (m,2H),3.09, t,1H),7.66(d, 42H), 2(m,1H),2.63(m,1H),2.6t,1H),7.66(d,1H)5(m, 17H).

LCMS m/z＝635.3[M+1]⁺

Example 36

2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) - [1,3 '-azetidine ] -1' -yl) isoindoline-1, 3-dione (Compound 36)

2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]in dol-2-yl)benzyl)(methyl)amino)-[1,3'-biazetidin]-1'-yl)isoindoline-1,3-dione

The first step is as follows: tert-butyl 3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) - [1,3 '-diazidine ] -1' -carboxylate (36A)

tert-butyl 3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)-[1,3'-biazetidine]-1'-carboxylate

2- (4- ((azetidin-3-yl (methyl) amino) methyl) phenyl) -8-fluoro-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-6-one (35B) (210mg, 0.556mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (285mg, 1.66mmol), anhydrous zinc chloride (406mg, 2.98mmol) were added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (140mg, 2.24mmol) 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 methylene chloride 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 (36A) (120mg, 40% yield).

LCMS m/z＝534.3[M+1]⁺

The second step is that: 2- (4- (([1,3' -azetidine ] -3-yl (methyl) amino) toluene) phenyl) -8-fluoro-2, 3,4, 6-tetrahydro-1H-aza [5,4,3-cd ] indol-6-one (36B)

2-(4-(([1,3'-biazetidin]-3-yl(methyl)amino)methyl)phenyl)-8-fluoro-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl 3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) - [1,3 '-diazidine ] -1' -carboxylate (36A) (105mg, 0.19mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added and reacted at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (36B) as a yellow oil (60mg, yield 70%) which was used in the next step without further purification.

LCMS m/z＝434.3[M+1]⁺

The third step: 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) - [1,3 '-azetidine ] -1' -yl) isoindoline-1, 3-dione (Compound 36)

2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)-[1,3'-biazetidin]-1'-yl)isoindoline-1,3-dione

2- (4- (([1,3' -azetidine ] -3-yl (methyl) amino) toluene) phenyl) -8-fluoro-2, 3,4, 6-tetrahydro-1H-aza [5,4,3-cd ] indol-6-one (36B) (40mg, 0.093mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (31mg, 0.11mmol) was dissolved in 2mL of DMSO, N-diisopropylethylamine (60mg, 0.46mmol) was added, and after 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 solution was washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and sent to the liquid phase for preparation to give Compound 7 as a yellow solid (8mg, yield 13%).

¹H NMR(400MHz,DMSO-d₆)δ11.65(s,1H),11.04(s,1H),8.22(t,1H),7.64(d,1H),7.59(d,2H),7.46–7.37(m,3H),7.31(dd,1H),6.79(d,1H),6.66(dd,1H),5.05(dd,1H),4.05(t,2H),3.85–3.78(m,2H),3.67–3.60(m,1H),3.46–3.36(m,6H),3.15–3.10(m,1H),3.07–3.01(m,2H),2.98(t,2H),2.91–2.80(m,1H),2.61–2.53(m,2H),2.05–1.93(m,4H).

LCMS m/z＝690.3[M+1]⁺

Example 37

2- (2, 6-dioxopiperidin-3-yl) -5- (3- (4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) piperidin-1-yl) azetidin-1-yl) isoindoline-1, 3-dione (Compound 37)

2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione

The first step is as follows: tert-butyl 4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) piperidine-1-carboxylate (37A)

tert-butyl

4-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)piperidine-1-carboxylate

8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-ef ] [2] benzazepin-6-one (34A) (320mg, 1mmol) was dissolved in 10mL of N, N-dimethylacetamide, N-Boc-piperidone (239mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) was added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the title compound as a yellow solid (37A) (240mg, 48% yield).

LCMS m/z＝507.3[M+1]⁺

The second step is that: 8-fluoro-2- (4- (((methyl (piperidin-4-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-6-one (37B)

8-fluoro-2-(4-((methyl(piperidin-4-yl)amino)methyl)phenyl)-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl 4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) piperidine-1-carboxylate (37A) (120mg, 0.238mmol) was dissolved in 5mL of dichloromethane and 2mL of trifluoroacetic acid was added and reacted at room temperature for 2H. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8-9 with aqueous sodium bicarbonate solution at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (37B) as a yellow oil (70mg, yield 73%) which was used in the next step without further purification.

LCMS m/z＝407.3[M+1]⁺

The third step: tert-butyl 3- (4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino ] piperidin-1-yl) azetidine-1-carboxylate (37C)

tert-butyl 3-(4-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)piperidin-1-yl)azetidine-1-carboxylate

8-fluoro-2- (4- (((methyl (piperidin-4-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-6-one (8B) (200mg, 0.49mmol) was dissolved in a mixed solvent of 8mL of methanol and 2mL of tetrahydrofuran, 1-Boc-3-azetidinone (140mg, 0.83mmol), anhydrous zinc chloride (406mg, 2.98mmol) was added, stirring was performed at 55 ℃ for 1H, sodium cyanoborohydride (120mg, 1.92mmol) 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 methylene chloride 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) to give the title compound (37C) as a yellow solid (110mg, 40% yield).

LCMS m/z＝562.3[M+1]⁺

The fourth step: 2- (4- ((((1- (azetidin-3-yl) piperidin-4-yl) (methyl) amino) methyl) phenyl) -8-fluoro-1, 3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-6-one (37D)

2-(4-(((1-(azetidin-3-yl)piperidin-4-yl)(methyl)amino)methyl)phenyl)-8-fluoro-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl 3- (4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino ] piperidin-1-yl) azetidine-1-carboxylate (37C) (110mg, 0.19mmol) was dissolved in 5mL dichloromethane, 1mL trifluoroacetic acid was added, the reaction was carried out at room temperature for 2H, the solvent and trifluoroacetic acid were removed under reduced pressure, 20mL dichloromethane was added, the pH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extraction was carried out 2 times with dichloromethane (20mL × 2), washing was carried out once with a saturated saline solution (20mL × 1), drying was carried out over anhydrous sodium sulfate, and concentration was carried out under reduced pressure to give the title compound (37D) as a yellow oil (80mg, yield 80%) was used directly in the next step.

LCMS m/z＝462.3[M+1]⁺

The fifth step: 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (4- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) piperidin-1-yl) azetidin-1-yl) isoindoline-1, 3-dione (Compound 37)

The starting material 2- (4- ((((1- (azetidin-3-yl) piperidin-4-yl) (methyl) amino) methyl) phenyl) -8-fluoro-1, 3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-6-one (37D) (80mg, 0.18mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) was dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.92mmol) was added thereto, and after completion of the reaction, the mixture was cooled to room temperature, 10mL of water was added thereto, and filtration was carried out, the cake was dissolved in 20mL of dichloromethane, washed with 5mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was prepared by liquid phase chromatography to give the title compound 37 as a yellow solid (20mg, 16% yield).

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),11.05(br.s,1H),8.22(t,1H),7.65(d,1H),7.58(d,2H),7.49–7.37(m,3H),7.31(dd,1H),6.79(d,1H),6.65(dd,1H),5.05(dd,1H),4.10(t,2H),3.89–3.78(m,2H),3.61(s,2H),3.48–3.36(m,4H),3.07–3.01(m,2H),2.95–2.82(m,3H),2.65–2.53(m,2H),2.48–2.40(m,1H),2.15(s,3H),2.05–1.96(m,1H),1.87–1.76(m,3H),1.63–1.48(m,2H).

LCMS m/z＝718.3[M+1]⁺

Example 38

2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) -7-azaspiro [3.5] nonan-7-yl) isoindoline-1, 3-dione (Compound 38)

2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)-7-azaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione

The first step is as follows: tert-butyl 2- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) -7-azaspiro [3.5] nonane-7-carboxylate (38A)

tert-butyl 2-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)-7-azaspiro[3.5]nonane-7-carboxylate

The starting material, 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-ef ] [2] benzazepin-6-one (34A) (240mg, 0.743mmol), was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (286mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) was added, stirring was carried out at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1-5:1) to give the title compound (38A) as a yellow solid (150mg, 38% yield).

LCMS m/z＝547.3[M+1]+

The second step is that: 8-fluoro-2- (4- (((methyl (7-azaspiro [3.5] nonan-2-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-6-one (38B)

8-fluoro-2-(4-((methyl(7-azaspiro[3.5]nonan-2-yl)amino)methyl)phenyl)-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl 2- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) -7-azaspiro [3.5] nonane-7-carboxylate (38A) (150mg, 0.274mmol) was dissolved in 5mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out overnight at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, the PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (38B) as a yellow oil (100mg, 82%) which was used in the next step.

LCMS m/z＝447.3[M+1]+

The third step: 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepin [5,4,3-cd ] indol-2-yl) benzyl) (methyl) amino) -7-azaspiro [3.5] nonan-7-yl) isoindoline-1, 3-dione (Compound 38)

8-fluoro-2- (4- (((methyl (7-azaspiro [3.5] nonan-2-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-6-one (38B) (100mg, 0.22mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.22mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after 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 was concentrated under reduced pressure and sent to the liquid phase for preparation to give the title compound 38 as a yellow solid (25mg, 16% yield).

¹H NMR(400MHz,DMSO-d₆)δ11.78(s,1H),11.05(s,1H),9.95(br.s,1H),8.27(t,1H),7.75(d,2H),7.68(d,1H),7.66(d,1H),7.45(dd,1H),7.38–7.33(m,2H),7.26(dd,1H),5.06(dd,1H),4.44–4.37(m,1H),4.13(dd,1H),3.88–3.78(m,2H),3.54–3.46(m,2H),3.46–3.37(m,4H),3.12–3.03(m,2H),2.93–2.84(m,1H),2.65–2.53(m,4H),2.32–2.22(m,2H),2.13–1.97(m,3H),1.71–1.58(m,4H).

LCMS m/z＝703.3[M+1]⁺

Example 39

2- (2, 6-dioxopiperidin-3-yl) -5- ((3aR, 6aS) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepan [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) isoindoline-1, 3-dione (Compound 39)

2-(2,6-dioxopiperidin-3-yl)-5-((3aR,6aS)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)isoindoline-1,3-dione

The first step is as follows: tert-butyl (3aR,6aS) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (39A)

tert-butyl(3aR,6aS)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)benzyl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

The starting material 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-ef ] [2] benzazepin-6-one (34A) (240mg, 0.743mmol) was dissolved in a mixed solvent of 8mL methanol and 2mL tetrahydrofuran, and (3aR,6aS) -5-oxohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (270mg, 1.2mmol), anhydrous zinc chloride (545mg, 4mmol) were added, stirred at 55 ℃ for 1H, sodium cyanoborohydride (188mg, 3mmol) 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 methylene chloride and 20mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1 to 5:1) to give the title compound (39A) (200mg, yield 49%) as a yellow solid.

LCMS m/z＝533.3[M+1]⁺

The second step is that: 8-fluoro-2- (4- ((methyl (((3aR, 6aS) -octahydrocyclopenta [ c ] pyrrol-5-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azido [5,4,3-cd ] indol-6-one (39B)

8-fluoro-2-(4-((methyl((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)amino)methyl)phenyl)-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one

Tert-butyl (3aR,6aS) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepane [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (39A) (145mg, 0.274mmol) was dissolved in 5mL dichloromethane and 2mL trifluoroacetic acid was added and reacted at room temperature overnight. The solvent and trifluoroacetic acid were removed under reduced pressure, 20mL of dichloromethane was added, PH was adjusted to 8 to 9 with an aqueous solution of sodium hydrogencarbonate at 0 ℃, extracted 2 times with dichloromethane (20mL × 2), washed once with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (39B) as a yellow oil (90mg, 76%) which was used in the next reaction.

LCMS m/z＝433.3[M+1]⁺

The third step: 2- (2, 6-dioxopiperidin-3-yl) -5- ((3aR, 6aS) -5- ((4- (8-fluoro-6-oxo-1, 3,4, 5-tetrahydro-1H-azepan [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) isoindoline-1, 3-dione (Compound 39)

8-fluoro-2- (4- ((methyl (((3aR, 6aS) -octahydrocyclopenta [ c ] pyrrol-5-yl) amino) methyl) phenyl) -1,3,4, 5-tetrahydro-1H-azido [5,4,3-cd ] indol-6-one (39B) (90mg, 0.22mmol), 2- (2, 6-dioxo-3-piperidinyl) -5-fluoroisoindoline-1, 3-dione (62mg, 0.21mmol) were dissolved in 2mL of DMSO, N-diisopropylethylamine (120mg, 0.93mmol) was added, and after completion of the addition, reaction was carried out at 90 ℃ for 2 hours, and after cooling to room temperature, 10mL of water was added, filtration was carried out, the cake was dissolved in 20mL of dichloromethane and washed with 5mL of saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate the resulting crude product under reduced pressure and send to the liquid phase for preparation to give compound 39 as a yellow solid (22mg, 15% yield).

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),11.04(s,1H),8.21(t,1H),7.65(d,1H),7.56(d,2H),7.49–7.39(m,3H),7.31(dd,1H),6.97(d,1H),6.88(d,1H),5.05(dd,1H),3.64–3.54(m,4H),3.43–3.37(m,4H),3.07–3.00(m,2H),2.98–2.87(m,2H),2.85–2.78(m,2H),2.62–2.55(m,2H),2.25–2.16(m,2H),2.09(s,3H),2.05–1.96(m,1H),1.54–1.43(m,2H).

LCMS m/z＝689.3[M+1]⁺

Biological assay

1. Cell proliferation inhibition assay (1)

Lymphoma cell K562 purchased from SIBS in RPMI1640+ 10% FBS medium, cultured at 37 deg.C and 5% CO₂An incubator. Cells in exponential growth phase were collected on the first day and viable cells were counted using a Vi-Cell XR Cell counter (Beckman Coulter, TACEL 0030). After the cell suspension was adjusted to 3000 cells/90. mu.L with the medium, 90. mu.L of the cell suspension was added to each well of a 96-well cell culture plate and incubated overnight. The next day, compounds of different concentrations were added and placed at 37 ℃ with 5% CO₂Incubate for 72 hours. After the completion of the culture, 50. mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well according to the instructions of CellTiter-Glo kit (Promega, G7572), mixed by a microplate shaker for 2 minutes, left at room temperature for 10 minutes, and then the fluorescence signal value was measured by an Envision2104 plate reader (Perkinelmer, TAREA 0011). Cell viability was calculated using formula (1), wherein V_sampleReading for the drug treatment group, V_{vehicle control}Mean values for the solvent control group. Sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 5.0 software and IC calculated₅₀The value is obtained. IC of Compounds of the invention on K562 cells₅₀The values are shown in Table 1.

V_sample/V_{vehicle control}x 100% (formula 1)

TABLE 1 IC of the Compounds of the invention on K562 cells₅₀Value of

Compound numbering	IC₅₀ K562(nM)
		Compound 2	63
Compound 3	8
		Compound 6	38
Compound 7	86
		Compound 8	63
Compound 12	97
		Compound 14	47
Compound 17	91
		Compound 18	12
Compound 20	29
		Compound 21	2
Compound 22	0.8
		Compound 23	0.5
Compound 24	1.3
		Compound 25	0.7
Compound 26	0.5
		Compound 27	1.3
Compound 29	31

And (4) conclusion: the compound synthesized by the technology has good proliferation inhibition activity on K562 cells (lymphoma cells), IC₅₀Values were less than 200 nM.

2. Cell proliferation inhibition assay (2)

Mammary tumor cell MDA-MB-436 purchased from ATCC in a culture medium of Leibovitz's L-15+ 10% FBS, cultured at 37 ℃ without CO₂An incubator. Ovarian cancer cell A2780 purchased from ECACC in RPMI-1640+ 10% FBS culture at 37 deg.C and 5% CO₂An incubator. Cells in exponential growth phase were collected on the first day and the cell suspension was adjusted to the corresponding concentration with medium, wherein the MDA-MB-436 cell concentration was 4000/135. mu.L and the A2780 cell concentration was 500/135. mu.L. Add 135. mu.L of cell suspension to 96-well cell culture plates per well and incubate overnight. The next day, compounds at different concentrations were added and incubated in incubators with MDA-MB-436 cells incubated for 7 days and A2780 cells for 5 days. After the completion of the culture, 75. mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well according to the instructions of CellTiter-Glo kit (Promega, G7573), mixed by a microplate shaker for 2 minutes, left at room temperature for 10 minutes, and then the fluorescence signal value was measured by an Envision2104 plate reader (Perkinelmer). The inhibition rate was calculated using equation (1), where RLU_compoundFor the drug treatment group readings, RLU_controlRLU as the mean value of the solvent control group_blankMean cell-free wells. IC50 values were calculated using GraphPad Prism software. IC of Compounds of the invention on A2780 and MDA-MB-436 cells₅₀The values are shown in Table 2.

IR(％)＝(1–(RLU_compound–RLU_blank)/(RLU_control–RLU_blank) 100% (formula 1)

TABLE 2 IC of the Compounds of the invention on A2780 and MDA-MB-436 cells₅₀Value of

Compound numbering	A2780 IC₅₀(μM)	MDA-MB-436 IC₅₀(μM)
			Compound 37	0.65	0.18
Compound 38	0.57	0.41

And (4) conclusion: the compound synthesized by the technology has obvious cell proliferation inhibition activity on A2780 (ovarian cancer cells) and MDA-MB-436 cells (breast cancer cells), and the IC50 value of the cell proliferation inhibition activity on A2780 and MDA-MB-436 cells is less than 1 mu M.

Claims

1. A compound or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (Ia), (Ib), (Ic), (Id) or (Ie),

B-K (Ia)

B-Cy1-K (Ib)

B-Cy1-Cy2-K (Ic)

B-Cy1-Cy2-Cy3-K (Id)

B-Cy1-Cy2-Cy3-Cy4-K (Ie)

b is selected from

or B is selected from

cy1, Cy2, Cy3, Cy4 are each independently selected from 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 bicycloalkyl, 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 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy 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;

k is selected from

R^k2each independently selected from CH₂、C＝O、S＝O、SO₂；

R^k5is selected from C ═ O or

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

n1, n2, n3, n4 or n5 are each independently selected from 0, 1,2,3 or 4.

2. 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

n1, n2, n3, n4 or n5 are each independently selected from 0, 1,2,3 or 4.

3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

k is selected from

4. The compound of claim 3, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: azetidinyl, azepinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentoazetidinyl, cyclopentaizetidinyl, cyclohexyloazetidinyl, azetidinylboazetidinyl, azetidineazetidiazacyclohexyl, azetidineaiperidyl, cyclopentaizetidinyl, cyclopentaietioazetidinyl, cyclopentaizetidinyl, cyclopentaizazetidinyl, and, cyclopentaizazetidinyl, and, cyclopentaizazetidinyl, cyclopentaizacylyl, cyclopentaizacylo, and, Azacyclohexylazacyclobutyl, azacyclohexylazacyclopentyl, azacyclohexylazacyclohexyl, azacyclohexylpiperidine, cyclobutylSpiroazetidinyl, cyclobutylspiroazacyclopentyl, cyclobutylspiroazacyclohexyl, cyclopentylspiroazetidinyl, cyclopentylspiroazacyclopentyl, cyclopentylspiroazacyclohexyl, cyclohexylspiroazetidinyl, cyclohexylspiroazacyclopentyl, cyclohexylspiroazacyclohexyl, azetidinylspiroazetidinyl, azetidinylspiroazacyclopentyl, azetidinylspiroazacyclohexyl, azacyclohexylspiroazetidinyl, azacyclohexylspiroazacyclopentyl, azacyclohexylspiroazacyclohexyl, cyclobutylspiropiperidine, cyclopentylspiropiperidine, cyclohexylspiropiperidine, azetidinylspiropiperidine, azacyclopentylspiropiperidine, azacyclohexylspiropiperidine, azacyclobutylpiperidine, azacyclobutylspiropiperidine, azacyclopentylspiropiperidine, azacyclohexylspiropiperidine, azacyclobutylpiperidine, azacyclopiperidine, azacyclobutylpiperidine, 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;

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

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

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

b is selected from

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

Cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

or Cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

Wherein the left side is connected with B;

Wherein the left side is connected with B;

Wherein the left side is connected with B;

Wherein the left side is connected with B;

represented by the general formula (Ie)The compound of (1) wherein Cy1-Cy2-Cy3-Cy4 is selected from the group consisting of

Wherein the left side is connected to B.

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

K is selected from

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

K is selected from

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

B is selected from

10. The compound of claim 6, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

11. a compound represented by the following structure or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,

12. 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

R^b1、R^b2Or R^b4Each independentlySelected from H, F, Cl, Br, I, OH, NH₂、CN、CONH₂、COOH、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;

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

13. The compound of claim 12, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

k is selected from

14. The compound of claim 13, or a stereoisomer, deutero, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

Cy1, Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: azetidinyl, azacyclopentyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclopropylaminopiperidine, cyclonexidineButyl-and-azetidinyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylpiperidine, cyclopentoazacyclobutyl, cyclopentoazacyclopentyl, cyclopentoazacyclohexyl, cyclopentylpiperidine, cyclohexyloazacyclobutyl, cyclohexyloazacyclopentyl, cyclohexyloazacyclohexyl, cyclohexylaminopiperidine, azetidinoazacyclobutyl, azetidinoazacyclopentyl, azetidinoazacyclohexyl, azetidinobutylpiperidine, azepinoazeutyl, azepinoazetidicyclopentyl, azepinoazacyclopentyl, azepinoazacyclohexyl, azepinopiperidine, azacyclohexyloazacyclobutyl, azacyclohexyloazetidinyl, azacyclohexylazacyclohexylazacyclohexylazacyclohexylazacyclohexapeptide, cyclobutylspiroazetidinyl, cyclobutylspiroazacyclopentylpiperidine, cyclobutylazacyclobutylazacyclobutylcyclo-, Cyclobutyl spiroazacyclohexyl, cyclopentyl spiroazacyclobutyl, cyclopentyl spiroazacyclopentyl, cyclopentyl spiroazacyclohexyl, cyclohexyl spiroazacyclobutyl, cyclohexyl spiroazacyclopentyl, cyclohexyl spiroazacyclohexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclobutyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazacyclopentyl, azetidinyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine or azaheterocyclohexylspiropiperidine, when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH.₂、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;

R^b3selected from H, methyl or cyclopropyl, said methyl or cyclopropyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I;

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

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

15. A compound according to claim 14 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

k is selected from

R^b3Is selected from methyl;

n1, n2 or n3 is selected from 0.

16. A compound according to claim 15 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

Cy1 in the compound represented by the general formula (Ib) is selected from

Wherein the left side is connected with B;

Wherein the left side is connected with B;

Wherein the left side is connected to B.

17. A compound according to claim 16 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

K is selected from

18. A compound according to claim 17 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

K is selected from

19. A compound according to claim 18 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein

B is selected from

20. The compound according to claim 16, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:

21. the compound of any one of claims 1-20, or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the salt is selected from trifluoroacetate.

22. A pharmaceutical composition comprising a compound of any one of claims 1-20, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.

23. Use of a compound according to any one of claims 2-11, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with Bcr-Abl activity or expression.

24. Use of a compound according to any one of claims 2-11, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with inhibition or degradation of Bcr-Abl.

25. The use according to any one of claims 23 to 24, wherein the disease is selected from the group consisting of a tumor.

26. The use of claim 25, wherein the neoplasm is selected from the group consisting of lung cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, gastric cancer, renal cancer, ovarian cancer, hematological disorders, lymphoma, myeloma, chronic myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, myeloproliferative disorders, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protruberans, and gastrointestinal stromal tumors.

27. Use of a compound according to any one of claims 12-20, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with PARP activity or expression.

28. Use of a compound according to any one of claims 12-20, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with the inhibition or degradation of PARP.

29. The use according to any one of claims 27 to 28, wherein the disease is selected from the group consisting of a tumor.

30. The use of claim 29, wherein the tumor is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal tumor, prostate cancer, pancreatic cancer, lung cancer, and gastric cancer.