ZESTE enhancer homolog 2 inhibitors and uses thereof

Abstract

The present invention discloses a compound of formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated compounds, or pharmaceutical compositions containing them, and use thereof as EZH2 inhibitors in the preparation of drugs for treating related diseases. The groups in formula (I) are consistent with the definitions in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a compound having EZH2 inhibitory activity, its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated compounds, and use thereof in preparing medicines for treating related diseases. Background Art

[0002] Currently, cancer treatments mainly include radiotherapy, surgical therapy, and drug therapy. Targeted drug therapy has become the main means of clinical tumor treatment today. However, due to the rapid development of tumor cell drug resistance, people are still basically helpless against tumor metastasis and recurrence at this stage.

[0003] Lysine methyltransferase can methylate histones and non-histones. Its abnormal expression is closely related to the occurrence of various tumors. It has become a hot topic in the field of epigenetics for more than a decade. Targeting lysine methyltransferase and reversing abnormal histone or non-histone methylation levels is considered to be another new method for tumor treatment. PRC2 (polycomb repressive complex 2) is a multi-subunit protein complex composed of EZH1 (Enhancer of zeste homologue 1, KMT6B) or EZH2 (Enhancer of zeste homologue 2, KMT6A), SUZ12 (Suppressor of zeste 12), and EED (Embyronic ectoderm development), which is used to catalyze H3K27 trimethylation. The PCR2 complex methylates nucleosomal protein H3K9 and lysine 27 through the SET domain of EZH2, and then triggers the PCR1 complex to gather at specific gene sites to silence target genes (CDKN1C, CDH1, RUNX3, etc.) and promote cell proliferation. Studies have shown that whether EZH2 is overexpressed or SET region mutations occur (Y641F, Y641N, A687V, A677G point mutations), it leads to abnormal increase of H3K27me3, promoting the growth and development of various types of tumors, such as breast cancer, prostate cancer, leukemia, etc. Summary of the invention

[0004] The compounds provided by the present invention and their stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated products have an inhibitory effect on EZH2, can inhibit cell proliferation, have good pharmacokinetic characteristics, high bioavailability, good safety, low toxic and side effects, have no inhibition on CYP enzymes, can be orally administered, have rapid absorption and high clearance rate.

[0005] The present invention provides a compound having EZH2 inhibitory activity, and its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated substances, wherein the compound is represented by formula (I):

[0006]

[0007] Among them, R 1 Selected from H, D, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-4 alkyl; in certain embodiments, R 1 Selected from H, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-4 alkyl; in certain embodiments, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl; in certain embodiments, R 1 Selected from C 1-4 alkyl; in certain embodiments, R 1 is selected from methyl; in certain embodiments, R 1 is selected from cyclopropyl; in certain embodiments, R 1 Selected from H;

[0008] R 2 Select from H, D or C 1-4 alkyl; in certain embodiments, R 2 Select from H or C 1-4 alkyl; in certain embodiments, R 2 is selected from H; in certain embodiments, R 2 Selected from methyl;

[0009] R 3 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: D, OH, CN, amino, halogen; in certain embodiments, R 3 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: OH, cyano, amino, halogen; in certain embodiments, R 3 Selected from C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: OH, halogen; in certain embodiments, R 3 Selected from methyl, hydroxyethyl, oxetanyl, In certain embodiments, R 3 Selected from methyl;

[0010] Alternatively, R 1 and R 2 To form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally substituted with 1-3 halogens, D, CN, OH, amino, C 1-4 Alkyl substituted; in certain embodiments, R 1 and R 2 To form a 3-6 membered cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogens; in certain embodiments, R 1 and R 2 Formation of cyclopentyl group;

[0011] or

[0012] Alternatively, R 2 and R 3 Forming a 3-6 membered heterocycloalkyl group (R2 and R3 together with the atoms to which they are attached form a 3-6 membered heterocycloalkyl group), wherein the heterocycloalkyl group is optionally substituted by 1-3 halogen, D, OH, amino, C 1-4 alkyl, CN substituted; in certain embodiments, R 2 and R 3 To form a 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1-3 halogens, OH, or amino groups; in certain embodiments, R 2 and R 3 Formation of thiolanyl groups;

[0013] R 4 , R 5 are each independently selected from H, D, halogen, C 1-4 alkyl; in certain embodiments, R 4 , R 5 are each independently selected from H, halogen, C 1-4 alkyl; in certain embodiments, R 4 , R 5 are each independently selected from H;

[0014] R 4' , R 5’ The carbon atom connected to form C 3-6 carbocyclic ring, or a 3-7 membered heterocycloalkyl ring containing 1-3 heteroatoms selected from N, S, and O; in certain embodiments, R 4' , R 5’Together with the common carbon atom to which it is attached, it forms an oxetane group;

[0015] or

[0016] R 4' With R 5’ co-form = O;

[0017] R 6 Selected from H, D, C 1-4 alkyl; in certain embodiments, R 6 Selected from H;

[0018] R 7 is selected from H, D or halogen; in certain embodiments, R 7 is selected from H, Cl, F; in certain embodiments, R 7 is selected from H; in certain embodiments, R 7 does not exist;

[0019] R 8 Selected from H, D, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -NR 8a R 8b -、-NR 8a -C(O)-C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogens, D, C 1-4 Alkyl, OH, CN, amino substitution; in certain embodiments, R 8 Selected from H, halogen, C 3-6 Cycloalkyl, 3-6 heterocycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 halogens; in certain embodiments, R 8 is selected from halogen; in certain embodiments, R 8 Selected from Cl, cycloalkyl, oxetanyl, methoxy, In certain embodiments, R 8 Selected from Cl; or

[0020] R 7 , R8 Together with the atoms connected to it, it forms C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogens, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substituted; in certain embodiments, R 7 , R 8 Together with the atoms connected to it, it forms C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl substituted; in certain embodiments, R 7 , R 8 Together with the atoms connected to it, it forms a 5-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 5-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0021] R 8a , R 8b are each independently selected from H, D, halogen, C 1-4 alkyl, OH, CN; in certain embodiments, R 8a , R 8b Each independently selected from H or C 1-4 alkyl;

[0022] R 9 Selected from C 1-4 Alkyl, C 2-6 Alkynyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 The alkyl, cycloalkyl, alkoxy group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl substituted; in certain embodiments, R 9 Selected from C 1-4 alkyl; in certain embodiments, R 9 is selected from methyl, cyclopropyl, ethynyl, propynyl, methoxy, trifluoromethoxy; in certain embodiments, R 9 Selected from methyl;

[0023] R 10 Selected from C 1-4Alkyl, wherein the alkyl is optionally substituted by 1-3 halogens, D, CN, OH, -O-Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 10 is selected from methyl, the methyl group is optionally substituted by 1-3 -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 10 is selected from methyl and ethyl, wherein the methyl and ethyl are optionally substituted by trimethylsilyl; in certain embodiments, R 10 is selected from methyl, ethyl; in certain embodiments, R 10 Selected from methyl;

[0024] B is a 3-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, Si, and the carbocyclic or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, amino, -C(O)C 1-4 In some embodiments, B is a 4-10 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, and O, and the carbocyclic or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from =O, C 1-4 In some embodiments, B is N-heterocyclic cyclohexyl; In some embodiments, B is cyclohexyl; In some embodiments, B is N-heterocyclic cyclohexyl; In some embodiments, B is

[0025] Alternatively, two substituents on the same carbon atom of the carbocyclic or heterocyclic ring of Ring B together with the carbon atom to which they are attached form a C 3-6 Carbocyclic or 3-6 heterocyclic alkyl;

[0026] R 11 is selected from halogen, =O, OH, CN, =NR 11d 、-OR b 、-C(O)R 11c 、-(CH 2 ) n -NR 11a -C(O)R 11c , C 1-4 Alkyl, halogenated C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, C1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 、-S(O) 2 NR 11a R 11b 、-S(O) 2 R 11c 、-(CH 2 ) n -C(O)NR 11a R 11b 、-(CH 2 ) n -NR 11a R 11b , the CH 2 , alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a 'R 11b '、-C(O)-NR 11a 'R 11b '、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, the CH 2, alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a In certain embodiments, R 11 Selected from halogen, =O, OH, CN, =NR 11d 、-OR b 、-C(O)R 11c 、-(CH 2 ) n -NR 11a -C(O)R 11c , C 1-4 Alkyl, halogenated C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 、-S(O) 2 NR 11a R 11b 、-S(O) 2 R 11c 、-(CH 2 ) n -C(O)NR 11a R 11b 、-(CH 2 ) n -NR 11a R 11b , the CH 2 , alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl substitution, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a In certain embodiments, R 11 Selected from -NR 11a R 11b , =NR 11d 、-OR b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The aryl, heteroaryl, cycloalkyl, heterocycloalkyl group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11 Selected from -NR 11a R 11b , =NR 11d 、-OR b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 Alkyl substituted; in certain embodiments, R 11 Selected from -NR 11a R11b 、-C(O)R 11c , 6-12 membered aryl, 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 Alkyl substituted; in certain embodiments, R 11 Selected from -NR 11a R 11b 、-C(O)R 11c , 5-10 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 Alkyl substituted; in certain embodiments, R 11 Selected from -NR 11a R 11b In certain embodiments, R 11 Selected from -C(O)R 11c In certain embodiments, R 11 is selected from 5-10 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)C 1-4 Alkyl substitution;

[0027] R 11a , R 11b Each independently selected from H, D, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R 11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a Substitution; in certain embodiments, R 11a , R 11b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c , 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a Substitution; in certain embodiments, R 11a , R 11b Each independently selected from H, C 1-4 Alkyl, -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, wherein the alkyl, alkoxy, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11a Selected from H, C 1-4 alkyl; in certain embodiments, R 11b Selected from -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11b Selected from -C(O)R 11c In certain embodiments, R 11b is selected from 5-12 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11b Selected from C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11b is selected from 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1-3 R a replace;

[0028] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 R c Substitution; in certain embodiments, R 11a , R 11b Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms an azetidinyl group, which is optionally substituted by 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl) substituted;

[0029] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n-(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl group may be optionally substituted with 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4alkyl) 3 Substitution; in certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 , -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The heterocycloalkyl and cycloalkyl groups are optionally substituted with 1 to 3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NH (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, the heterocycloalkyl, cycloalkyl optionally 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 In certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy; in certain embodiments, R 11c Selected from -NHC 1-4 Alkyl, -NH (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl and alkyl are optionally substituted with 1-3 halogens, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC3-6 Cycloalkyl, -OC 3-6 In certain embodiments, R 11c Selected from -NHC 1-4 Alkyl, -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl;

[0030] R 11d Select from -OR a In certain embodiments, R 11d Selected from -O-(3-6 heterocycloalkyl);

[0031] R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substituted; in certain embodiments, R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , the alkyl group or alkoxy group is optionally substituted by 1-3 halogen groups, cyano groups, or hydroxy groups; in certain embodiments, R a Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4Alkoxy, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, cyano or hydroxyl groups;

[0032] R b Selected from -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C(O)-NR 11a 'R 11b ', the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, alkenyl, alkynyl are optionally substituted with 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN, -(CH 2 ) n -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R b is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 halogens; in certain embodiments, R b Selected from C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by 1 to 3 halogens;

[0033] R c Selected from halogen, =O, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -C 3-6Cycloalkyl, -NH(3-6 membered heterocycloalkyl), -NHC 3-6 Cycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, -O-(CH 2 ) n -(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted with 1-3 halogen, D, CN, OH, amino, C 1-4 Alkyl, C 1-4 Alkoxy substituted; in certain embodiments, R c Selected from CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -NH(3-6 membered heterocycloalkyl), -NHC 3-6 Cycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, -O-(CH 2 ) n -(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted with 1-3 halogens, C 1-4 Alkyl substituted; in certain embodiments, R c Selected from methoxy, ethoxy, cyano, -N(CH 3 ) 2 、-CH 2 -methoxy, hydroxyl, -O-(CH 2 ) 2 -C 3-6Cycloalkyl, -C(O)N(CH 3 ) 2 , 5-6 membered heterocycloalkyl, -Si(CH 3 ) 3 、-O-CD 3 In some embodiments, R c Selected from

[0034] R 11a' , R 11b' Each independently selected from H, D, C 1-4 Alkyl, halogen, CN, OH; in some embodiments, R 11a' , R 11b' are each independently selected from H;

[0035] Alternatively, R 11a' , R 11b' Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substituted; in some embodiments, R 11a' , R 11b' Together with the nitrogen atom to which it is connected, it forms a 5-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0036] X is selected from -C- or -N-; in certain embodiments, X is selected from -C-; in certain embodiments, X is N, provided that when X is N, R 7 does not exist;

[0037] n is selected from 0, 1, 2, 3, 4, 5; in certain embodiments, n is selected from 0, 1, 2, 3; in certain embodiments, n is selected from 0, 1;

[0038] Provided that the compound of formula (I) is not selected from the following compounds: 1 Selected from methyl, R 2 Selected from H, R 3 Selected from methyl, R 4 , R 5 Selected from H, R 4' , R 5’ The carbon atom to which it is attached forms =O, R 6 , R 7 is selected from H, X is selected from -C-, R8 Selected from Cl, R 9 Selected from methyl, R 10 When Y is selected from -CH-:

[0039] (1)R 11 Selected from -N(CH 3 ) 2 , or

[0040] (2) If R 11a , R 11b Together with the nitrogen atom, it forms an azetidinyl group or R 11 is selected from azetidinyl, the azetidinyl being substituted by the following substituents: F, difluoromethoxy, cyclopropyloxy, methoxy.

[0041] Scheme 1 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0042]

[0043] Among them, R 1 Selected from H, D, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-4 alkyl;

[0044] R 2 Select from H, D or C 1-4 alkyl;

[0045] R 3 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: D, OH, CN, amino, halogen;

[0046] Alternatively, R 1 and R 2 To form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally substituted with 1-3 halogens, D, CN, OH, amino, C 1-4 Alkyl substitution; or

[0047] Alternatively, R 2 and R 3 To form a 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 halogens, D, OH, amino, C 1-4 Alkyl, CN substituted;

[0048] R 4 , R5 are each independently selected from H, D, halogen, C 1-4 alkyl;

[0049] R 4' , R 5’ The carbon atom connected to form C 3-6 Carbocyclic ring, or 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O; or

[0050] R 4' With R 5’ co-form = O;

[0051] R 6 Selected from H, D, C 1-4 alkyl;

[0052] R 7 is selected from H, D or halogen;

[0053] R 8 Selected from H, D, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -NR 8a R 8b -、-NR 8a -C(O)-C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogens, D, C 1-4 Alkyl, OH, CN, amino substitution; or

[0054] R 7 , R 8 Together with the atoms connected to it, it forms C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogens, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0055] R 8a , R 8b are each independently selected from H, D, halogen, C 1-4Alkyl, OH, CN;

[0056] R 9 Selected from C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 The alkyl, cycloalkyl, alkoxy group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl substitution;

[0057] R 10 Selected from C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1-3 halogens, D, CN, OH, -O-Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0058] B is a 3-12 membered carbocyclic or heterocyclic ring containing 0-3 heteroatoms selected from N, S, O, Si, and the carbocyclic or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from ═O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, amino, -C(O)C 1-4 Alkyl, hydroxyl and halogen groups are substituted; alternatively, two substituents on the same carbon atom of the carbocyclic or heterocyclic ring together with the attached carbon atom form a C 3-6 Carbocyclic or 3-6 heterocyclic alkyl;

[0059] R 11 is selected from halogen, =O, OH, CN, =NR 11d 、-OR b 、-C(O)R 11c 、-(CH 2 ) n -NR 11a -C(O)R 11c , C 1-4 Alkyl, halogenated C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -(6-12 membered aryl), -(CH 2 )n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 、-S(O) 2 NR 11a R 11b 、-S(O) 2 R 11c 、-(CH 2 ) n -C(O)NR 11a R 11b 、-(CH 2 ) n -NR 11a R 11b , the CH 2 , alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R 11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a The group substitution;

[0060] R 11a , R 11b Each independently selected from H, D, C1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R 11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a replace;

[0061] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-12-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 R c replace;

[0062] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 )n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace;

[0063] R 11d Select from -OR a ;

[0064] R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0065] R b Selected from -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n-(5-12 membered heteroaryl), -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C(O)-NR 11a' R 11b' The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, alkenyl, alkynyl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN, -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0066] R c Selected from halogen, =O, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -NH(3-6 membered heterocycloalkyl), -NHC 3-6 Cycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, -O-(CH 2 ) n -(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted with 1-3 halogen, D, CN, OH, amino, C 1-4 Alkyl, C 1-4 Alkoxy substitution;

[0067] R 11a', R 11b' Each independently selected from H, D, C 1-4 Alkyl, halogen, CN, OH;

[0068] Alternatively, R 11a' , R 11b' Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0069] X is selected from -C- or -N-; provided that when X is selected from N, R 7 does not exist;

[0070] n is selected from 0, 1, 2, 3, 4, 5.

[0071] Scheme 2 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated product thereof, wherein the compound has a structure of formula (Ia):

[0072]

[0073] Among them, R 1 Selected from H, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-4 alkyl;

[0074] R 2 Select from H or C 1-4 alkyl;

[0075] R 3 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: OH, cyano, amino, halogen;

[0076] Alternatively, R 1 and R 2 To form a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally substituted by 1-3 halogens; or

[0077] Alternatively, R 2 and R 3 Forming a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, OH, or amino groups;

[0078] R4 , R 5 are each independently selected from H, halogen, C 1-4 alkyl;

[0079] R 4' , R 5’ Together with the common carbon atom, it forms a 3-5 membered heterocycloalkyl group; or

[0080] R 4' With R 5’ co-form = O;

[0081] R 6 Selected from H, C 1-4 alkyl;

[0082] R 7 is selected from H or halogen;

[0083] R 8 Selected from H, halogen, C 3-6 Cycloalkyl, 3-6 heterocycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 halogens; or

[0084] R 7 , R 8 Together with the atoms connected to it, it forms C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0085] R 9 Selected from C 1-4 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkyl, cycloalkyl, alkoxy group is optionally substituted by 1-3 halogens;

[0086] R 10 Selected from C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1-3 halogens, -Si(C 1-4 alkyl) 3 replace;

[0087] R 11 Selected from -NR 11a R 11b , =NR11d 、-OR b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The aryl, heteroaryl, cycloalkyl, heterocycloalkyl group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0088] R 11a , R 11b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c , 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a replace;

[0089] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0090] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl group may be optionally substituted with 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace;

[0091] R 11d Selected from -O-(3-6 heterocycloalkyl);

[0092] R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3, the alkyl group and alkoxy group are optionally substituted by 1-3 halogen groups, cyano groups, or hydroxy groups;

[0093] R b is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted with 1-3 halogen, -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0094] X is selected from -C- or -N-;

[0095] Y is selected from -CH- or -N-;

[0096] n is selected from 0, 1, 2, 3;

[0097] Provided that the compound of formula (I) is not selected from the following compounds: 1 Selected from methyl, R 2 Selected from H, R 3 Selected from methyl, R 4 , R 5 Selected from H, R 4' , R 5’ The carbon atom to which it is attached forms =O, R 6 , R 7 is selected from H, X is selected from -C-, R 8 Selected from Cl, R 9 Selected from methyl, R 10 When Y is selected from C:

[0098] (1)R 11 Selected from -N(CH 3 ) 2 , or

[0099] (2) If R 11a , R 11b Together with the nitrogen atom, it forms an azetidinyl group or R 11 is selected from azetidinyl, the azetidinyl being substituted by the following substituents: F, difluoromethoxy, cyclopropyloxy, methoxy.

[0100] Scheme 3 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0101] R 4 , R 5 Each independently selected from H or D;

[0102] R4' With R 5’ co-form = O;

[0103] R 6 Selected from H;

[0104] The remaining groups are defined the same as in Scheme 1 or Scheme 2.

[0105] Scheme 4 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated product thereof, wherein the compound has a structure of formula (I-1):

[0106]

[0107] The condition is that when R 1 Selected from methyl, R 2 Selected from H, R 3 Selected from methyl, R 4 , R 5 Selected from H, R 6 , R 7 is selected from H, X is selected from -C-, R 8 Selected from Cl, R 9 Selected from methyl, R 10 is selected from methyl, Y is selected from -CH-, R 11 Not selected from -N(CH 3 ) 2 , trifluoroethyl, substituted by F, difluoromethoxy, cyclopropyloxy, methoxy;

[0108] Y is selected from -CH- or -N-;

[0109] The definitions of the remaining groups are the same as in Scheme 1.

[0110] Scheme 5 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0111] B is a 4-5 membered carbocyclic ring, a 6-12 membered spirocyclic ring containing 0-3 heteroatoms selected from N, S, O, and Si, a 5-10 membered bridged ring containing 0-3 heteroatoms selected from N, S, O, and Si, a 5-10 membered cyclic ring containing 0-3 heteroatoms selected from N, S, O, and Si, or a 4-5 membered heterocyclic ring, wherein the carbocyclic ring, spirocyclic ring, bridged ring, cyclic ring, or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from ═O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, amino, -C(O)C 1-4 Alkyl, hydroxy and halogen radical substitution;

[0112] The definitions of the remaining groups are the same as in Scheme 1.

[0113] Scheme 6 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0114] B is a 4-5 membered cycloalkyl, an 8-11 membered spiro ring containing 0-3 heteroatoms selected from N, S, O, and Si, a 5-8 membered bridged ring containing 0-3 heteroatoms selected from N, S, O, and Si, a 6-10 membered cyclic ring containing 0-3 heteroatoms selected from N, S, O, and Si, or a 4-5 membered heterocycloalkyl, wherein the carbocyclic ring, spirocyclic ring, bridged ring, cyclic ring, or heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from ═O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, -C(O)C 1-4 Alkyl and halogen radical substitution;

[0115] The definitions of the remaining groups are the same as in Scheme 5.

[0116] Scheme 7 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated product thereof, wherein:

[0117] B is an 8-10 membered spiro ring containing 0-3 heteroatoms selected from N, S, O, and Si, a 6-8 membered bridged ring containing 0-3 heteroatoms selected from N, S, O, and Si, or an 8-10 membered cyclic ring containing 0-3 heteroatoms selected from N, S, O, and Si, wherein the spiro ring, bridged ring, and cyclic ring are optionally substituted by 1-3 heteroatoms selected from ═O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, -C(O)C 1-4 Alkyl and halogen radical substitution;

[0118] The remaining groups are defined the same as in Scheme 5 or Scheme 6.

[0119] Scheme 8 of the present invention relates to a compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated product thereof, wherein:

[0120] R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-4 alkyl;

[0121] R 2 Selected from H;

[0122] R 3 Selected from C 1-6 Alkyl, 3-6 heterocycloalkyl, C3-6 Cycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: OH, halogen;

[0123] Alternatively, R 1 and R 2 To form a 3-6 membered cycloalkyl group; or

[0124] Alternatively, R 2 and R 3 Forming a 3-6 membered heterocycloalkyl;

[0125] The definitions of other groups are the same as those in any one of Schemes 1 to 7.

[0126] Scheme 9 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0127] R 7 Selected from H;

[0128] R 8 Selected from halogen, C 3-6 Cycloalkyl, 3-6 heterocycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 halogens; or

[0129] R 7 , R 8 Together with the atoms connected to it, it forms a 5-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 5-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0130] R 9 Selected from C 1-4 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkyl, cycloalkyl, alkoxy group is optionally substituted by 1-3 halogens;

[0131] R 10 is selected from methyl, the methyl group is optionally substituted by 1-3 -Si(C 1-4 alkyl) 3 replace;

[0132] The definitions of other groups are the same as those in any one of Schemes 1 to 8.

[0133] Scheme 10 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0134] R 1 is selected from H, cyano, methyl or cyclopropyl;

[0135] R 2 Selected from H or methyl;

[0136] R 3 Selected from oxetanyl, fluorocyclopropyl, methyl, hydroxyethyl;

[0137] Alternatively, R 2 and R 1 together to form a cyclopentyl group; or

[0138] Alternatively, R 2 and R 3 Together they form the thiolanyl group;

[0139] R 4 , R 5 Selected from H or D;

[0140] R 4' , R 5’ Together they form = O;

[0141] R 6 Selected from H;

[0142] R 7 is selected from H or halogen;

[0143] R 8 Selected from H, Cl, methoxy, cyclopropyl, oxetanyl, -Si(CH 3 ) 3 or

[0144] R 9 is selected from methyl, methoxy, trifluoromethoxy, cyclopropyl, ethynyl, -Si(CH 3 ) 3 or propynyl;

[0145] R 10 Selected from methyl or -CH 2 -Si(CH 3 ) 3 ;

[0146] The definitions of other groups are the same as those in any one of Schemes 1 to 7.

[0147] Scheme 11 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein the compound has a structure of formula (II):

[0148]

[0149] R 11 Selected from -NR 11a R 11b , =NR 11d 、-OR b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The aryl, heteroaryl, cycloalkyl, heterocycloalkyl group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0150] R 11a , R 11b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c , 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a replace;

[0151] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 cyano groups, -N(C 1-4 alkyl) 2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0152] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl group may be optionally substituted with 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace;

[0153] R 11d Selected from -O-(3-6 heterocycloalkyl);

[0154] R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH2 ) n -Si(C 1-4 alkyl) 3 , the alkyl group and alkoxy group are optionally substituted by 1-3 halogen groups, cyano groups, or hydroxy groups;

[0155] R b is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted with 1-3 halogen, -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0156] Y is selected from -CH- or -N-;

[0157] n is selected from 0, 1, 2;

[0158] Provided that the compound of formula (I) is not selected from the following compounds: when Y is selected from C:

[0159] (1)R 11 Selected from -N(CH 3 ) 2 , or

[0160] (2) If R 11a , R 11b Together with the nitrogen atom, it forms an azetidinyl group or R 11 is selected from azetidinyl, the azetidinyl being substituted by F, difluoromethoxy, cyclopropyloxy, or methoxy.

[0161] Scheme 12 of the present invention relates to a compound of formula (II), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0162] R 11 Selected from -NR 11a R 11b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0163] R 11a Selected from H, C1-4 alkyl;

[0164] R 11b Selected from -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0165] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 cyano groups, -N(C 1-4 alkyl) 2 , C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0166] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 alkyl, -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 ;

[0167] R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, cyano or hydroxyl groups;

[0168] The definitions of other groups are consistent with Scheme XI.

[0169] Scheme 13 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0170] R 11 Selected from -NR 11a R 11b ;

[0171] R 11a Selected from H, C 1-4 alkyl;

[0172] R 11b Selected from -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0173] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 cyano groups, -N(C 1-4 alkyl) 2 , C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0174] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl;

[0175] R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, cyano or hydroxyl groups;

[0176] The definitions of other groups are consistent with those in Scheme 11 or Scheme 12.

[0177] Scheme 14 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0178] R 11 is selected from 6-12 membered aryl and 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C1-4 Alkyl, -C(O)C 1-4 Alkyl substitution;

[0179] The definitions of other groups are consistent with Scheme XI;

[0180] In certain embodiments, other groups are defined in accordance with Scheme XII.

[0181] The fifteenth solution of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated product thereof, having a structure of formula (I-2), (I-3), (I-4) or (I-5),

[0182]

[0183] R 11 Selected from halogen, =O, OH, CN, =NR 11d 、-OR b 、-C(O)R 11c 、-(CH 2 ) n -NR 11a -C(O)R 11c , C 1-4 Alkyl, halogenated C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 、-S(O) 2 NR 11a R 11b 、-S(O) 2 R 11c 、-(CH 2 ) n -C(O)NR 11a R 11b 、-(CH 2 ) n -NR11a R 11b , the CH 2 , alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R 11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl substitution, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a The group substitution;

[0184] The condition is that R 11 Not selected from -N(CH 3 ) 2 , trifluoroethyl, substituted by F, difluoromethoxy, cyclopropyloxy, methoxy;

[0185] The definitions of other groups are consistent with Scheme 1.

[0186] Scheme 16 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein the compound has a structure of formula (IV):

[0187]

[0188] Cy1 is a 3-5 membered heterocycloalkyl group containing 1-3 O, N, S heteroatoms;

[0189] Y is selected from -CH- or -N-;

[0190] The definitions of other groups are consistent with those in the first embodiment.

[0191] Scheme 17 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0192] for

[0193] The definitions of other groups are consistent with those in Embodiment 16.

[0194] Scheme 18 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0195] (1) R 11 Selected from -NR 11a R 11b ;

[0196] R 11a Selected from H, D, C 1-4 Alkyl, C 1-4 Alkoxy;

[0197] R 11b Selected from D, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R 11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , wherein the heteroatom in the heterocycloalkyl contains at least one Si atom, and the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0198] R 11c Selected from C 1-4Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace; or

[0199] (2) R 11 Selected from -NR 11a R 11b ;

[0200] R 11a Selected from H, D, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0201] R 11b is selected from 3-12 membered heterocycloalkyl containing 1-3 N, O, S heteroatoms, wherein the heterocycloalkyl is optionally substituted by D, OH, cyano, alkyl, cyano, C 2-6 Alkenyl, C2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution; or

[0202] (3)R 11 Selected from -(CH 2 ) 1-3 -NR 11a R 11b 、-(CH 2 ) n -C(O)NR 11a R 11b 、-C(O)R 11c 、-OR b 、-(CH 2 ) n -NR 11a -C(O)R 11c ;

[0203] R 11a , R 11b Each independently selected from H, D, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R 11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -S(O) 2 C 1-4Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a replace;

[0204] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-12-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 R c replace;

[0205] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3replace;

[0206] R b Selected from -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C(O)-NR 11a' R 11b' The aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, alkenyl, alkynyl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN, -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0207] R c Selected from halogen, =O, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -NH(3-6 membered heterocycloalkyl), -NHC 3-6 Cycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, -O-(CH 2 ) n -(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3The alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted with 1-3 halogens, D, CN, OH, amino, C 1-4 Alkyl, C 1-4 Alkoxy substitution; or

[0208] (4) R 11 Selected from -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(8-12 membered heterocycloalkyl), -(CH 2 ) 1-3 -(4-7 membered heterocycloalkyl), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkoxy, C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R 11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 groups selected from R a or

[0209] (5) R 11 is selected from 4-7 membered heterocycloalkyl, wherein R 11 Not selected from R 11 The heterocycloalkyl group with the linking point to the B group being the N atom, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R 11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a or

[0210] (6)R 11 Selected from -NR 11a R 11b ;

[0211] R 11a With R 11b form Optionally CN, =O, OH, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 , -C 1-4 Alkyl C 1-4 Alkoxy, -C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -NH(3-6 membered heterocycloalkyl), -NHC 3-6 Cycloalkyl, -O-(CH 2 ) 1-3 -C 3-6 Cycloalkyl, -O-(CH 2 ) n -(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl)3 The alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted with 1-3 halogens, D, CN, OH, amino, C 1-4 Alkyl, C 1-4 Alkoxy substitution; or

[0212] (7) R 11 Selected from =NR 11d , R 11d Select from -OR a ;or

[0213] (8) R 11 Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 R 11c , OH, cyano-substituted alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkenyl, and alkynyl groups are optionally substituted by 1 to 3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, CN;

[0214] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace;

[0215] (9) R 11 Selected from -NR 11a R 11b ;

[0216] R 11a Selected from H, D, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0217] R 11b Selected from -(CH 2 ) 1-3 - a 3-12 membered heterocycloalkyl containing 1-3 N, O, S heteroatoms, the heterocycloalkyl being optionally substituted by D, OH, C 1-4 Alkyl, cyano-substituted alkyl, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0218] Each of the above R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0219] Each of the above R 11a' , R 11b' Each independently selected from H, D, C 1-4 Alkyl, halogen, CN, OH;

[0220] Alternatively, each of the above R 11a' , R 11b' Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0221] Each n above is 0, 1, 2, or 3;

[0222] The definitions of other groups are consistent with those in any of Schemes 1 to 10;

[0223] In certain embodiments, other groups are defined in accordance with any one of Schemes 15 to 17.

[0224] Scheme 19 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0225] (1) R 11 Selected from -NR 11a R 11b ;

[0226] R 11a Selected from H, D, C 1-4 alkyl,;

[0227] R 11b Selected from D, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -6-12 membered heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl contains at least 1 Si atom, and the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0228] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, heteroaryl groups are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0229] R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, D or cyano;

[0230] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0231] n is 0, 1, 2, or 3; or

[0232] (2) R 11 Selected from -NR 11a R 11b ;

[0233] R 11a Selected from H;

[0234] R 11b A 4-7 membered monocyclic heterocycloalkyl containing 1-3 N, O, S heteroatoms, a 5-8 membered bridged ring containing 1-3 N, O, S heteroatoms, a 5-6 membered heteroaryl containing 1-3 N, O, S heteroatoms, an 8-10 membered spiro ring containing 1-3 N, O, S heteroatoms, an 8-10 membered cyclic ring containing 1-3 N, O, S heteroatoms, wherein the monocyclic heterocycloalkyl, bridged ring, heteroaryl, spiro ring, cyclic ring are optionally substituted by 1-3 D, cyano, alkyl, cyano, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 substituted with an alkyl group; or

[0235] (3)R 11 Selected from -(CH 2 ) 1-3 -NR 11a R 11b 、-(CH 2 ) n -C(O)NR 11a R 11b 、-C(O)R 11c 、-OR b 、-(CH 2 ) n -NR 11a -C(O)R 11c ;

[0236] R 11a , R 11b Each independently selected from H, D, C 1-4 Alkyl, -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), wherein the alkyl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 R a replace;

[0237] R 11c Selected from C1-4 Alkyl, C 1-4 Alkoxy, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy substitution;

[0238] R a Selected from halogen, D, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1-3 halogens, D, or cyano;

[0239] R b Selected from -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -(3-6 membered heterocycloalkyl), -(CH 2 ) n -C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C(O)-NR 11a' R 11b' The heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, alkenyl, alkynyl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN substituted;

[0240] R 11a' , R 11b' Each independently selected from H, D, C 1-2 Alkyl, halogen;

[0241] Alternatively, R 11a' , R 11b' Together with the nitrogen atom connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, D, C 1-4Alkyl substitution;

[0242] n is 0, 1, 2, or 3; or

[0243] (4) R 11 Selected from -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-10 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(8-12 membered heterocycloalkyl), -(CH 2 ) 1-3 -(4-7 membered heterocycloalkyl), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkoxy, C 1-4 Alkyl, =O, -O-(CH 2 ) n -C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally substituted by 1-3 groups selected from R a The group substitution;

[0244] R a Selected from halogen, D, C 1-4 alkyl;

[0245] n is 0, 1, 2, 3; or,

[0246] (5) R 11 is selected from 4-6 membered heterocycloalkyl, wherein R 11 Not selected from R 11 The heterocycloalkyl group with the linking point to the B group being the N atom, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, =O, CN, OH, -C 1-4 Alkyl C 1-4 Alkoxy, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, -O-(CH 2 ) n -Si(C 1-4alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted by 1-3 halogens, D, or OH;

[0247] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0248] n is selected from 0, 1, 2, 3; or

[0249] (6)R 11 Selected from -NR 11a R 11b ;

[0250] R 11a With R 11b form Optionally CN, OH, -C 1-4 Alkyl C 1-4 Alkoxy, -N(C 1-4 alkyl) 2 、-C(O)-NR 11a' R 11b' , 3-6 membered heterocycloalkyl, -O-(CH 2 ) 1-3 -C 3-6 Cycloalkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted by 1-3 halogens, D, or OH;

[0251] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0252] n is selected from 0, 1, 2, 3; or,

[0253] (7) R 11 Selected from =NR 11d , R 11d Select from -OR a ;

[0254] R ais selected from 3-6 membered heterocycloalkyl; or

[0255] (8) R 11 Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 R 11c , OH, cyano-substituted alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 ;

[0256] R 11c Selected from C 1-4 Alkyl, -NHC 1-4 Alkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 3 halogens, C 1-4 Alkyl substitution;

[0257] n is 0, 1, 2, 3; or,

[0258] (9) R 11 Selected from -NR 11a R 11b ;

[0259] R 11a Selected from H;

[0260] R 11b Selected from -(CH 2 ) 1-3 A 4-7 membered monocyclic heterocycloalkyl containing 1-3 N, O, S heteroatoms, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 groups selected from D, C 1-4 Alkyl, cyano-substituted alkyl, cyano, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl radical substitution;

[0261] The definitions of other groups are consistent with those in Schemes 1 to 10;

[0262] In certain embodiments, other groups are defined in accordance with any one of Schemes 15 to 17.

[0263] Scheme 20 of the present invention, in certain embodiments,

[0264] (1) R 11 Selected from -NR 11a R 11b ;

[0265] R 11aSelected from H, D, C 1-4 alkyl;

[0266] R 11b Selected from D, -C(O)R 11c 、-C(O)-(CH 2 )-R 11c 、-S(O) 2 -NR 11a 'R 11b '、-S(O) 2 R 11c 、-(CH 2 ) n -5-membered heteroaryl, -(CH 2 ) n -6-membered heteroaryl, -(CH 2 ) n -3-membered monocyclic cycloalkyl, -(CH 2 ) n -4-membered monocyclic cycloalkyl, -(CH 2 ) n -5-membered monocyclic cycloalkyl, -(CH 2 ) n -6-membered monocyclic cycloalkyl, -(CH 2 ) n -6-membered monocyclic heterocycloalkyl, -(CH 2 ) n -10-membered bicyclic heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl contains at least 1 Si atom, and the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0267] R 11c Selected from C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkyl-C 1-2 Alkoxy, -NHC 1-2 Alkyl, -N(C 1-2 alkyl) 2 、-(CH 2 ) n -3-membered monocyclic cycloalkyl, -(CH 2 ) n -4-membered monocyclic cycloalkyl, -(CH 2 ) n -5-membered monocyclic cycloalkyl, -(CH 2 ) n -6-membered monocyclic cycloalkyl, -(CH 2 ) n -5-membered bicyclic cycloalkyl, -(CH 2 ) n-6-membered bicyclic cycloalkyl, -(CH 2 ) n -(4-membered heterocycloalkyl), -(CH 2 ) n -(5-membered heterocycloalkyl), -(CH 2 ) n -(6-membered heterocycloalkyl), -(CH 2 ) n -(5-membered heteroaryl), -(CH 2 ) n -(6-membered heteroaryl), -(CH 2 ) n -Si(C 1-2 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, heteroaryl groups are optionally substituted with 1-3 halogens, C 1-2 Alkyl, halogenated C 1-2 Alkyl substitution;

[0268] R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, C 1-2 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -S(O) 2 C 1-2 Alkyl, -C(O)C 1-2 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, D or cyano;

[0269] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0270] n is 0, 1; or

[0271] (2) R 11 Selected from -NR 11a R 11b ;

[0272] R 11a Selected from H;

[0273] R 11bis selected from a 4-membered monocyclic heterocycloalkyl group containing 1-3 N, O, S heteroatoms, a 5-membered monocyclic heterocycloalkyl group containing 1-3 N, O, S heteroatoms, a 6-membered monocyclic heterocycloalkyl group containing 1-3 N, O, S heteroatoms, a 5-membered bridged ring containing 1-3 N, O, S heteroatoms, a 6-membered bridged ring containing 1-3 N, O, S heteroatoms, a 7-membered bridged ring containing 1-3 N, O, S heteroatoms, an 8-membered bridged ring containing 1-3 N, O, S heteroatoms, wherein the monocyclic heterocycloalkyl group and the bridged ring are optionally substituted by 1-3 alkyl groups selected from D, cyano, cyano, -S(O) 2 C 1-2 Alkyl, -C(O)C 1-2 Alkyl radical substitution; or

[0274] (3) R 11 Selected from -(CH 2 )-NR 11a R 11b 、-(CH 2 ) n -C(O)NR 11a R 11b 、-C(O)R 11c 、-OR b 、-(CH 2 ) n -NR 11a -C(O)R 11c ;

[0275] R 11a Each independently selected from H, D, C 1-2 alkyl;

[0276] R 11b Each independently selected from C 1-2 Alkyl, -(CH 2 ) n -(5-membered heteroaryl), -(CH 2 ) n -(6-membered heteroaryl), -(CH 2 ) n -3-membered cycloalkyl, -(CH 2 ) n -4-membered cycloalkyl, -(CH 2 ) n -5-membered cycloalkyl, -(CH 2 ) n -6-membered cycloalkyl, -(CH 2 ) n -(4-membered heterocycloalkyl), -(CH 2 ) n -(5-membered heterocycloalkyl), -(CH 2 ) n-(6-membered heterocycloalkyl), wherein the alkyl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 R a replace;

[0277] R 11c Selected from C 1-2 Alkyl, C 1-2 Alkoxy, -(CH 2 ) n -3-membered cycloalkyl, -(CH 2 ) n -4-membered cycloalkyl, -(CH 2 ) n -5-membered cycloalkyl, -(CH 2 ) n -6-membered cycloalkyl, -(CH 2 ) n -(3-membered heterocycloalkyl), -(CH 2 ) n -(4-membered heterocycloalkyl), -(CH 2 ) n -(5-membered heterocycloalkyl), -(CH 2 ) n -(6-membered heterocycloalkyl), -(CH 2 ) n -(5-membered heteroaryl), -(CH 2 ) n -(6-membered heteroaryl), -(CH 2 ) n -Si(C 1-2 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy substitution;

[0278] R a Selected from halogen, D, cyano, C 1-2 Alkyl, halogenated C 1-2 Alkyl, wherein the alkyl is optionally substituted by 1-3 halogens, D, or cyano;

[0279] R b Selected from -(CH 2 ) n -(5-membered heteroaryl), -(CH 2 ) n -(6-membered heteroaryl), -(CH 2 ) n -3-membered cycloalkyl, -(CH 2 ) n -4-membered cycloalkyl, -(CH2 ) n -5-membered cycloalkyl, -(CH 2 ) n -6-membered cycloalkyl, C 1-2 Alkyl, C 2-4 Alkenyl, -(CH 2 ) n -C(O)-NR 11a' R 11b' The heteroaryl, cycloalkyl, alkyl, alkenyl may be optionally substituted with 1-3 halogens, C 1-2 Alkyl, halogenated C 1-2 Alkyl, CN substituted;

[0280] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0281] Alternatively, R 11a' , R 11b' Together with the nitrogen atom connected, it forms a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 halogens, D, C 1-2 Alkyl substitution;

[0282] n is 0, 1; or

[0283] (4) R 11 Selected from -(CH 2 ) n -phenyl, -(CH 2 ) n -5-membered heteroaryl, -(CH 2 ) n -6-membered heteroaryl, -(CH 2 ) n -8-membered heteroaryl, -(CH 2 ) n -9-membered heteroaryl, -(CH 2 ) n -10-membered heteroaryl, -(CH 2 ) n -3-membered cycloalkyl, -(CH 2 ) n -4-membered cycloalkyl, -(CH 2 ) n -5-membered cycloalkyl, -(CH 2 ) n -6-membered cycloalkyl, -(CH 2 ) n -(8-12 membered bicyclic heterocycloalkyl), -(CH 2 )-(4-membered heterocycloalkyl), -(CH2 )-(5-membered heterocycloalkyl), -(CH 2 )-(6-membered heterocycloalkyl), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-2 Alkoxy, C 1-2 Alkyl, =O, -O-(CH 2 ) n -3-membered cycloalkyl, -O-(CH 2 ) n -4-membered cycloalkyl, -O-(CH 2 ) n -5-membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally substituted by 1-3 groups selected from R a The group substitution;

[0284] R a Selected from halogen, D, C 1-2 alkyl;

[0285] n is 0, 1; or,

[0286] (5) R 11 is selected from 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, wherein R 11 Not selected from R 11 The heterocycloalkyl group with the linking point to the B group being the N atom, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, D, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy, CN, OH; or

[0287] (6)R 11 Selected from -NR 11a R 11b ;

[0288] R 11a With R 11b form Optionally CN, OH, -C 1-2 Alkyl C 1-2 Alkoxy, -N(C 1-2 alkyl) 2 、-C(O)-NR 11a' R 11b' , 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -O-(CH 2 )-3-membered cycloalkyl, -O-(CH 2 )-4-membered cycloalkyl, -O-(CH 2 )-5-membered cycloalkyl, -(CH 2 ) n -Si(C1-2 alkyl) 3 , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl may be further substituted by 1-3 halogens, D, or OH;

[0289] R 11a' , R 11b' Each independently selected from H, D, C 1-2 alkyl;

[0290] n is selected from 0, 1; or,

[0291] (7) R 11 Selected from =NR 11d , R 11d Select from -OR a ;

[0292] R a Selected from 4-membered heterocycloalkyl, 5-membered heterocycloalkyl; or

[0293] (8) R 11 Selected from C 2-6 Alkynyl, -S(O) 2 R 11c , OH, cyano-substituted alkyl, -(CH 2 ) n -Si(C 1-2 alkyl) 3 ;

[0294] R 11c Selected from C 1-2 Alkyl, -NHC 1-2 Alkyl, -(CH 2 ) n -3-membered cycloalkyl, -(CH 2 ) n -4-membered cycloalkyl, or -(CH 2 ) n -5-membered cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 halogens, C 1-2 Alkyl substitution;

[0295] n is 0, 1; or,

[0296] (9) R 11 Selected from -NR 11a R 11b ;

[0297] R 11a Selected from H;

[0298] R 11b Selected from -(CH 2)-a 4-7 membered monocyclic heterocycloalkyl containing 1-3 N, O, S heteroatoms, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 groups selected from D, C 1-2 Alkyl, cyano-substituted alkyl, cyano, -S(O) 2 C 1-2 Alkyl, -C(O)C 1-2 Alkyl radical substitution;

[0299] The definitions of other groups are consistent with those in Schemes 1 to 10;

[0300] In certain embodiments, other groups are defined in accordance with any one of Schemes 15 to 17.

[0301] The twenty-first technical solution of the present invention, in certain embodiments,

[0302] R 11 Selected from cyclopropyl, oxetanyl,

[0303]

[0304] or R 11 Selected from methoxy or hydroxy;

[0305] The definitions of other groups are consistent with those in Schemes 1 to 10;

[0306] In certain embodiments, other groups are defined in accordance with any one of Schemes 15 to 17.

[0307] Scheme 22 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0308] R 11 Selected from -NR 11a R 11b , 3-6 membered heterocycloalkyl or C 1-4 Alkyl, the heterocycloalkyl, alkyl is optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-C 1-4 Alkoxy, =O, CN, OH, -NR 11a' R 11b' 、-C(O)-NR 11a' R 11b' 、-C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl)3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, -O-(CH 2 ) n -C 3-6 Cycloalkyl, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 groups selected from R a The group substitution;

[0309] R 11a , R 11b Each independently selected from H, D, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c 、-C(O)-(CH 2 ) n -R 11c 、-S(O) 2 -NR 11a' R 11b' 、-S(O) 2 R 11c 、-(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -C 3-12 Cycloalkyl, -(CH 2 ) n -(3-12 membered heterocycloalkyl), -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a replace;

[0310] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-12-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 R c replace;

[0311] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkyl-C 1-4 Alkoxy, amino, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -(3-6 membered heterocycloalkyl), -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -(6-12 membered aryl), -(CH 2 ) n -(5-12 membered heteroaryl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl, aryl, heteroaryl groups are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 replace;

[0312] R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogen, D, cyano, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0313] R 11a' , R 11b' Each independently selected from H, D, C 1-4 Alkyl, halogen, CN, OH;

[0314] Alternatively, R 11a' , R 11b' Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogens, D, CN, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0315] n is 0, 1, 2, or 3;

[0316] The definitions of other groups are consistent with those in Schemes 5 to 7.

[0317] Scheme 23 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0318] R 1 is selected from H, cyano, methyl or cyclopropyl;

[0319] R 2 Selected from H or methyl;

[0320] R 3 Selected from oxetanyl, fluorocyclopropyl, methyl, hydroxyethyl;

[0321] Alternatively, R 2 and R 1 together to form a cyclopentyl group; or

[0322] Alternatively, R 2 and R 3 Together they form the thiolanyl group;

[0323] R 4 , R 5 Selected from H;

[0324] R 4' , R 5’ Together they form = O;

[0325] R6 Selected from H;

[0326] R 7 is selected from H or halogen;

[0327] R 8 Selected from H, Cl, methoxy, cyclopropyl, oxetanyl, -Si(CH 3 ) 3 or

[0328] R 9 is selected from methyl, methoxy, trifluoromethoxy, cyclopropyl, ethynyl, -Si(CH 3 ) 3 or propynyl;

[0329] R 10 Selected from methyl or -CH 2 -Si(CH 3 ) 3 ;

[0330] The definitions of other groups are consistent with Scheme 20.

[0331] Scheme 24 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein the compound has a structure of formula (III):

[0332]

[0333] Ring A is a 5-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 5-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0334] Y is selected from -CH- or -N-;

[0335] The definitions of other groups are consistent with Scheme 1.

[0336] Scheme 25 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0337] The structure is as follows: The A ring may be optionally replaced by 1-3 C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution;

[0338] The definitions of other groups are consistent with Scheme 24.

[0339] Scheme 26 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0340] R 11 Selected from -NR 11a R 11b ;

[0341] R 11a Selected from H, C 1-4 alkyl;

[0342] R 11b Selected from -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a replace;

[0343] Alternatively, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1-3 cyano groups, -N(C 1-4 alkyl) 2 , C 1-4 Alkoxy, halogenated C 1-4 Alkoxy substitution;

[0344] R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl;

[0345] R a Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 halogens, cyano or hydroxyl groups;

[0346] The definitions of other groups are consistent with Scheme 24 or Scheme 25.

[0347] Scheme 27 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0348] R 11 Selected from -NR 11a R 11b ;

[0349] R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms an azetidinyl group, wherein the azetidinyl group is optionally substituted by 1-3 C 1-4 Alkoxy substitution;

[0350] The definitions of other groups are consistent with those in Embodiment 24 or Embodiment 25.

[0351] Scheme 28 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein the compound has a structure of formula (V):

[0352]

[0353] R 8 Selected from CN, -NR 8a R 8b -、-NR 8a -C(O)-C 1-4 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heterocycloalkyl, heteroaryl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, OH substitution;

[0354] R 8a , R 8b Each independently selected from H or C 1-4 alkyl;

[0355] Y is selected from -CH- or -N-;

[0356] The definitions of other groups are consistent with those in the first embodiment.

[0357] Scheme 29 of the present invention relates to a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, a cocrystal or a deuterated substance thereof, wherein:

[0358] R 1 Selected from C 1-4 Alkyl, CN, C 3-6 Cycloalkyl;

[0359] R 2 Selected from H, C 1-4 alkyl;

[0360] R 3Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 of the following groups: D, OH, halogen;

[0361] Alternatively, R 1 and R 2 To form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally substituted with 1-3 halogens, D, C 1-4 Alkyl substitution; or

[0362] Alternatively, R 2 and R 3 To form a 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-3 halogens, D, C 1-4 Alkyl substitution;

[0363] R 4 , R 5 Each independently selected from H, D;

[0364] R 4' , R 5’ Together with the common carbon atom, it forms a 4-5 membered heterocycloalkyl group; or

[0365] R 4' With R 5’ co-form = O;

[0366] R 6 Selected from H;

[0367] R 7 is selected from H, halogen;

[0368] R 9 Selected from C 1-4 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 The alkyl, cycloalkyl, alkoxy group is optionally substituted with 1-3 halogens, D, C 1-4 Alkyl substitution;

[0369] R 10 Selected from C 1-4 Alkyl, wherein the alkyl is optionally substituted by 1-3 -(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0370] The definitions of other groups are consistent with those in Embodiment 28.

[0371] In certain embodiments of the present invention, R 1 Selected from H, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl; In certain embodiments of the present invention, R 1 Selected from C 1-4 In certain embodiments of the present invention, R 1 Selected from cyano, C 3-6 Cycloalkyl; In certain embodiments of the present invention, R 1 Selected from C 3-6 Cycloalkyl; In certain embodiments of the present invention, R 1 is selected from H, cyano, cyclopropyl, methyl; in certain embodiments of the present invention, R 1 Selected from methyl.

[0372] In certain embodiments of the present invention, R 2 Select from H or C 1-4 In certain embodiments of the present invention, R 2 is selected from H, methyl; in certain embodiments of the present invention, R 2 Selected from H.

[0373] In certain embodiments of the present invention, R 3 Selected from C 1-6 Alkyl, 3-6 heterocycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl or heterocycloalkyl is optionally substituted by 1-3 of the following groups: OH, halogen; in certain embodiments of the present invention, R 3 Selected from methyl, oxetanyl, hydroxyethyl, In certain embodiments of the present invention, R 3 Selected from C 1-6 In certain embodiments of the present invention, R 3 Selected from methyl.

[0374] In certain embodiments of the present invention, R 1 and R 2 To form a 3-6 membered cycloalkyl, the cycloalkyl is optionally substituted by 1-3 halogens; in certain embodiments of the present invention, R 1 and R 2 A cyclopentyl group is formed.

[0375] In certain embodiments of the present invention, R 2 and R 3 To form a 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1-3 halogens, OH, or amino groups; in certain embodiments of the present invention, R 2 and R 3 The sulfur atom connected to it forms a thiocyclopentyl group.

[0376] In certain embodiments of the present invention, R 4 , R 5 Each independently selected from H, C 1-4 In certain embodiments of the present invention, R 4 , R 5 are each independently selected from H.

[0377] In certain embodiments of the present invention, R 4' , R 5’ and the common carbon atom to form an oxetane group; in certain embodiments, R 4' With R 5’ Together they form =O.

[0378] In certain embodiments of the present invention, R 6 In certain embodiments of the present invention, R 6 Selected from methyl.

[0379] In certain embodiments of the present invention, R 7 is selected from H|, F, Cl; in certain embodiments of the present invention, R 7 Selected from H|.

[0380] In certain embodiments of the present invention, R 8 Selected from H, halogen, C 3-6 Cycloalkyl, 3-6 heterocycloalkyl, C 1-4 Alkoxy, wherein the alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1-3 F, Cl; in certain embodiments of the present invention, R 8 Selected from H, methoxy, cyclopropyl, Cl, oxetanyl, In certain embodiments of the present invention, R 8 Selected from Cl.

[0381] In certain embodiments of the present invention, R 7 , R 8 Together with the atoms connected to it, it forms C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 6-12 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, halogenated C 1-4 In certain embodiments of the present invention, R 7 , R 8 Together with the atoms connected to it, it forms a 5-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 5-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 C 1-4 Alkyl, halogenated C 1-4 Alkyl substitution.

[0382] In certain embodiments of the present invention, R 9 Selected from C 1-4 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, -Si(C 1-4 alkyl) 3 , the alkyl, cycloalkyl, alkoxy group is optionally substituted by 1-3 F, Cl; in certain embodiments of the present invention, R 9 Selected from C 1-4 In certain embodiments of the present invention, R 9 is selected from methyl, trifluoromethoxy, methoxy, cyclopropyl, ethynyl, propynyl; in certain embodiments of the present invention, R 9 Selected from methyl.

[0383] In certain embodiments of the present invention, R 10 is selected from methyl, ethyl; in certain embodiments of the present invention, R 10 In certain embodiments of the present invention, R 10 is selected from methyl, the methyl group is optionally replaced by -Si(CH 3 ) 3 replace.

[0384] In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b , =NR 11d 、-OR b 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group is optionally substituted with 1-3 halogen, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b 、-ORb 、-C(O)R 11c , C 2-6 Alkynyl, 6-12 membered aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted with 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b , 6-12 membered aryl, 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b In certain embodiments of the present invention, R 11 is selected from 6-12 membered aryl and 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, -C(O)C 1-4 In certain embodiments of the present invention, R 11 is selected from 5-10 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, -C(O)C 1-4 In certain embodiments of the present invention, R 11 Selected from cyclopropyl, oxetanyl,

[0385]

[0386]

[0387] In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b ; R 11a Selected from H, D, C 1-4 Alkyl; R 11b Selected from -(CH 2 ) n -C 3-12 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 R a Replacement; R a Selected from halogen, D, OH, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, wherein the alkyl or alkoxy group is optionally substituted by 1-3 halogen, D, or cyano; n is 0, 1, 2, or 3; in certain embodiments, R 11 Selected from -NR 11a R 11b ; R 11a Selected from H, D, C 1-2 Alkyl; R 11b Selected from -(CH 2 ) n -3-membered monocyclic cycloalkyl, -(CH 2 ) n -4-membered monocyclic cycloalkyl, -(CH 2 ) n -5-membered monocyclic cycloalkyl, the cycloalkyl group is optionally substituted by 1-3 R a Replacement; R a Selected from F, Cl, D, OH, cyano, C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, the alkyl and alkoxy groups are optionally substituted by 1-3 F, Cl, D, and cyano groups; n is 0 or 1.

[0388] In certain embodiments of the present invention, R 11 Selected from -NR 11a R 11b ; R 11a Selected from H; R 11b is selected from a 4-7 membered monocyclic heterocycloalkyl containing 1-3 N, O, S heteroatoms, wherein the monocyclic heterocycloalkyl is optionally substituted by 1-3 D, cyano, alkyl, cyano, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl substituted; in certain embodiments, R 11 Selected from -NR 11a R 11b ; R 11a Selected from H, D; R 11b It is selected from a 4-membered monocyclic heterocycloalkyl group containing 1-3 N, O, and S heteroatoms, a 5-membered monocyclic heterocycloalkyl group containing 1-3 N, O, and S heteroatoms, and a 6-membered monocyclic heterocycloalkyl group containing 1-3 N, O, and S heteroatoms, wherein the monocyclic heterocycloalkyl group is optionally substituted by 1-3 groups selected from D, alkyl substituted by cyano, and cyano.

[0389] In certain embodiments of the present invention, R 11 Selected from -(CH 2 ) n-C 3-12 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 groups selected from the following groups: halogen, D, C 1-4 Alkoxy, C 1-4 Alkyl, =O, -O-(CH 2 ) n -C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally substituted by 1-3 groups selected from R a The group substituted; R a Selected from halogen, D, C 1-4 alkyl.

[0390] In certain embodiments of the invention, n is 0 or 1; in certain embodiments of the invention, n is 0; in certain embodiments of the invention, n is 1.

[0391] In certain embodiments of the present invention, R 11a , R 11b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)R 11c , 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl group may be optionally substituted with 1 to 3 R a Substitution; in certain embodiments, R 11a Selected from H, C 1-4 alkyl; in certain embodiments, R 11b Selected from -C(O)R 11c , 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11b Selected from -C(O)R 11c , 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -S(O) 2 C 1-4 Alkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a Substitution; in certain embodiments, R11b Selected from -C(O)R 11c In certain embodiments, R 11b is selected from 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 R a Substitution; in certain embodiments, R 11a , R 11b Together with the nitrogen atom to which it is connected, it forms a 3-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11a , R 11b Together with the nitrogen atom to which it is attached, it forms an azetidinyl, azacyclopentyl, or azacyclohexyl group, optionally substituted by 1 to 3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -O-(CH 2 ) n -Si(C 1-4 alkyl) 3 、-(CH 2 ) n -Si(C 1-4 alkyl) 3 replace;

[0392] In certain embodiments of the present invention, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, amino, -NHC 1-4Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -(CH 2 ) n -Si(C 1-4 alkyl) 3 The alkyl, alkoxy, heterocycloalkyl, cycloalkyl group may be optionally substituted with 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-(3-6 membered heterocycloalkyl), -Si(C 1-4 alkyl) 3 Substitution; in certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 , -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, wherein the alkyl, alkoxy, heterocycloalkyl, cycloalkyl are optionally substituted with 1-3 halogen, cyano, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-NH(3-6 membered heterocycloalkyl)、-NHC 3-6 Cycloalkyl, -OC 3-6 In certain embodiments, R 11c Selected from C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl) 2 , -NH(3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl; In certain embodiments, R 11c Selected from methyl, methoxy, methylamino.

[0393] In certain embodiments of the present invention, Ra Selected from halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O) 2 C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -(CH 2 ) n -Si(C 1-4 alkyl) 3 , the alkyl group or alkoxy group is optionally substituted by 1-3 halogen groups, cyano groups, or hydroxy groups; in certain embodiments, R a Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, the alkyl and alkoxy groups are optionally substituted by 1-3 halogens, cyano and hydroxyl groups.

[0394] In certain embodiments of the present invention, R b is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted with 1-3 halogen, -(CH 2 ) n -Si(C 1-4 alkyl) 3 In certain embodiments, R b is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkyl are optionally substituted by 1-3 halogens.

[0395] In certain embodiments of the present invention, R 11d Selected from -O-oxetanyl.

[0396] In certain embodiments of the present invention, X is selected from -C- or -N-; in certain embodiments, X is selected from -C-.

[0397] The compounds of formula (I-1), (Ia), (I-2), (I-3), (I-4), (I-5), (II), (III), (IV), (V) of the present invention, their stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated substances, in certain embodiments, Y is selected from -CH- or -N-; in certain embodiments, Y is selected from -CH-; in certain embodiments, Y is selected from -N-.

[0398] Scheme 30 of the present invention relates to compounds of formula (I), (Ia), (I-1), (I-2), (I-3), (I-4), (I-5), (II), (III), (IV), (V), and stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals, or deuterated derivatives thereof, wherein the compound is selected from one of the following structures:

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414] The present invention also relates to a pharmaceutical composition comprising the compound of the present invention, its stereoisomer, pharmaceutically acceptable salt, solvate, cocrystal or deuterated substance, and pharmaceutically acceptable excipients and / or carriers.

[0415] The present invention also relates to the use of the compound of the present invention, its stereoisomer, pharmaceutically acceptable salt, solvate, cocrystal or deuterated substance, or the pharmaceutical composition in the preparation of a drug for treating an EZH2-mediated disease, wherein the EZH2-mediated disease is a tumor or an autoimmune disease.

[0416] The present invention also relates to a therapeutic method for treating an EZH2-mediated disease, which comprises administering the compound of the present invention, its stereoisomer, pharmaceutically acceptable salt, solvate, cocrystal or deuterated substance, or the pharmaceutical composition, wherein the EZH2-mediated disease is a tumor or an autoimmune disease.

[0417] Synthetic route

[0418] Patent document WO2019204490A1 introduces a method for preparing a class of EZH2 inhibitors. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, and the starting materials are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0419] Reference books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide reference to articles describing such preparation methods. These reference books and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4thEdition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModernCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2ndEdition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial OrganicChemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes;and“Chemistry of FunctionalGroups”John Wiley&Sons,in 73volumes.

[0420] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis factories, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0421] the term

[0422] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0423] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0424] "Halo" or "halogen substituted" means substituted by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be substituted by the same or different halogens.

[0425] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; the alkyl group may be further substituted by any substituent.

[0426] "Deuterated" refers to the situation where the hydrogen atoms on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, etc. are replaced by at least one isotope deuterium, and the upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms are replaced, more preferably 1-10 deuterium atoms are replaced, more preferably 1-6 deuterium atoms are replaced, and further preferably 1-3 deuterium atoms are replaced.

[0427] "Cycloalkyl" refers to a monovalent saturated or unsaturated non-aromatic carbon ring hydrocarbon group, which may be a monocyclic, bicyclic, spirocyclic, bridged, or fused ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, The cycloalkyl group may be further substituted by any substituent.

[0428] The bicyclic ring described in the present invention includes a spiro ring, a bridged ring or a fused ring.

[0429] "Heterocycloalkyl" refers to a substituted or unsubstituted, saturated or unsaturated non-aromatic ring. When not specifically limited, it contains 1 to 3 heteroatoms selected from N, O, P, Si or S. It can be a monocyclic, bicyclic, bridged, fused or spirocyclic ring. When not specifically limited, it is a 3-12-membered heterocyclic ring, more preferably a 4-12-membered heterocyclic ring, and more preferably a 4-10-membered heterocyclic ring. The N, S, and P selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. Non-limiting examples include heterocyclopropyl, oxacyclopropyl, thicyclopropyl, azetidinyl, azopentyl, piperidine, oxetanyl, oxolanyl, oxhexyl, thibutyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocycloalkyl group may be further substituted by any substituent.

[0430] "Aryl" refers to a substituted or unsubstituted 5 to 15-membered aromatic carbon ring, including monocyclic aromatic groups and condensed aromatic groups. Preferably, the aromatic ring is 5 to 10 members, and more preferably, the aromatic ring is 5 to 8 members. Non-limiting examples thereof include phenyl, naphthyl, anthracenyl, and phenanthrenyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0431]

[0432] The aryl group may be optionally further substituted by any substituent.

[0433] "Heteroaryl" refers to a substituted or unsubstituted 5-15-membered aromatic ring containing 1 to 5 heteroatoms selected from N, O, P, Si or S and various oxidized forms of heteroatoms, preferably a 5-10-membered heteroaromatic ring, and more preferably a 5-8-membered heteroaromatic ring. Non-limiting examples of heteroaryl include, but are not limited to, furanyl, oxazolyl, furanyl, thienyl, N-alkylpyrrolyl, pyrazinyl, pyridazinyl, piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include The heteroaryl group may be optionally further substituted by any substituent.

[0434] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0435] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples are ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0436] "Alkoxy" or "alkyloxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0437] "Haloalkoxy" refers to -O-haloalkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0438] "Alkylamino" or "alkylamino" refers to an amino group substituted with one or two alkyl groups, also written as -N-(alkyl) 2 Or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0439] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0440] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0441] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0442] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0443] "Excipient" refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0444] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0445] "Solvate" refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0446] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates. DETAILED DESCRIPTION

[0447] The content of the present invention will be described in detail below through examples. If no specific conditions are specified in the examples, the experimental method according to conventional conditions is carried out. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Those skilled in the art can make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still belongs to the protection scope of the present invention.

[0448] Test Method

[0449] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard was tetramethylsilane (TMS);

[0450] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0451] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0452] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0453] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0454] Intermediate 1 and Intermediate 2

[0455] 7-Chloro-2,4-dimethyl-2-(4-carbonylcyclohexyl)benzo[d][1,3]dioxane-5-carboxylic acid methyl ester

[0456] methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate

[0457]

[0458] first step:

[0459] Dissolve methyl 3,4-dihydroxy-2-methylbenzoate (5.11 g, 27.9 mmol) in tetrahydrofuran (200 mL). Slowly add sulfonyl chloride (2.45 mL, 30.6 mmol) at -20 ° C. After the addition is complete, continue to stir at -20 ° C for 3 h. After the reaction is completed by TLC monitoring, quench the reaction with saturated ammonium chloride solution (50 mL), and extract the residue with ethyl acetate (25 mL × 3). The organic phase is backwashed with saturated brine (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound 1b (4.12 g, 68%).

[0460] LC-MS (ESI): m / z = 217.1 [M+H] + .

[0461] Step 2:

[0462] Dissolve 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (1.2g, 5.53mmol), triruthenium dodecacarbonyl (176mg, 0.28mmol), and triphenylphosphine (145mg, 0.55mmol) in toluene (8.1mL) in turn. Heat under reflux for half an hour under nitrogen protection. Dissolve 4-ethynylcyclohexyl-1-one (1.34g, 11mmol) in toluene (17mL) and add it to the reaction system, reflux and stir for 23h. After the reaction is completed, the reaction system is cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain compound 1d (1.33g, 70%).

[0463] LC-MS (ESI): m / z = 361.1 [M+H] + .

[0464] Step 3:

[0465] Compound 1d was separated by chiral preparative HPLC to obtain intermediate 1 and intermediate 2. Chiral preparative separation conditions: preparative instrument Waters UPCC with PDA Detector, preparative column Chiralpak AY-3 150×4.6mm ID, 3um, mobile phase system: A:CO 2 ; B: isopropanol (0.05% DEA), peak position: intermediate 1: 2.871 min, intermediate 2: 2.904 min.

[0466] LC-MS (ESI): m / z = 361.1 [M+H] + .

[0467] Intermediate 3 and Intermediate 4

[0468] 7-Chloro-2,4-dimethyl-2-(piperidin-4-yl)benzo[d][1,3]dioxane-5-carboxylic acid methyl ester hydrochloride

[0469] methyl 7-chloro-2,4-dimethyl-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylate hydrochloride

[0470]

[0471] first step:

[0472] Compound 3a (50.0 g, 234.4 mmol) was dissolved in methanol (400 mL), and a methanol solution (400 mL) of dimethyl (1-diazo-2-oxopropyl)phosphonate (45.0 g) was added dropwise at 0°C. After addition, the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (2.0 L), and stirred for 10 minutes. After filtering, the filter cake was washed twice with ethyl acetate, and the combined filtrate was concentrated under reduced pressure and separated by column chromatography to obtain compound 3b (47 g, 95.8%).

[0473] Step 2:

[0474] 3b (82 g, 378.5 mmol) was dissolved in toluene (1.5 L), 1b (158.4 g, 757.0 mmol) was added, nitrogen was replaced three times, and PPh 3 (9.9 g, 37.9 mmol) and triruthenium dodecacarbonyl (12.1 g, 18.9 mmol), after addition, nitrogen was replaced again 3 times and then the temperature was raised to 90°C and stirred overnight. After the reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure and the residue was separated and purified by column chromatography to obtain compound 3c (33.2 g, 20.6%).

[0475] 1 H NMR(400MHz,DMSO-d6)δ7.45(s,1H),3.79(s,3H),7.74-7.65(m,2H),2.32(s,3H) ),2.16-2.10(m,1H),1.75(d,2H),1.65(s,3H),1.38(s,9H),1.25-1.16(m,4H).

[0476] Step 3:

[0477] Compound 3c (33.2 g, 78.0 mmol) was placed in a 1L single-mouth bottle, and hydrochloric acid-1,4-dioxane (4M, 400 mL) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with EA / EtOH = 10 / 1 to obtain compound racemate 3d (24.8 g, 87.8%).

[0478] 1 H NMR(400MHz,DMSO-d6)δ7.45(s,1H),3.79(s,3H),3.11(d,2H),2.60(t,2H),2.3 2(s,3H),2.14-2.08(m,1H),1.77-1.74(m,2H),1.66(s,3H),1.42-1.33(m,2H).

[0479] LC-MS (ESI): m / z = 326.2 [M+H] + .

[0480] Step 4:

[0481] Compound 3d was separated by chiral preparative HPLC to obtain intermediates 3 and 4. Chiral preparative separation conditions: preparative instrument Waters UPC2 analytical SFC (SFC-H), preparative column ChiralCel OX, 100×4.6mm ID, 3μm, mobile phase system: A:CO 2 ; B: ethanol (0.05% DEA), peak position: intermediate 3: 3.882 min, intermediate 4: 4.229 min.

[0482] Intermediate 5

[0483] 3-(Methylamino)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride

[0484] 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-onehydrochloride

[0485]

[0486] Intermediate 5 was prepared according to the method of patent WO2019094552.

[0487] Intermediate 6

[0488] 3-(Aminomethyl-d2)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 6)

[0489] 3-(aminomethyl-d2)-6-methyl-4-(methylthio)pyridin-2(1H)-onehydrochloride

[0490]

[0491] first step:

[0492] Add 30 mL of toluene to sodium tert-butoxide (16.6 g, 172 mmol) and replace with nitrogen three times. Add acetone (5.00 g, 86 mmol) dropwise at 0°C. After the addition is complete, slowly add carbon disulfide (6.6 g, 86 mmol) dropwise at 0-5°C. After the addition is complete, keep the temperature at 0°C and react for 4 hours. After the reaction is complete, filter and dry the filter cake to obtain compound 6b (12.8 g, crude product), which is directly used in the next step without further purification.

[0493] Step 2:

[0494] Compound 6b (12.8 g, 72 mmol) was dissolved in 100 ml of methanol, and iodomethane (20.5 g, 142 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 70 °C and the reaction was allowed to react for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove methanol. 200 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and crystallized from petroleum ether to obtain compound 6c (5.3 g, 45%).

[0495] LC-MS (ESI): m / z = 163.1 [M+H] + .

[0496] Step 3:

[0497] Compound 6c (5.3 g, 32.7 mmol) and cyanoacetamide (2.75 g, 32.7 mmol) were dissolved in 50 mL of tert-butanol, and potassium tert-butoxide (4.03 g, 36.0 mmol) was added. After the addition, the temperature was raised to 80 ° C and stirred for 12 hours. After the reaction was completed, 20 mL of water was added, and then the pH was adjusted to 5-6 with 1N hydrochloric acid. After stirring for 30 minutes, it was filtered and the filter cake was dried to obtain compound 6d (4.6 g, 78%).

[0498] LC-MS (ESI): m / z = 181.1 [M+H] + .

[0499] Step 4:

[0500] Compound 6d (1.0 g, 5.5 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C under nitrogen protection, and lithium tetradeuterium aluminum (236.0 mg, 5.6 mmol) was added. After stirring for 30 minutes, 10% aqueous sodium hydroxide solution (1 mL) was slowly added dropwise to quench the reaction. The reaction solution was filtered and the filtrate was concentrated to obtain compound 6e (0.9 g).

[0501] LC-MS (ESI): m / z = 187.1 [M+H] + .

[0502] Step 5:

[0503] Compound 6e (0.9 g, 4.8 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (0.97 g, 9.6 mmol), (Boc) 2 O (1.26 g, 5.8 mmol) was added and reacted at room temperature for 15 hours. After the reaction, 10 mL of water was added, and the residue was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate compound 6f (0.9 g, 65%).

[0504] LC-MS (ESI): m / z = 287.1 [M+H] + .

[0505] Step 6:

[0506] Compound 6f (0.9 g, 3.1 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in dioxane (5 mL) was added. The mixture was stirred at room temperature for 5 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain intermediate 6 (310 mg, 45%).

[0507] LC-MS (ESI): m / z = 187.1 [M+H] + .

[0508] 1 H NMR (400 MHz, D 2 O)δ6.49(s,1H),2.63(s,3H),2.40(s,3H).

[0509] Example 1

[0510] 7-Chloro-2-(4-(3-(dimethylamino)acridin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxy-5-carboxamide (Compound 1)

[0511] 7-chloro-2-(4-(3-(dimethylamino)azetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0512]

[0513] first step:

[0514] At room temperature, dichloromethane (4 mL), N,N-dimethylazetidinamine (0.14 g, 0.77 mmol), and two drops of glacial acetic acid were added to intermediate 2 (0.2 g, 0.59 mmol) in sequence, and stirred for 1 h. Sodium triacetylborohydride (0.25 g, 1.2 mmol) was added, and stirred at room temperature for 2 h. Water and dichloromethane were added for extraction, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1B (0.22 g, 88%).

[0515] LC-MS (ESI): m / z = 423.3 [M + H] + .

[0516] Step 2:

[0517] At room temperature, methanol (10 mL) and 2 mol / L sodium hydroxide (2.5 mL) were added to 1B (0.22 g, 0.52 mmol) in sequence, and stirred at 65°C for 2 h. After the reaction was cooled to room temperature, the pH was adjusted to 5-6 with 3N hydrochloric acid, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product 1C (0.2 g, 94%).

[0518] LC-MS (ESI): m / z = 409.3 [M+H]+ .

[0519] Step 3:

[0520] At room temperature, intermediate 5 (0.11 g, 0.49 mmol), DCM (4 mL), HATU (2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 0.19 g, 0.49 mmol), N,N-diisopropylethylamine (0.2 g, 1.59 mmol) were added to 1C (0.2 g, 0.49 mmol) in sequence, and stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by preparative HPLC to obtain isomer 1 of compound 1 (0.04 g, 14%) and isomer 2 of compound 1 (0.04 g, 14%).

[0521] Preparative HPLC separation method: 1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. Dissolve the sample in DMF and filter with a 0.45μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 1% TFA); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate 12ml / min; d. Elution time 20min.

[0522] Isomer 1 retention time: 14.8 min;

[0523] 1 H NMR (400 MHz, CDCl 3 )δ12.32(s,1H),7.16-7.13(t,1H),6.90(s,1H),6.02(s,1H),4.60-4.59(d,2H),3.56(s,2H),2.88-2.86(m,2H),2.48(s,3H),2 .30(s,3H),2.26(s,3H),2.10(s,6H),1.93-1.86(m,5H),1.81-1.78(m,1H),1.59(s,3H),1.26-1.16(m,3H),1.09-0.99(m,2H).

[0524] LC-MS (ESI): m / z = 575.3 [M + H] + .

[0525] Isomer 2 retention time: 15.2min:

[0526] 1H NMR (400 MHz, CDCl 3 )δ12.36(s,1H),7.16-7.13(t,1H),6.89(s,1H),6.02(s,1H),4.60-4.59(d,2H),3.44(s,2H),2.78-2.76(m,2H),2.48 (s,3H),2.30(s,3H),2.27(s,3H),2.13(s,6H),1.81-1.71(m,5H),1.59(s,3H),1.58-1.53(m,3H),1.30-0.26(m,3H).

[0527] LC-MS (ESI): m / z = 575.3 [M + H] + .

[0528] Example 2

[0529] 7-Chloro-2-(4-(3-cyanoacridin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxy-5-carboxamide (Compound 2)

[0530] 7-chloro-2-(4-(3-cyanoazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0531]

[0532] first step:

[0533] At room temperature, dichloromethane (4 mL), 3-cyanoazetidinamine (0.1 g, 0.84 mmol), and two drops of glacial acetic acid were added to intermediate 2 (0.22 g, 0.65 mmol) in sequence, and stirred for 1 h. Sodium triacetylborohydride (0.28 g, 1.3 mmol) was added, and stirred at room temperature for 2 h. Water and dichloromethane were added for extraction, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column to obtain 2B (83 mg, 31.7%) and 2C (90 mg, 34.3%) (eluent: ethyl acetate / petroleum ether = 0%-60% to obtain 2B, ethyl acetate / petroleum ether = 80% to obtain 2C).

[0534] LC-MS (ESI): m / z = 405.2 [M + H] + .

[0535] Step 2:

[0536] At room temperature, methanol (5 mL) and 2 mol / L sodium hydroxide (1.2 mL) were added to 2B (0.083 g, 0.2 mmol) in sequence, and stirred at 65°C for 2 h. The pH was adjusted to 5-6 with 3N hydrochloric acid, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product 2D (0.08 g, 100%).

[0537] LC-MS (ESI): m / z = 391.2 [M+H] + .

[0538] At room temperature, methanol (5 mL) and 2 mol / L sodium hydroxide (1.2 mL) were added to 2C (0.09 g, 0.2 mmol) in sequence, and stirred at 65°C for 2 h. The pH was adjusted to 5-6 with 3N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2E (0.085 g, 98%).

[0539] LC-MS (ESI): m / z = 391.2 [M+H] + .

[0540] Step 3:

[0541] At room temperature, intermediate 5 (0.05 g, 0.22 mmol), DCM (4 mL), HATU (0.086 g, 0.22 mmol), N,N-diisopropylethylamine (0.08 g, 0.66 mmol) were added to 2D (0.08 g, 0.2 mmol) in sequence. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain isomer 1 of compound 2 (0.04 g, 35%).

[0542] 1 H NMR (400 MHz, CDCl 3)δ12.26(s,1H),7.08-7.06(t,1H),6.89(s,1H),6.03(s,1H),4.59-4.58(d,2H),3.51(s,2H),3.19-3.17(m,2H),2.48(s ,3H),2.32(s,3H),2.26(s,3H),1.82-1.78(m,1H),1.66-1.63(m,3H),1.59(s,3H),1.57-1.49(m,4H),1.34-1.27(m,3H).

[0543] LC-MS (ESI): m / z = 557.2 [M+H] + .

[0544] At room temperature, intermediate 5 (0.056 g, 0.24 mmol), DCM (4 mL), HATU (0.09 g, 0.24 mmol), N,N-diisopropylethylamine (0.09 g, 0.72 mmol) were added to 2E (0.085 g, 0.218 mmol) in sequence. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain isomer 2 of compound 2 (0.04 g, 30%).

[0545] 1 H NMR (400 MHz, CDCl 3 )δ12.09(s,1H),7.06-7.04(t,1H),6.90(s,1H),6.04(s,1H),4.59-4.57(d,2H),3.61-3.60(m,2H),3.30-3.27(m,2H),2.48(s,3H),2 .32(s,3H),2.26(s,3H),2.03-2.00(m,1H),1.93-1.90(m,2H),1.81-1.78(m,3H),1.60(s,3H),1.26-1.17(m,3H),1.02-0.93(m,2H).

[0546] LC-MS (ESI): m / z = 557.2 [M+H] + .

[0547] Example 3

[0548] 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2,-dihydropyridin-3-yl)methyl)-2-(4-(((3-methyloxetan-3-yl)methyl)amino)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxamide trifluoroacetate (Compound 3)

[0549] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(((3-methyloxetan-3-yl)methyl)amino)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamideTrifluoroacetic acid

[0550]

[0551] first step:

[0552] At room temperature, dichloromethane (4 mL), (3-methyloxetan-3-yl)methylamine (0.078 g, 0.77 mmol), and two drops of glacial acetic acid were added to intermediate 2 (0.2 g, 0.59 mmol) in sequence, and stirred for 1 h. Sodium triacetylborohydride (0.25 g, 1.2 mmol) was added, and stirred at room temperature for 2 h. Water and dichloromethane were added for extraction, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3B (0.22 g, 88%).

[0553] LC-MS (ESI): m / z = 424.2 [M + H] + .

[0554] Step 2:

[0555] At room temperature, methanol (10 mL) and 2 mol / L sodium hydroxide (2.5 mL) were added to 3B (0.22 g, 0.52 mmol) in sequence, and stirred at 65°C for 2 h. The pH was adjusted to 5-6 with 3N hydrochloric acid, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3C (0.2 g, 94%).

[0556] LC-MS (ESI): m / z = 410.2 [M+H] + .

[0557] Step 3:

[0558] At room temperature, intermediate 5 (0.11 g, 0.49 mmol), DCM (4 mL), HATU (0.19 g, 0.49 mmol), N,N-diisopropylethylamine (0.2 g, 1.59 mmol) were added to 3C (0.2 g, 0.49 mmol) in sequence. Stir at room temperature for 2 hours, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. Separation and purification by preparative HPLC gave isomer 1 of compound 3 (0.04 g, 12%) and isomer 2 of compound 3 (0.015 g, 5%). Preparative HPLC separation method: 1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm×250 mm). 2. The sample was dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparation of chromatographic conditions: a. Composition of mobile phase A, B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate 12 ml / min; d. Elution time 20 min.

[0559] Retention time of isomer 1 of compound 3: 14.2 min;

[0560] 1 H NMR (400MHz, DMSO) δ11.51(s,1H),8.31(s,2H),8.01(t,1H),6.88(s,1H),6. 08(s,1H),4.38(d,2H),4.27(d,2H),4.24(d,2H),3.26-3.24(m,2H),3.13-3 .15(m,1H),2.45(s,3H),2.17(s,3H),2.15(s,3H),2.15–2.11(m,2H),1.96- 1.94(m,3H),1.62(s,3H),1.47–1.34(m,2H),1.33(s,3H),1.31–1.18(m,2H).

[0561] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0562] Retention time of isomer 2 of compound 3: 14.6 min;

[0563] 1H NMR(400MHz,DMSO)δ11.51(s,1H),8.30(s,2H),8.01(t,1H),6.89(s,1H),6.08(s,1H),4.38(d,2H),4.28-4.25(m, 4H),3.31-3.29(m,3H),2.45(s,3H),2.17(s,6H),2.03-2.00(m,3H),1.72-1.68(m,6H),1.62(s,3H),1.38(s,3H).

[0564] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0565] Example 4

[0566] 7-Chloro-2-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxane-5-carboxamide (Compound 4)

[0567] 7-chloro-2-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0568]

[0569] first step:

[0570] Intermediate 2 (400 mg, 1.18 mmol) was dissolved in DCM (10 mL), and 3,3-difluorocyclobutylamine hydrochloride (4A, 186 mg, 1.30 mmol) and a drop of glacial acetic acid were added in sequence. After stirring at room temperature for 2 h, sodium triacetylborohydride (751 mg, 3.54 mmol) was added, and the reaction was continued at room temperature for 3 h. Water (30 mL) was added to the reaction solution, and ethyl acetate (50 mL×2) was used for extraction. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4B (400 mg) as a yellow solid.

[0571] LC-MS (ESI): m / z = 430.1 [M+H] + .

[0572] Step 2:

[0573] Compound 4B (500 mg, 1.16 mmol) was dissolved in THF / MeOH / H 2 O=1 / 1 / 1 mixed solvent (6mL), potassium hydroxide (979mg, 17.45mmol) was added, and the reaction was refluxed overnight. After the reaction was cooled to room temperature, dilute hydrochloric acid was added to adjust the pH to about 4, and water (50mL) was added for dilution, and ethyl acetate (70mL×2) was used for extraction. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4C (400mg) as a yellow solid.

[0574] LC-MS (ESI): m / z = 416.1 [M+H] + .

[0575] Step 3:

[0576] Compound 4C (400 mg, 0.96 mmol) was dissolved in DCM (16 mL), and intermediate 5 (354 mg, 1.92 mmol), HATU (548 mg, 1.44 mmol), and DIEA (N,N-diisopropylethylamine, 372 mg, 2.89 mmol) were added thereto in sequence, and the mixture was reacted at room temperature for 4 h. Water (30 mL) and ethyl acetate (50 mL × 2) were added for extraction, and the mixture was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid crude compound 4 (400 mg). The crude compound 4 (400 mg) was separated by preparative HPLC under the following separation conditions: Instrument: waters 2767 preparative liquid phase; Chromatographic column: XSelect@CSHPrep (19 mm × 150 mm). The sample was dissolved in water and filtered with a 0.45 μm filter head to prepare a sample solution. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 0.3% ammonia water). Gradient elution, mobile phase A content from 30% to 75%, flow rate 12mL / min, elution time 20min. Isomer 1 of compound 4 (retention time 15.30min, 100mg, 18%) and isomer 2 of compound 4 (retention time 15.8min, 50mg, 9%) were separated.

[0577] Isomer 1 of compound 4:

[0578] LC-MS (ESI): m / z = 582.1 [M+H] + .

[0579] 1 H NMR (400MHz, CD 3OD)δ6.88(s,1H),6.27(s,1H),4.49(s,2H),3.28-3.25(m,1H),2.81-2.71(m,2H),2.52(s,3H),2.4 6-2.27(m,6H),2.18(s,3H),1.98-1.83(m,5H),1.60(s,3H),1.33-1.23(m,2H),1.16-1.07(m,2H).

[0580] Isomer 2 of compound 4:

[0581] LC-MS (ESI): m / z = 582.1 [M+H] + .

[0582] 1 H NMR (400 MHz, CDCl 3 )δ6.88(s,1H),6.27(s,1H),4.49(s,2H),3.23-3.20(m,1H),2.87-2.74(m,3H),2.52(s,3H ),2.42-2.29(m,5H),2.20(s,3H),1.93-1.87(m,1H),1.81-1.79(m,2H),1.69-1.48(m,9H).

[0583] Example 5

[0584] 7-Chloro-2-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxy-5-carboxamide (Compound 5)

[0585] 7-chloro-2-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0586]

[0587] first step:

[0588] In a 50 mL single-necked bottle, intermediate 3 (230 mg, 0.64 mmol) and DMF (6 mL) were added to dissolve, triethylamine (193 mg, 1.91 mmol) and HATU (365 mg, 0.96 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Then, 3,3-difluorocyclobutane-1-carboxylic acid (131 mg, 0.96 mmol) was added, and the mixture was stirred at room temperature for 1 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with EA (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain yellow solid 5B (230 mg, 81% yield).

[0589] LC-MS (ESI): m / z = 444.1 [M + H] + .

[0590] In a 50 mL single-necked bottle, intermediate 4 (230 mg, 0.64 mmol) and DMF (6 mL) were added to dissolve, triethylamine (193 mg, 1.91 mmol) and HATU (365 mg, 0.96 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. 3,3-difluorocyclobutane-1-carboxylic acid (131 mg, 0.96 mmol) was added, and the mixture was stirred at room temperature for 1 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with EA (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain yellow solid 5C (230 mg, 81% yield).

[0591] LC-MS (ESI): m / z = 444.1 [M + H] + .

[0592] Step 2:

[0593] In a 50mL single-mouth bottle, 5B (230mg, 0.52mmol) and methanol (8mL) were added to dissolve, and then NaOH (104mg, 2.60mmol, 2mL) aqueous solution was added and stirred at 25°C. TLC monitored the complete reaction of the raw material. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product. The crude product was soaked with a mixed solvent (DCM:MeOH=10:1, 20mL), then filtered, and the filtrate was concentrated to obtain 5D (180mg, 81%).

[0594] LC-MS (ESI): m / z = 430.1 [M+H] + .

[0595] 5C (230 mg, 0.52 mmol) and methanol (8 mL) were added to a 50 mL single-mouth bottle to dissolve, and then NaOH (104 mg, 2.60 mmol, 2 mL) aqueous solution was added and stirred at 25 ° C. TLC monitored the reaction of the raw material. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product. The crude product was soaked in a mixed solvent (DCM: MeOH = 10: 1, 20 mL), then filtered, and the filtrate was concentrated to obtain 5E (180 mg, 81% yield).

[0596] LC-MS (ESI): m / z = 430.1 [M+H] + .

[0597] Step 3:

[0598] 5D (180 mg, 0.42 mmol) and DMF (6 mL) were added to a 50 mL single-necked bottle to dissolve, triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 0.5 h, and intermediate 5 (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain isomer 1 of compound 5 (100 mg, yield 40%).

[0599] LC-MS (ESI): m / z = 596.2 [M+H] + .

[0600] 1 H NMR (400 MHz, DMSO-d 6 )δ11.49(s,1H),8.00(t,1H),6.87(s,1H),6.07(s,1H),4.45-4.48(m,1H),4.27(d,2H),3.80-3.83(m,1H),321-3.25(m,1H),2.92-2.98 (m,1H),2.67-2.78(m,4H),2.53-2.57(m,2H),2.44(s,3H),2.17(s,3H),2.14(s,3H),1.77-1.79(m,2H),1.61(s,3H),1.17-1.29(m,2H).

[0601] 5E (180 mg, 0.42 mmol) was added to a 50 mL single-mouth bottle, dissolved in DMF (6 mL), triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol), stirred at room temperature for 0.5 h, intermediate 5 (186 mg, 0.84 mmol) was added, and stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, extracted with EA (20 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain isomer 2 of compound 5 (60 mg, yield 24%).

[0602] LC-MS (ESI): m / z = 596.2 [M+H] + .

[0603] 1 H NMR (400 MHz, DMSO-d 6 )δ11.51(s,1H),8.00(t,1H),6.87(s,1H),6.08(s,1H),4.45-4.48(m,1H),4.27(d,2H),3.80-3.83(m,1H),321-3.25(m,1H),2.92-2.98 (m,1H),2.67-2.78(m,4H),2.53-2.57(m,2H),2.45(s,3H),2.17(s,3H),2.14(s,3H),1.77-1.79(m,2H),1.61(s,3H),1.17-1.29(m,2H).

[0604] Example 6

[0605] 7-Chloro-2-(4-(3,3-difluorocyclobutane-1-carboxamido)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxane-5-carboxamide (Compound 6)

[0606] 7-chloro-2-(4-(3,3-difluorocyclobutane-1-carboxamido)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0607]

[0608] first step:

[0609] At room temperature, anhydrous ethanol (30 mL), ammonium acetate (1 g), sodium triacetoxyborohydride (1.9 g, 8.88 mmol) were added to intermediate 2 (1.0 g, 2.96 mmol) in sequence, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (50 mL), the pH value was adjusted to 7-8 with potassium carbonate, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with water (30 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6A (0.6 g, 60%).

[0610] LC-MS (ESI): m / z = 340 [M + H] + .

[0611] Step 2:

[0612] At room temperature, DMF (10 mL), 3,3-difluorocyclobutane-1-carboxylic acid (150 mg, 1.11 mmol), HATU (421 mg, 1.11 mmol), DIPEA (N,N-diisopropylethylamine, 286 mg, 2.22 mmol) were added to compound 6A (250 mg, 0.74 mmol) in sequence, and stirred at room temperature for 1 hour. Water (30 mL) was added to quench the reaction, and ethyl acetate (50 mL × 2) was used for extraction. The combined organic phase was washed with water (30 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6B (250 mg, 73%).

[0613] LC-MS (ESI): m / z = 458 [M + H] + .

[0614] Step 3:

[0615] At room temperature, methanol (10 mL), water (10 mL), and sodium hydroxide (250 mg) were added to compound 6B (250 mg, 0.54 mmol) in sequence, and the mixture was heated under reflux for 3 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to remove most of the methanol, and water (30 mL) was added to the residue, and extracted with ethyl acetate (50 mL × 1). The aqueous phase was adjusted to pH 5-6 with 3N hydrochloric acid, and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 6C (200 mg, 84%).

[0616] LC-MS (ESI): m / z = 444 [M + H] + .

[0617] Step 4:

[0618] At room temperature, THF (20 mL), HOBt (1-hydroxybenzotriazole, 92 mg, 0.68 mmol), EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide, 130 mg, 0.68 mmol), intermediate 5 (180 mg, 0.82 mmol), triethylamine (212 mg, 2.1 mmol) were added to compound 6C (200 mg, 0.45 mmol) in sequence, and stirred at room temperature for 4 hours. The reaction solution was poured into (30 mL) water, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product separated by chiral preparative HPLC. Separation conditions: Instrument: Gilson GX-281 preparative liquid phase; Chromatographic column: CHIRALPAK@AD_H (19 mm × 250 mm); The sample was dissolved in ethanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatographic conditions: mobile phase A: n-hexane, mobile phase B: isopropanol; isocratic elution, mobile phase A: 30%; flow rate: 9 mL / min; elution time 20 min.

[0619] Isomer 1 of compound 6 was obtained (35 mg, yield 12%), with the elution time being about 17 min.

[0620] LC-MS (ESI): m / z = 610 [M+H] + .

[0621] 1 H NMR (400 MHz, DMSO-d 6 )δ11.49(s,1H),8.03-7.97(m,1H),7.90(d,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),3.46(s,1H),2.86-2.73(m ,1H),2.70-2.58(m,4H),2.45(s,3H),2.17(s,3H),2.14(s,3H),1.89-1.80(m,5H),1.60(s,3H),1.25-1.13(m,4H).

[0622] Isomer 2 of compound 6 was obtained (25 mg, yield 9%), with the elution time being about 18 min.

[0623] LC-MS (ESI): m / z = 610.3 [M+H] + .

[0624] 1 H NMR (400 MHz, DMSO-d 6)δ11.50(s,1H),8.02-7.95(m,1H),7.89(d,J=6.5Hz,1H),6.86(s,1H),6.08(s,1H),4.27(d,J=4.4Hz,2H),3.82(s,1H),3.0 4-2.84(m,1H),2.75-2.57(m,4H),2.45(s,3H),2.17(s,3H),2.15(s,3H),1.92-1.69(m,3H),1.61(s,5H),1.51-1.36(m,4H).

[0625] Example 7

[0626] 7-Chloro-2-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3)-yl)methyl)benzo[d][1,3]dioxane-5-carboxamide (Compound 7)

[0627] 7-chloro-2-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0628]

[0629] first step:

[0630] The intermediate compound 3 (250 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL), and cyclopropylcarbonyl chloride (108 mg, 1.04 mmol) and potassium carbonate (144 mg, 1.04 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated and separated by column chromatography to obtain compound 7B (257 mg, 94%).

[0631] LC-MS (ESI): m / z = 394.1 [M+H] + .

[0632] Step 2:

[0633] Compound 7B (257 mg, 0.65 mmol) was dissolved in methanol (5 mL), and a solution of sodium hydroxide (130 mg, 3.25 mmol) in water (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, dilute hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound 7D (320 mg).

[0634] LC-MS (ESI): m / z = 380.1 [M+H] + .

[0635] Step 3:

[0636] The crude product of compound 7D (320 mg) was dissolved in DMF (5 mL), and DIPEA (277 mg, 2.15 mmol), HATU (371 mg, 0.98 mmol), and intermediate 5 (186 mg, 0.85 mmol) were added thereto in sequence, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product obtained after reduced pressure concentration was further separated and purified by preparative HPLC to obtain isomer 1 of compound 7 (80 mg, total yield of the second and third steps was 22%). Preparative HPLC separation conditions: preparative instrument Waters 2767, preparative column SunFire C18; mobile phase system: acetonitrile: 1% trifluoroacetic acid water; peak position 11.73 min.

[0637] LC-MS (ESI): m / z = 546.2 [M+H] + .

[0638] 1 H NMR(400MHz,Chloroform-d)δ12.26(s,1H),7.14(s,1H),6.92(s,1H),6.04 (s,1H),4.72(s,1H),4.59(d,2H),4.31(s,1H),3.05(s,1H),2.53(s,1H),2 .48(s,3H),2.31(s,3H),2.26(s,3H),2.11(t,1H),1.89(s,2H),1.73(t,1H ),1.43(d,2H),1.28(d,2H),0.97(s,2H),0.91–0.81(m,1H),0.74(dd,2H).

[0639] Referring to the synthesis of isomer 1 of compound 7, intermediate 4 was used as a raw material to obtain isomer 2 of enantiomeric compound 7. Preparative HPLC separation conditions: preparative instrument Waters 2767, preparative column SunFire C18; mobile phase system: acetonitrile: 1% trifluoroacetic acid water; peak position 12.68 min.

[0640] LC-MS (ESI): m / z = 546.2 [M+H] + .

[0641] 1 H NMR(400MHz,Chloroform-d)δ12.26(s,1H),7.14(s,1H),6.92(s,1H),6.04 (s,1H),4.72(s,1H),4.59(d,2H),4.31(s,1H),3.05(s,1H),2.53(s,1H),2. 48(s,3H),2.31(s,3H),2.26(s,3H),2.11(tt,1H),1.89(s,2H),1.73(tt,1 H),1.43(d,2H),1.28(d,2H),0.97(s,2H),0.91-0.81(m,1H),0.74(dd,2H).

[0642] Example 8

[0643] 7-Chloro-2,4-dimethyl-2-(4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxane-5-carboxamide (Compound 8)

[0644] 7-chloro-2,4-dimethyl-2-(4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0645]

[0646] first step:

[0647] Add intermediate 2 (0.40 g, 1.18 mmol) and THF (10 mL) to a 100 mL three-necked flask. Add LDA (lithium diisopropylamide, 1.77 mL, 1.77 mmol, 1M in THF) dropwise at -78 °C. After 1 h of reaction, add a tetrahydrofuran solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.50 g, 1.42 mmol). After addition, naturally warm to room temperature and stir for 16 h. Quench the reaction with saturated aqueous ammonium chloride (30 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (PE:EA=10:1) to obtain a colorless transparent liquid 8A (0.25 g, 45% yield).

[0648] 1 H NMR (400 MHz, CDCl 3 )δ7.56(s,1H),5.80-5.74(m,1H),3.86(s,3H),2.49-2.33(m,6H),2.30-2.18(m,2H),2.11(d,1H),1.68(s,3H),1.26(d,1H).

[0649] Step 2:

[0650] 8A (200 mg, 0.425 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (133 mg, 0.437 mmol), potassium carbonate (117 mg, 0.850 mmol), water (1.5 mL) and ethylene glycol dimethyl ether (6 mL) were added in sequence into a 50 mL single-mouth bottle. Under nitrogen protection, the reaction temperature was raised to 80 ° C and stirred for 4 hours. After TLC monitoring, the reaction mixture was cooled to room temperature, concentrated, and 10 mL of water was added. The reaction mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (PE: EA = 5: 1) to obtain a white solid 8B (0.16 g, 93% yield).

[0651] LC-MS (ESI): m / z = 403.1 [M+H] + .

[0652] Step 3:

[0653] Substrate 8B (0.16 g, 0.40 mmol) was added to a 50 mL single-necked bottle and dissolved in methanol (10 mL). Palladium carbon (0.1 g) and dioxane hydrochloride (1 mL, 4 mol / L) were added. The mixture was stirred at room temperature for 1.0 h under a hydrogen atmosphere, filtered, and concentrated to obtain a crude product 8C (160 mg) which was directly used in the next step reaction.

[0654] LC-MS (ESI): m / z = 405.1 [M+H] + .

[0655] Step 4:

[0656] 8C (160 mg, 0.40 mmol), MeOH (10 mL), and NaOH aqueous solution (2N, 5 mL) were added to a 50 mL single-mouth bottle in sequence and stirred at room temperature for 16 h. HCl (2 M) was added dropwise to adjust the pH to 3-4, and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oil 8D (110 mg) which was directly used in the next step.

[0657] LC-MS (ESI): m / z = 391.1 [M+H] + .

[0658] Step 5:

[0659] 8D (110 mg, 0.28 mmol) was added to a 50 mL single-mouth bottle, dissolved in DCM (10 mL), and triethylamine (84 mg, 0.85 mmol) and HATU (128 mg, 0.338 mmol) were added. Stir at room temperature for 0.5 h, and intermediate 5 (93 mg, 0.50 mmol) was added. Stir at room temperature for 5 h, water (10 mL) was added to the reaction solution, and DCM (10 mL×3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, and the crude product obtained after concentration under reduced pressure was separated by preparative HPLC to obtain isomer 1 of compound 8 (28 mg, yield 18%) and isomer 2 of compound 8 (2.0 mg, yield 1%).

[0660] LC-MS (ESI): m / z = 557.2 [M+H] + .

[0661] 1. Preparative HPLC separation conditions: Instrument: Gilson GX-281 preparative liquid phase; Chromatographic column: CHIRALPAK@AD_H (19mm×250mm). 2. The sample was dissolved in ethanol and filtered with a 0.45μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: n-hexane; Mobile phase B: isopropanol; b. Isocratic elution, mobile phase A: 30%; c. Flow rate: 9mL / min; d. Elution time 60min. Retention time: Isomer 1 (35min), Isomer 2 (55min).

[0662] Isomer 1: 1 H NMR (400 MHz, CDCl 3)δ7.37(s,1H),7.21(s,1H),7.15(s,1H),6.92(s,1H),6.07(s,1H),4.61(s,2H),3.90(s,3H),3.00(s, 1H),2.50(s,3H),2.33(s,3H),2.25(s,3H),1.99(d,3H),1.72(d,4H),1.60(d,3H),1.55-1.41(m,3H).

[0663] Isomer 2: 1 H NMR (400 MHz, CDCl 3 )δ7.49(s,1H),7.24(s,1H),6.88(s,1H),6.47(s,1H),6.41(s,1H),4.63(d,2H),4.01(s,3H),2.56 (s,3H),2.51(d,3H),2.27-2.21(m,3H),2.03(dd,5H),1.90(s,1H),1.65(s,3H),1.44-1.22(m,5H).

[0664] Example 9

[0665] 7-Chloro-2-(4-((trans-3-methoxycyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxane-5-carboxamide (Compound 9)

[0666] 7-chloro-2-(4-((trans-3-methoxycyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0667]

[0668] first step:

[0669] Compound 9A (1.0 g, 8.09 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (5.59 g, 40.5 mmol) and benzyl bromide (2.91 g, 16.99 mmol) were added, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, and most of the acetonitrile was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (50 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (E: EA = 3: 1) to obtain a white solid 9B (2.0 g, 93% yield).

[0670] LC-MS (ESI): m / z = 268.3 [M + H] + .

[0671] Step 2:

[0672] Compound 9B (0.60 g, 2.24 mmol) was dissolved in 100 mL THF, and NaH (0.294 g, 6.73 mmol) was slowly added at room temperature, stirred for 0.5 hours, and iodomethane (1.59 g, 11.2 mmol) was added, and continued to stir at room temperature for 2 hours. After the reaction was complete, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate was used for extraction (30 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 9C (0.6 g), which was directly used in the next step.

[0673] LC-MS (ESI): m / z = 282.3 [M + H] + .

[0674] Step 3:

[0675] Compound 9C (0.60 g) was dissolved in 20 mL of methanol, palladium carbon (300 mg) was added, and the mixture was stirred at room temperature overnight under a hydrogen balloon atmosphere. After the reaction was complete, the mixture was filtered, the filter cake was washed with methanol, 4N hydrochloric acid dioxane (1 mL) was added to the filtrate, and the crude compound 9D (0.20 g) was obtained after concentration under reduced pressure, which was directly used in the next step.

[0676] LC-MS (ESI): m / z = 102.3 [M + H] + .

[0677] Step 4:

[0678] Dissolve the crude compound 9D (0.2 g) in 1,2-dichloroethane (20 mL), add intermediate 2 (0.44 g, 1.29 mmol) and acetic acid (100 mg, 1.61 mmol), stir at room temperature for 1.0 h, add NaBH(OAc) 3(1.38 g, 6.5 mmol). Stir at room temperature for 2 h, add water to quench, add saturated sodium bicarbonate aqueous solution to adjust the pH to 8-9, extract with DCM (2×100 mL), and the combined organic phases are dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (DCM: MeOH = 20:1) to obtain cis-trans isomers 9E (100 mg, yield 19%) and intermediate 9F (250 mg, yield 47%).

[0679] LC-MS (ESI): m / z = 424.1 [M+H] + .

[0680] Step 5:

[0681] Intermediate 9E (0.10 g, 0.236 mmol) was dissolved in MeOH (6 mL) and NaOH aqueous solution (2N, 3 mL) and stirred at room temperature for 16 h. The pH was adjusted to 6-7 with dilute hydrochloric acid (2 M), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oil 9G (90 mg) which was directly used in the next step.

[0682] LC-MS (ESI): m / z = 410.2 [M+H] + .

[0683] Step 6:

[0684] 9G (90 mg, 0.22 mmol) was added to a 50 mL single-mouth bottle, dissolved in DCM (10 mL), triethylamine (74 mg, 0.73 mmol) and HATU (111 mg, 0.29 mmol), stirred at room temperature for 0.5 h, intermediate 5 (93 mg, 0.50 mmol) was added, and continued to stir at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and DCM (10 mL × 2) was used for extraction three times. The combined organic phase was dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was separated by preparative HPLC to obtain isomer 1 of compound 9 (35 mg, yield 28%).

[0685] Preparative HPLC separation conditions: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm); The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 1% TFA); b. Gradient elution, mobile phase A content from 20% to 60%; c. Flow rate 12ml / min; d. Elution time 20min; Retention time 16min.

[0686] LC-MS (ESI): m / z = 576.2 [M+H] + .

[0687] 1 H NMR (400 MHz, CDCl 3 )δ6.94(t,1H),6.88(s,1H),6.05(s,1H),4.57(d,2H),4.07-3.96(m,1H),3.66-3.59(m,1H),3.22(s,3H),2 .97(s,2H),2.48(s,3H),2.33(s,3H),2.24(s,7H),1.96-1.80(m,3H),1.77-1.62(m,3H),1.62-1.46(m,7H).

[0688] Referring to the synthesis method of isomer 1 of compound 9, isomer 2 of compound 9 (60 mg, yield 21%) was obtained using 9F (250 mg) as the raw material.

[0689] 1 H NMR (400MHz, CDCl3) δ6.97(s,1H),6.90(s,1H),6.02(s,1H),4.58(d,3H),4.02(s,1H),3.68(s,1H) ,3.22(s,4H),2.57(s,1H),2.48(s,3H),2.32(d,3H),2.26(d,6H),2.11-1.80(m,8H),1.58(s,5H).

[0690] Example 10

[0691] 7-Chloro-2-(1-((3,3-difluorocyclobutyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylmercapto)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclic-5-amide (Compound 10)

[0692] 7-chloro-2-(1-((3,3-difluorocyclobutyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0693]

[0694] first step:

[0695] In a 50 mL single-mouth bottle, add intermediate 3 (0.3 g, 0.9 mmol), dissolve in dichloromethane (10 mL), add 3,3-difluorocyclobutylcarboxaldehyde (0.3 g, 3.0 mmol), acetic acid (60 mg, 0.9 mmol), stir at room temperature for 1 h, add sodium triacetylborohydride (0.4 g, 2.0 mmol), stir at room temperature for 3 h. Quench the reaction with saturated sodium bicarbonate solution (20 mL), extract with dichloromethane (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain colorless oil 10B (0.34 g, 90% yield).

[0696] LC-MS (ESI): m / z = 430.1 [M+H] + .

[0697] Step 2:

[0698] 10B (0.34 g, 0.79 mmol), MeOH (2 mL), THF (2 mL) and water (2 mL) were added to a 50 mL single-mouth bottle to dissolve, and NaOH (0.16 g, 4.0 mmol) was added and stirred at room temperature for 16 h. The pH was adjusted to 3-4 with dilute hydrochloric acid (2 M), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid 10D (0.3 g, 91% yield).

[0699] LC-MS (ESI): m / z = 416.1 [M+H] + .

[0700] Step 3:

[0701] 10D (0.12 g, 0.29 mmol) was added to a 50 mL single-mouth bottle, dissolved in DMF (5 mL), triethylamine (88 mg, 0.87 mmol) and HATU (0.13 g, 0.35 mmol) were added, and stirred at room temperature for 0.5 h. Intermediate 5 (80 mg, 0.43 mmol) was added, and stirred at room temperature for 16 h. Water (10 mL) was added to the reaction solution, and EA (10 mL × 2) was used for extraction twice. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain isomer 1 of compound 10 (0.040 g, 24% yield).

[0702] LC-MS (ESI): m / z = 582.2 [M+H] + .

[0703] 1 H NMR (400 MHz, CDCl 3)δ12.01(s,1H),7.12(t,1H),6.90(s,1H),6.02(s,1H),4.59(d,2H),3.05-2.85(m,2H),2.68-2 .66(m,2H),2.48(s,5H),2.33-2.29(m,3H),2.25(s,5H),1.98(s,2H),1.82(d,4H),1.61(s,3H).

[0704] Referring to compound 10, the synthesis method of isomer 1 uses intermediate 4 as a raw material to obtain isomer 2 of compound 10.

[0705] LC-MS (ESI): m / z = 582.2 [M+H] + .

[0706] Embodiment 11

[0707] 7-Chloro-2-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxy-5-carboxamide (Compound 11)

[0708] 7-chloro-2-(1-(3,3-difluorocyclobutane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0709]

[0710] first step:

[0711] Intermediate 3 (200 mg, 0.55 mmol) was dissolved in DMF (6 mL), potassium carbonate (152 mg, 1.10 mmol) and bromomethylcyclopropane (149 mg, 1.10 mmol) were added thereto, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and EA (20 mL) was used for extraction three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain a yellow solid 11B (190 mg, 91% yield).

[0712] LC-MS (ESI): m / z = 380.2 [M+H] + .

[0713] Intermediate 4 (200 mg, 0.55 mmol) was dissolved in DMF (6 mL), potassium carbonate (152 mg, 1.10 mmol) and bromomethylcyclopropane (149 mg, 1.10 mmol) were added thereto, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and EA (20 mL) was used for extraction three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain yellow solid 11C (190 mg, 91% yield).

[0714] LC-MS (ESI): m / z = 380.2 [M+H] + .

[0715] Step 2:

[0716] 5B (190 mg, 0.50 mmol) was dissolved in methanol (8 mL), and an aqueous solution of NaOH (201 mg, 5.00 mmol, 2 mL) was added. The reaction was stirred at 25°C, and the reaction was completed by TLC monitoring. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product. The crude product was soaked in a mixed solvent (DCM: MeOH = 10:1, 20 mL), and then filtered. The filtrate was concentrated to obtain 11D (180 mg, 95%).

[0717] LC-MS (ESI): m / z = 380.2 [M+H] + .

[0718] 11C (190 mg, 0.50 mmol) was dissolved in methanol (8 mL), and NaOH (201 mg, 5.00 mmol, 2 mL) aqueous solution was added, and the reaction was stirred at 25°C. TLC monitored the reaction of the raw material. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product. The crude product was soaked in a mixed solvent (DCM: MeOH = 10:1, 20 mL), then filtered, and the filtrate was concentrated to obtain 11E (180 mg, 95%).

[0719] LC-MS (ESI): m / z = 380.2 [M+H] + .

[0720] Step 3:

[0721] 11D (180 mg, 0.47 mmol) and DMF (6 mL) were added to a 50 mL single-mouth bottle to dissolve, triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 5 (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain isomer 1 of compound 11 (110 mg, yield 44%).

[0722] LC-MS (ESI): m / z = 532.2 [M+H] + .

[0723] 1 H NMR (400 MHz, DMSO-d 6 )δ11.50(s,1H),8.00(t,1H),6.86(s,1H),6.08(s,1H),4.28(d,2H),3.04(d,2H),2.45(s,3H),2.17(s,3H),2.15(s,3H),2.12-2.16( m,2H),1.87-1.91(m,3H),1.69-1.72(m,2H),1.62(s,3H),1.34-1.41(m,2H),0.80-0.83(m,1H),0.43-0.46(m,2H),0.01-0.06(m,2H).

[0724] 11E (180 mg, 0.47 mmol) and DMF (6 mL) were added to a 50 mL single-mouth bottle to dissolve, triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 5 (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain isomer 2 of compound 11 (60 mg, yield 24%).

[0725] LC-MS (ESI): m / z = 532.2 [M+H] + .

[0726] 1 H NMR (400 MHz, DMSO-d 6)δ11.49(s,1H),8.00(t,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),3.01(d,2H),2.45(s,3H),2.17(s,3H),2.14(s,3H),2.12-2.16( m,2H),1.82-1.87(m,3H),1.69-1.72(m,2H),1.62(s,3H),1.33-1.42(m,2H),0.78-0.81(m,1H),0.41-0.44(m,2H),0.00-0.05(m,2H).

[0727] Example 12

[0728] 7-Chloro-2-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 12)

[0729] 7-chloro-2-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0730]

[0731] first step:

[0732] Compound 12A (682 mg, 4.63 mmol), dichloromethane (20 mL), intermediate 3 (400 mg, 1.10 mmol), and glacial acetic acid (66 mg, 1.10 mmol) were added to a 50 mL single-necked bottle in sequence and stirred at room temperature for 5 h. NaBH(OAc) was added. 3 (700 mg, 3.30 mmol), stirred at room temperature for 1 h. Quenched with water, adjusted pH to 8-9 with saturated sodium bicarbonate, extracted with DCM (3×50 mL), combined organic phases, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20:1) to obtain yellow viscous liquid 12B (120 mg, yield 26%).

[0733] LC-MS (ESI): m / z = 416.1 [M+H] + .

[0734] Compound 12A (682 mg, 4.63 mmol), dichloromethane (20 mL), intermediate 4 (400 mg, 1.10 mmol), and glacial acetic acid (66 mg, 1.10 mmol) were added to a 50 mL single-necked bottle in sequence and stirred at room temperature for 5 h. NaBH(OAc) was added. 3 (700 mg, 3.30 mmol), stirred at room temperature for 1 h, quenched with water, adjusted the pH to 8-9 with saturated sodium bicarbonate, extracted with DCM (3×50 mL), combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM:MeOH=20:1) to obtain 12C (80 mg, yield 18%) as a yellow viscous liquid.

[0735] LC-MS (ESI): m / z = 416.1 [M+H] + .

[0736] Step 2:

[0737] 12B (120 mg, 0.29 mmol) and methanol (8 mL) were added to a 50 mL single-mouth bottle to dissolve, and then NaOH (116 mg, 2.9 mmol, 2 mL) aqueous solution was added, and the reaction was stirred at 25°C. TLC monitored the complete reaction of the raw material. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product 12D (220 mg, 100%), which was directly used in the next step.

[0738] LC-MS (ESI): m / z = 402.1 [M+H] + .

[0739] 12C (80 mg, 0.19 mmol) and methanol (8 mL) were added to a 50 mL single-mouth bottle to dissolve, and then NaOH (76 mg, 1.9 mmol, 2 mL) aqueous solution was added, and the reaction was stirred at 25°C. TLC monitored the complete reaction of the raw material. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product 12E (130 mg, 100%), which was directly used in the next step.

[0740] LC-MS (ESI): m / z = 402.1 [M+H] + .

[0741] Step 4:

[0742] In a 50 mL single-mouth bottle, crude product containing 12D (116 mg, 0.29 mmol), DMF (6 mL), triethylamine (88 mg, 0.87 mmol), HATU (165 mg, 0.44 mmol) were added in sequence and stirred at room temperature for 0.5 h. Intermediate 5 (128 mg, 0.58 mmol) was added and stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the isomer 1 of compound 12 (30 mg, yield 44%) was separated by column chromatography (DCM: MeOH = 20: 1).

[0743] LC-MS (ESI): m / z = 568.2 [M+H] + .

[0744] 1 H NMR (400 MHz, DMSO-d 6 )δ11.49(s,1H),8.02(t,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),2.84-2.86(m,2H),2.57-2.67(m,3H),2.44(s,3H ),2.29-2.41(m,2H),2.16(s,3H),2.14(s,3H),1.86-1.92(m,1H),1.71-1.76(m,4H),1.62(s,3H),1.30-1.40(m,2H).

[0745] In a 50 mL single-mouth bottle, crude 12E (76 mg, 0.19 mmol), DMF (6 mL), triethylamine (58 mg, 0.57 mmol), HATU (108 mg, 0.29 mmol) were added in sequence and stirred at room temperature for 0.5 h. Intermediate 5 (84 mg, 0.38 mmol) was added and stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain isomer 2 of compound 12 (25 mg, yield 23%).

[0746] LC-MS (ESI): m / z = 568.2 [M+H] + .

[0747] 1 H NMR (400 MHz, DMSO-d 6)δ8.00(t,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),2.84-2.86(m,2H),2.57-2.67(m,3H),2.45(s,3H),2.30 -2.42(m,2H),2.17(s,3H),2.14(s,3H),1.86-1.92(m,1H),1.71-1.76(m,4H),1.62(s,3H),1.30-1.40(m,2H).

[0748] Example 13

[0749] 4-(7-Chloro-2,4-dimethyl-5-((((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxin-2-yl)-N-methylpiperidine-1-carboxamide (Compound 13)

[0750] 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)-N-methylpiperidine-1-carboxamide

[0751]

[0752] Step 1: 7-Chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (13A)

[0753] Methyl-7-chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylate

[0754]

[0755] Dissolve intermediate 3 (0.4 g, 1.23 mmol) in dichloromethane (10 mL), add DMAP (0.075 g, 0.61 mmol), DIEA (1.58 g, 12.28 mmol), triphosgene (0.73 g, 2.46 mmol), and react in an ice bath for 2 hours. Add methylamine hydrochloride (0.38 g, 12.28 mmol), and react at room temperature for 12 hours. Add toluene (10 mL), and react at 80°C for 6 hours. The reaction mixture was cooled to room temperature, and water (30 mL) was added to the reaction solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 7-chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (13A) as a yellow solid (0.4 g, yield 85%).

[0756] LCMS (ESI): m / z = 383.1 [M+1] + .

[0757] Step 2: 7-Chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid (13B)

[0758] 7-chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[0759]

[0760] 7-Chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (13A) (0.3 g, 0.78 mmol) was dissolved in a tetrahydrofuran / methanol / water (v / v / v=1 / 1 / 1) mixed solvent (12 mL), and sodium hydroxide (0.31 g, 7.84 mmol) was added, and the mixture was reacted at room temperature for 4 hours. Hydrochloric acid solution (6 mol / L) was added to the reaction solution until pH=2, and ethyl acetate was added for extraction (50 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid (13B), a light yellow liquid (0.28 g, yield 97%).

[0761] LCMS (ESI): m / z = 369.1 [M+1] + .

[0762] Step 3: 4-(7-chloro-2,4-dimethyl-5-((((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxa-2-yl)-N-methylpiperidine-1-carboxamide (Compound 13)

[0763] 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)-N-methylpiperidine-1-carboxamide

[0764]

[0765] 7-Chloro-2,4-dimethyl-2-(1-(methylcarbamoyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid (13B) (0.28 g, 0.76 mmol), intermediate 5 (0.14 g, 0.76 mmol), HATU (0.43 g, 1.14 mmol), and DIEA (0.29 g, 2.28 mmol) were dissolved in dichloromethane (12 mL) and reacted at room temperature for 12 hours. The reaction solution was diluted with water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 1:0 to 9:1) to give the title compound 4-(7-chloro-2,4-dimethyl-5-((((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxa-2-yl)-N-methylpiperidine-1-carboxamide (Compound 13), (51 mg, yield 13%).

[0766] 1 H NMR (400 MHz, DMSO-d 6)δ11.51(s,1H),8.00(t,1H),6.86(s,1H),6.34(s,1H),6.08(s,1H),4.27(d,2H),4.00(d,2H),2.59 (m,5H),2.45(s,3H),2.17(s,3H),2.14(s,3H),2.07(m,1H),1.70(m,2H),1.61(s,3H),1.18(m,2H).

[0767] LCMS (ESI): m / z = 535.2 [M+1] + .

[0768] Embodiment 14

[0769] 7-Chloro-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 14)

[0770] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0771]

[0772] Step 1: 7-Chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (14A)

[0773] methyl-7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylate

[0774]

[0775] Intermediate 3 (0.4 g, 1.23 mmol) was dissolved in dichloromethane (10 mL), and methylsulfonyl chloride (0.19 g, 1.47 mmol) and DIEA (0.48 g, 3.68 mmol) were added, and the mixture was reacted at room temperature for 4 hours. Water (30 mL) was added to the reaction solution, and the solution was separated. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phases were combined, washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (14A) as a yellow solid (0.42 g, yield 85%).

[0776] LCMS (ESI): m / z = 404.1 [M+1] + .

[0777] Step 2: 7-Chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid (14B)

[0778] 7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[0779]

[0780] Using compound 7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (14A) (0.42 g, 1.04 mmol) as raw material, referring to the second step synthesis method of compound 13, the title compound 7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxylic acid (14B) was obtained as a light yellow liquid (0.40 g, yield 99%).

[0781] LCMS (ESI): m / z = 390.1 [M+1] + .

[0782] Step 3: 7-Chloro-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 14)

[0783] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0784]

[0785] Using compound 7-chloro-2,4-dimethyl-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 14) (0.14 g, yield 33%) as raw material and referring to the third step synthesis method of Compound 14, the title compound 7-chloro-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 14) was obtained (0.14 g, yield 33%).

[0786] 1H NMR (400MHz, DMSO-d 6 )δ11.51(s,1H),8.00(t,1H),6.88(s,1H),6.08(s,1H),4.27(d,2H),3.63(d,2H),2.84(s,3H),2.68 (m,2H),2.45(s,3H),2.17(s,3H),2.15(s,3H),2.05(m,1H),1.87(m,2H),1.64(s,3H),1.41(m,2H).

[0787] LCMS (ESI): m / z = 556.1 [M+1] + .

[0788] Embodiment 15

[0789] 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 15)

[0790] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

[0791]

[0792] Step 1: 7-chloro-2-(4-(methoxymethylene)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15A)

[0793] methyl-7-chloro-2-(4-(methoxymethylene)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[0794]

[0795] Dissolve chloro-(methoxymethyl)-triphenylphosphine (0.91 g, 2.66 mol) in tetrahydrofuran (10 mL), add potassium tert-butoxide (0.30 g, 2.66 mmol), and react at 0°C for 30 minutes. Add 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)-1,3-benzodioxazole-5-carboxylic acid methyl ester (Intermediate 3) (0.3 g, 0.89 mmol), and react at 0°C for 1 hour and at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound, 7-chloro-2-(4-(methoxymethylene)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15A), as a colorless oil (0.25 g, yield 80%).

[0796] LCMS (ESI): m / z = 367.1 [M+1] + .

[0797] Step 2: 7-Chloro-2-(4-formylcyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15B)

[0798] methyl-7-chloro-2-(4-formylcyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[0799]

[0800] 7-Chloro-2-(4-(methoxymethylene)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15A) (0.25 g, 0.68 mol) was dissolved in a DCM / HCOOH (v / v=1 / 1) mixed solvent (10 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain the title compound 7-chloro-2-(4-formylcyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15B) as a yellow oil (0.23 g, yield 96%).

[0801] LCMS (ESI): m / z = 353.1 [M+1] + .

[0802] Step 3: 7-Chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15C)

[0803] methyl-7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxylate

[0804]

[0805] 7-Chloro-2-(4-formylcyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15B) (0.35 g, 0.99 mmol) was dissolved in DCM (10 mL), and oxetane-3-amine (0.15 g, 2.05 mmol) and a drop of glacial acetic acid were added in sequence. After stirring at room temperature for 2 hours, sodium triacetylborohydride (0.42 g, 1.98 mmol) was added and the reaction was continued at room temperature for 3 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15C) as a yellow solid (0.3 g, yield 74%).

[0806] LCMS (ESI): m / z = 410.2 [M+1] + .

[0807] Step 4: 7-Chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid (15D)

[0808] 7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxylic acid

[0809]

[0810] Using compound 7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15C) (0.3 g, 0.73 mmol) as raw material, referring to the second step synthesis method of compound 13, the title compound 7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid (15D) was obtained as a light yellow solid (0.27 g, yield 93%).

[0811] LCMS (ESI): m / z = 396.2 [M+1] + .

[0812] Step 5: 7-Chloro-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((oxetane-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 15)

[0813] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

[0814]

[0815] Compound 7-chloro-2,4-dimethyl-2-(4-((oxetan-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxylic acid (15D) (0.3 g, 0.76 mmol) was used as raw material, and the third step of the synthesis method of compound 13 was referred to to obtain the title compound 7-chloro-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-2-(4-((oxetane-3-ylamino)methyl)cyclohexyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 15), (0.2 g, yield 47%). Compound 15 was separated by preparative HPLC to give Isomer 1 of Compound 15 (retention time: 12.27 s, 1.5 mg) and Isomer 2 of Compound 15 (retention time: 13.25 s, 1.6 mg).

[0816] Preparative HPLC separation conditions: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: XSelect @ CSH Prep (19 mm × 150 mm). Mobile phase A: acetonitrile Mobile phase B: water (containing 5 nM ammonium bicarbonate). Gradient elution, mobile phase A content from 30% to 75%, flow rate 12 mL / min, elution time 20 min.

[0817] Isomer 1 of compound 15: 1 H NMR (400MHz, CD 3OD)δ6.90(s,1H),6.27(s,1H),4.90(t,2H),4.66(m,2H),4.49(s,2H),4.39(m,1H),2.82(d,2H ),2.52(s,3H),2.29(s,3H),2.19(s,3H),1.97(m,5H),1.62(m,3H),1.29(m,3H),1.11(m,2H).

[0818] LCMS (ESI): m / z = 562.2 [M+1] + .

[0819] Isomer 2 of compound 15: 1 H NMR (400MHz, CD 3 OD)δ6.90(s,1H),6.27(s,1H),4.90(t,2H),4.67(m,2H),4.49(s,2H),4.37(m,1H),2.81(d,2H ),2.52(s,3H),2.29(s,3H),2.19(s,3H),1.99(m,5H),1.62(m,3H),1.29(m,3H),1.10(m,2H).

[0820] LCMS (ESI): m / z = 562.2 [M+1] + .

[0821] Example 16

[0822] 7-Chloro-2-(4-(((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 16)

[0823] 7-chloro-2-(4-((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0824]

[0825] first step:

[0826] 7-Chloro-2-(4-formylcyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (15B) (1g, 2.84mmol) and 2-methylbut-2-ene (2.58g, 36.93mmol) were dissolved in tert-butyl alcohol (15mL), and sodium chlorite (0.945g, 10.5mmol) and sodium dihydrogen phosphate dihydrate (2.2g, 14.2mmol) were dissolved in water (5mL) and then added dropwise to the reaction system. The mixture was reacted at room temperature for 1h. An aqueous ammonium chloride solution was added, and the mixture was extracted with EA (20mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)cyclohexanecarboxylic acid (16A) (1.28g).

[0827] LC-MS (ESI): m / z = 369.1 [M+H] + .

[0828] Step 2:

[0829] At room temperature, 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)cyclohexanecarboxylic acid (16A) (680 mg, 1.85 mmol), 3,3-difluorocyclobutylamine hydrochloride (396 mg, 2.77 mmol), HATU (1.05 g, 2.77 mmol) and DIPEA (716 mg, 5.55 mmol) were added to DCM (10 mL) and reacted at room temperature for 1 h. 15 mL of water was added, the liquids were separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 0:1 to 1:3) to obtain compound 7-chloro-2-(4-(((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (16B) (600 mg, yield 71%).

[0830] LC-MS (ESI): m / z = 458.1 [M+H] + .

[0831] Step 3:

[0832] MeOH (10 mL) and aqueous sodium hydroxide solution (2 mol / L, 3 mL) were added to methyl 7-chloro-2-(4-(((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylate (16B) (600 mg, 1.32 mmol) in sequence, and the temperature was raised to 65°C for reaction for 6 h. The reaction solution was cooled to room temperature, adjusted to pH=5-6 with aqueous hydrochloric acid solution, added with water (20 mL), extracted with DCM, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude compound 7-chloro-2-(4-(((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (16C) (576 mg).

[0833] LC-MS (ESI): m / z = 444.1 [M + H] + .

[0834] Step 4:

[0835] At room temperature, intermediate 5 (572 mg, 2.6 mmol), DCM (10 mL), HATU (988 mg, 2.6 mmol), and N,N-diisopropylethylamine (671 mg, 5.2 mmol) were added to 7-chloro-2-(4-(((3,3-difluorocyclobutyl)carbamoyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (16C) (576 mg, 1.3 mmol) in sequence, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative HPLC to give isomer 1 of compound 16 (110 mg, 14%) and isomer 2 of compound 16 (106 mg, 13%).

[0836] Preparative HPLC separation method: 1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate 12mL / min; d. Elution time 20min.

[0837] Retention time of isomer 1 of compound 16: 13.8 min;

[0838] 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.14(d,1H),8.00(t,1H),6.86(s,1H) ,6.08(s,1H),4.27(d,2H),4.01-3.96(m,2H),2.93-2.86(m,2H),2.49-2.45( m,1H),2.45(s,3H),2.17(s,3H),2.14(s,3H),2.04-1.98(m,1H),1.87-1.85( m,3H),1.80-1.77(m,2H),1.60(s,3H),1.36-1.30(m,2H),1.20-1.07(m,2H).

[0839] LC-MS (ESI): m / z = 610.2 [M+H] + .

[0840] Retention time of isomer 2 of compound 16: 14.1 min;

[0841] 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.04(d,1H),7.99(t,1H),6.85(s,1H) ,6.08(s,1H),4.27(d,2H),4.08-4.00(m,2H),2.91-2.80(m,2H),2.59-2.53( m,1H),2.44(s,3H),2.39-2.37(m,1H),2.17(s,3H),2.13(s,3H),2.02-1.98( m,2H),1.90-1.86(m,1H),1.60-1.56(m,2H),1.57(s,3H),1.46-1.42(m,4H).

[0842] LC-MS (ESI): m / z = 610.2 [M+H] + .

[0843] Embodiment 17

[0844] 7-Chloro-2-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 17)

[0845] 7-chloro-2-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0846]

[0847] first step:

[0848] At room temperature, 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)cyclohexanecarboxylic acid (16A) (600 mg, 1.63 mmol), 3,3-difluorotrimethyleneimine hydrochloride (317 mg, 2.45 mmol), HATU (931 mg, 2.45 mmol) and DIPEA (630 mg, 4.89 mmol) were added to DCM (10 mL) and reacted at room temperature for 1 h. 15 mL of water was added, the liquids were separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 0:1 to 1:3) to obtain compound 7-chloro-2-(4-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (17A) (580 mg, yield 80%).

[0849] LC-MS (ESI): m / z = 444.1 [M + H] + .

[0850] Step 2:

[0851] 7-Chloro-2-(4-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (17A) (580 mg, 1.31 mmol) was added to MeOH (10 mL), and then sodium hydroxide aqueous solution (2 mol / L, 3 mL) was added, and the temperature was raised to 65°C for 6 h. The reaction solution was cooled to room temperature, adjusted to pH=5-6 with hydrochloric acid aqueous solution, water (20 mL) was added, and extracted with DCM. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound 7-chloro-2-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (17B) (560 mg).

[0852] LC-MS (ESI): m / z = 430.1 [M+H] + .

[0853] Step 3:

[0854] At room temperature, intermediate 5 (572 mg, 2.6 mmol), DCM (10 mL), HATU (988 mg, 2.6 mmol), and N,N-diisopropylethylamine (671 mg, 5.2 mmol) were added to 7-chloro-2-(4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (17B) (560 mg, 1.3 mmol) in sequence. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with DCM, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative HPLC to obtain isomer 1 of compound 17 (90 mg, 12%) and isomer 2 of compound 17 (60 mg, 8%). Preparative HPLC separation method: 1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, mobile phase A content from 5% to 50%; c. Flow rate 12mL / min; d. Elution time 20min.

[0855] Retention time of isomer 1 of compound 17: 14.2 min;

[0856] 1 H NMR (400 MHz, CDCl 3)δ7.01-6.99(m,1H),6.89(s,1H),6.08(s,1H),4.59(d,2H),4.43-4.30(m,4H),2.56–2.51(m,1H),2.49(s,3H),2 .32(s,3H),2.25(s,3H),2.01-1.95(m,3H),1.89–1.82(m,1H),1.81–1.70(m,4H),1.59(s,3H),1.55-1.49(m,2H).

[0857] Retention time of isomer 2 of compound 17: 14.5 min;

[0858] 1 H NMR (400 MHz, CDCl 3 )δ7.01-6.99(m,1H),6.90(s,1H),6.11(s,1H),4.59(s,2H),4.47-4.41(m,2H),4.33-4.27(m,2H),2.50(s,3H),2.35(s,3H),2.26(s ,3H),2.15-2.10(m,1H),2.01-1.98(m,2H),1.93-1.90(m,1H),1.86-1.82(m,3H),1.61(s,3H),1.57-1.54(m,2H),1.29-1.23(m,2H).

[0859] LC-MS (ESI): m / z = 596.2 [M+H] + .

[0860] Embodiment 18

[0861] 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 18)

[0862] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

[0863]

[0864] Step 1: 7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (18B & 18C)

[0865] methyl-7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxylate

[0866] 2,7-diazaspiro[4.4]nonan-3-one hydrochloride (18A) (370 mg, 2.1 mmol) and intermediate 3 (580 mg, 1.71 mmol) were dissolved in 1,2-dichloroethane (10 mL), and acetic acid (129 mg, 2.1 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (907 mg, 4.28 mmol) was slowly added, and the mixture was reacted at room temperature for 4 hours. Water (100 mL) was slowly added to the reaction solution to quench the mixture, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 0:1 to 1:1) to obtain the title compound 7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4 .4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxecarboxylic acid methyl ester (18B&18C), wherein 18B, Rf value is about 0.50 (petroleum ether:ethyl acetate (v / v) = 2:1), white powder solid (320 mg, yield 34%); 18C, Rf value is about 0.38 (petroleum ether:ethyl acetate (v / v) = 2:1), white powder solid (210 mg, yield 24%).

[0867] LC-MS (ESI): m / z = 463.1 [M+H] + .

[0868] Step 2: 7-Chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxetan-5-carboxylic acid (18D & 18E)

[0869] 7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxylic acid

[0870] 18B (320 mg, 0.69 mmol) was dissolved in methanol (15 mL), and 2M sodium hydroxide aqueous solution (5 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours. Dilute hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to about 3, and water (50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 mL×5), and the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid (18D) as a white powdery solid (280 mg, yield 90%).

[0871] LC-MS (ESI): m / z = 449.3 [M + H] + .

[0872] 18C (210 mg, 0.45 mmol) was dissolved in methanol (15 mL), and 2M sodium hydroxide aqueous solution (5 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours. Dilute hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to about 3, and water (50 ml) was added. The aqueous phase was extracted with ethyl acetate (50 mL×5), and the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid (18E) as a white powdery solid (180 mg, yield 86%).

[0873] LC-MS (ESI): m / z = 449.3 [M + H] + .

[0874] Step 3: 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 18)

[0875] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide

[0876] 7-Chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid (18D) (280 mg, 0.62 mmol), 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 5) (207 mg, 0.94 mmol), and HATU (285 mg, 0.75 mmol) were dissolved in DMF (15 mL), and DIPEA (316 mg, 3.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 8 hours. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL×5). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 0:1 to 10:1) to give the title compound 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxamide (isomer 1 of compound 18), (65 mg, yield 22%).

[0877] 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(t,1H),7.52(s,1H),6.86(s,1H),6.08(s,1H),4.27(d,2H),3.13(dd,2H),2.72(dd,4H),2.45(s, 3H),2.16(dd,7H),1.98(s,2H),1.89(d,3H),1.85(d,2H),1.78(dd,2H),1.60(s,3H),1.24-1.10(m,4H).

[0878] LC-MS (ESI): m / z = 615.3 [M+H] + .

[0879] 7-Chloro-2,4-dimethyl-2-(4-(8-oxo-2,7-diazaspiro[4.4]non-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid (18E) (180 mg, 0.40 mmol), 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 5) (133 mg, 0.60 mmol), and HATU (183 mg, 0.48 mmol) were dissolved in DMF (15 mL), and DIPEA (203 mg, 2.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 8 hours. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL×5). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 0:1 to 10:1) to give the title compound 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)cyclohexyl)benzo[d][1,3]dioxe-5-carboxamide (isomer 2 of compound 18), (68 mg, yield 28%).

[0880] 1 H NMR (400 MHz, DMSO-d 6 )δ8.01(t,1H),7.68(s,1H),6.89(s,1H),6.08(s,1H),4.28(d,2H),3.73-3.61(m,2H),3.28(ddd ,5H),2.45(d,3H),2.42-2.22(m,2H),2.17(s,6H),2.13-1.88(m,5H),1.69(dd,6H),1.61(s,3H).

[0881] LC-MS (ESI): m / z = 615.3 [M+H] + .

[0882] Embodiment 19

[0883] 7-Chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclic-5-amide (Compound 19)

[0884] 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0885]

[0886] Step 1: Methyl 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylate (19A)

[0887] Methyl 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[0888] 1-Fluorocyclopropane-1-carboxylic acid (96 mg, 0.92 mmol) was added to a 50 mL single-necked bottle, dissolved in dichloromethane (5 mL), triethylamine (230 mg, 2.30 mmol) and HATU (350 mg, 0.92 mmol) were added, and stirred at room temperature for 0.5 h. Intermediate 3 (250 mg, 0.77 mmol) was added, and stirred at room temperature for 16 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1 to 2:1) to give the title compound methyl 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxecyclopentane-5-carboxylate (19A) as a yellow oil (200 mg, yield 63%).

[0889] LCMS m / z=412.2[M+1] + .

[0890] Step 2: 7-Chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (19B)

[0891] 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[0892] 19A (200 mg, 0.49 mmol) was added to a 50 mL single-mouth bottle, methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL) were dissolved, lithium hydroxide (58 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 5 h. The pH was adjusted to 3-4 with hydrochloric acid (2 M), extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid (19B) as a white solid (150 mg, 78% yield).

[0893] LCMS m / z=398.1[M+1] + .

[0894] Step 3: 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclic-5-amide (Compound 19)

[0895] 7-chloro-2-(1-(1-fluorocyclopropane-1-carbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0896] 19B (150 mg, 0.38 mmol) was added to a 50 mL single-necked bottle and dissolved in DMF (5 mL). Triethylamine (110 mg, 1.10 mmol) and HATU (170 mg, 0.45 mmol) were added and stirred at room temperature for 0.5 h. Intermediate 5 (100 mg, 0.57 mmol) was added and stirred at room temperature for 16 h. Water (10 mL) was added to the reaction solution and extracted twice with EA (10 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified using a liquid phase preparation column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase was deionized water containing 0.1% trifluoroacetic acid (A), acetonitrile containing 0.1% trifluoroacetic acid (B), gradient elution, B content = 20% to 70%, elution time 20 min, flow rate 15 mL / min, retention time: 13.4 min, column temperature: 30°C); the title compound 19 was separated (20 mg, 9.4% yield).

[0897] 1 H NMR (400 MHz, CDCl 3 )δ7.06(s,1H),6.92(s,1H),6.10(s,1H),4.60(s,2H),3.14–2.57(m,2H),2.50(s,3H),2.35(s,3 H),2.26(s,3H),2.14(tt,1H),2.01–1.85(m,6H),1.62(s,3H),1.55–1.39(m,2H),1.21(dd,2H).

[0898] LCMS m / z=564.1[M+1] + .

[0899] Embodiment 20

[0900] 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxe-5-carboxamide (Compound 20)

[0901] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0902]

[0903] Step 1: 7-Chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (20B)

[0904] methyl

[0905] 7-chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)-piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylate

[0906]

[0907] Intermediate 3 (0.25 g, 0.69 mmol) and 1-trifluoromethylcyclopropane-1-carboxylic acid (20A) (159 mg, 1.04 mmol) were dissolved in DCM (5 mL), and EDCI (0.26 g, 1.38 mmol), HOBt (0.19 g, 1.38 mmol) and DIPEA (0.6 mL) were added and reacted at room temperature for 3 hours. DCM and water were added to the reaction solution, the liquid was separated, the aqueous phase was extracted with DCM (10 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1 to 5:1) to give the title compound 7-chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxecyclohexane-5-carboxylic acid methyl ester (20B) as a light yellow solid (228 mg, yield 72%).

[0908] LCMS m / z=462.1[M+1] + .

[0909] Step 2: 7-Chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxetan-5-carboxylic acid (20C)

[0910] 7-chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[0911] 7-Chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxe-5-carboxylic acid methyl ester (20B) (228 mg, 0.49 mmol) was dissolved in methanol (3 mL) and water (3 mL), and KOH (56 mg, 1 mmol) was added. The mixture was reacted at room temperature overnight. The reaction solution was distilled under reduced pressure to remove methanol, and the pH was adjusted to 7 with 1N HCl solution. The system was extracted with DCM (10 mL×3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxe-5-carboxylic acid (20C) crude product (200 mg), which was directly used for the next step.

[0912] LCMS m / z=448.1[M+1] + .

[0913] Step 3: 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxacyclopentane-5-carboxamide (Compound 20)

[0914] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methy l)-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0915] The crude product of 7-chloro-2,4-dimethyl-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxetan-5-carboxylic acid (20C) (200 mg, 0.45 mmol) was dissolved in DCM (8 mL), and HATU (254 mg, 0.68 mmol) and DIPEA (1.2 mL) were added. After reacting at room temperature for 15 minutes, 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 5) (137 mg, 0.63 mmol) was added. The reaction was continued at room temperature for 2 hours, and water was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (DCM: MeOH (v / v) = 50:1 to 5:1) to give the title compound 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxe-5-carboxamide (Compound 20), (120 mg, 43% yield).

[0916] 1 H NMR (400 MHz, CDCl 3 )δ6.90(s,1H),6.51(s,1H),6.48(s,1H),4.63(m,2H),4.06(m,2H),2.57(s,3H),2.50(s,3H),2 .23(s,3H),2.17-2.06(m,1H),1.94(m,2H),1.63(s,3H),1.41(m,2H),1.33(t,2H),1.15(t,2H).

[0917] LCMS m / z=614.1[M+1] + .

[0918] Embodiment 21

[0919] 7-Chloro-2,4-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-carboxamide (Compound 21)

[0920] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0921]

[0922] Step 1: 7-Chloro-2,4-dimethyl-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benz[d][1,3]dioxa-5-carboxylic acid methyl ester (21A)

[0923] methyl7-chloro-2,4-dimethyl-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylate

[0924] Intermediate 3 (0.25 g, 0.77 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.30 g, 2.30 mmol), HATU (0.35 g, 0.92 mmol), and 2-methyl-1,3-thiazole-4-carboxylic acid (0.13 g, 0.92 mmol) were added. After the addition was complete, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and saturated aqueous sodium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 3:1) to obtain the title compound 21A as a white solid (0.34 g, 98.2%).

[0925] LC-MS (ESI): m / z = 451.1 [M+H] + .

[0926] Step 2: 7-Chloro-2,4-dimethyl-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzene[d][1,3]dioxa-5-carboxylic acid (21B)

[0927] 7-chloro-2,4-dimethyl-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[0928] Dissolve 21A (0.34 g, 0.75 mmol) in methanol (10 mL), add water (2 mL) and sodium hydroxide (0.30 g, 7.50 mmol), and react at room temperature overnight. Add 2M dilute hydrochloric acid solution dropwise to adjust pH to 2-3, extract with ethyl acetate (25 mL × 3), and dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 21B as a white solid (0.33 g, 99.7%).

[0929] LC-MS (ESI): m / z = 437.1 [M+H] + .

[0930] Step 3: 7-chloro-2,4-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-carboxamide (Compound 21)

[0931] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(2-methylthiazole-4-carbonyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[0932] 21B (0.33 g, 0.76 mmol) was dissolved in DMF (10 mL), and N,N-diisopropylethylamine (0.29 g, 2.27 mmol), HATU (0.34 g, 0.91 mmol), and intermediate 5 (0.17 g, 0.91 mmol) were added. After the addition was complete, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, saturated aqueous sodium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 40:1, 30:1, 10:1) to obtain the product compound 21 (40 mg, 8.9%).

[0933] 1 H NMR (400 MHz, CDCl 3 )δ7.69(s,1H),6.91(s,1H),6.04(s,1H),4.59(d,2H),3.15-2.82(m,2H),2.72(s,3H),2. 48(s,3H),2.31(s,3H),2.26(s,3H),2.14(m,1H),1.85(m,4H),1.63(s,3H),1.53(m,2H).

[0934] LC-MS (ESI): m / z = 603.1 [M+H] + .

[0935] Embodiment 22

[0936] 7-Chloro-2-(1-(2-cyanoacetyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxa-5-amide (Compound 22)

[0937] 7-chloro-2-(1-(2-cyanoacetyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0938]

[0939] Step 1: tert-Butyl 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)piperidine-1-carboxylate (22A)

[0940] tert-butyl

[0941] 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate

[0942] Intermediate 3 (0.25 g, 0.76 mmol) was dissolved in DCM (10 mL), triethylamine (0.23 g, 2.30 mmol) was added, (Boc) 2O (0.20 g, 0.92 mmol), DMAP (9 mg, 0.07 mmol), after addition, react at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, saturated aqueous sodium chloride solution (30 mL) was added, extracted with dichloromethane (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to obtain the title compound 22A as a white solid (0.33 g, 99%).

[0943] LC-MS (ESI): m / z = 426.2 [M + H] + .

[0944] Step 2: 2-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxa-5-carboxylic acid (22B)

[0945] 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[0946] Dissolve 22A (0.33 g, 0.80 mmol) in methanol (10 mL), add water (2 mL) and sodium hydroxide (0.30 g, 8.0 mmol), and react at room temperature overnight. Add 2M dilute hydrochloric acid aqueous solution to adjust the pH to 2-3, extract with ethyl acetate (25 mL × 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 22B as a white solid (0.33 g, 99.7%).

[0947] LC-MS (ESI): m / z = 412.1 [M+H] + .

[0948] Step 3: tert-Butyl 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxin-2-yl)piperidine-1-carboxylate (22C)

[0949] tert-butyl

[0950] 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate

[0951] 22B (0.33 g, 0.80 mmol) was dissolved in DMF (10 mL), and N,N-diisopropylethylamine (0.31 g, 2.40 mmol), HATU (0.36 g, 0.96 mmol), and intermediate 5 (0.17 g, 0.96 mmol) were added. After the addition was complete, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and saturated aqueous sodium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 3). The combined organic layer was washed with saturated aqueous sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the title compound 22C as a white solid (0.30 g, 64.8%).

[0952] LC-MS (ESI): m / z = 578.2 [M+H] + .

[0953] Step 4: 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxa-5-amide hydrochloride (22D)

[0954] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide hydrochloride

[0955] 22C (0.30 g, 0.52 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane solution (10 mL), and the mixture was reacted at room temperature overnight. The mixture was concentrated to obtain the title compound 22D as a white solid (0.24 g, 96.8%).

[0956] LC-MS (ESI): m / z = 478.2 [M+H] + .

[0957] Step 5: 7-chloro-2-(1-(2-cyanoacetyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxa-5-amide (Compound 22)

[0958] 7-chloro-2-(1-(2-cyanoacetyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0959] 22D (0.33 g, 0.50 mmol) was dissolved in DCM (10 mL), and N,N-diisopropylethylamine (0.19 g, 1.50 mmol), HATU (0.23 g, 0.60 mmol), and cyanoacetic acid (0.05 g, 0.60 mmol) were added. After the addition, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and 30 mL of saturated aqueous sodium chloride solution was added. The mixture was extracted with dichloromethane (25 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 50:1, 25:1, 10:1) to obtain the title compound 22 (75 mg, 27.0%).

[0960] 1 H NMR (400 MHz, CDCl 3 )δ6.89(s,1H),6.44(s,1H),4.65(m,3H),3.78(d,1H),3.48(s,2H),3.16(t,1H),2.68-2.51( m,4H),2.49(s,3H),2.23(s,3H),2.13(t,1H),2.04-1.88(m,2H),1.64(s,3H),1.46(dd,2H).

[0961] LC-MS (ESI): m / z = 545.2 [M+H] + .

[0962] Embodiment 23

[0963] 7-Chloro-2-(1-((1S,2S)-2-fluorocyclopropylcarbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 23)

[0964] 7-chloro-2-(1-((1S,2S)-2-fluorocyclopropanecarbonyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0965]

[0966] first step:

[0967] Intermediate 3 (250 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL), and compound 23A (70 mg, 0.7 mmol), HATU (380 mg, 1.04 mmol), and triethylamine (210 mg, 2.1 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound 23B (270 mg, 95%)

[0968] LC-MS (ESI): m / z = 412.8 [M+H] + .

[0969] Step 2:

[0970] Compound 23B (270 mg, 0.8 mmol) was dissolved in methanol (5 mL), and a solution of sodium hydroxide (160 mg, 4 mmol) in water (0.5 mL) was added thereto, and the reaction was stirred at room temperature overnight. Dilute hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain a crude product of the title compound 23C (300 mg).

[0971] LC-MS (ESI): m / z = 398.1 [M+H] + .

[0972] Step 3:

[0973] The crude compound 23C (300 mg) was dissolved in DMF (5 mL), and DIPEA (277 mg, 2.15 mmol), HATU (371 mg, 0.98 mmol), and intermediate 5 (186 mg, 0.85 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was further separated and purified by preparative HPLC to obtain compound 23 (100 mg, two-step yield 27%). Preparative HPLC separation conditions: preparative instrument Waters 2767, preparative column SunFire C18; mobile phase system: acetonitrile: 1% trifluoroacetic acid water; peak position 9.83 min.

[0974] LC-MS (ESI): m / z = 565.0 [M+H] + .

[0975] 1 H NMR(400MHz,Chloroform-d)δ7.04(s,1H),6.92(s,1H),6.14(s,1H),4.62(s,1H),4.69(d,2H),4.21(s,1H),3.06(s,1H),2.61(s,1H),2 .50(s,3H),2.31(s,3H),2.26(s,3H),2.11(t,1H),1.84(s,2H),1.43(d,2H),1.28(d,2H),0.97(s,2H),0.91-0.81(m,2H),0.74(dd,2H).

[0976] Embodiment 24

[0977] 7-Chloro-2-(1-cyclopropylpiperidin-4-yl)-2,4-dimethyl-N-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 24)

[0978] 7-chloro-2-(1-cyclopropylpiperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0979]

[0980] first step:

[0981] Intermediate 3 (250 mg, 0.69 mmol) was dissolved in methanol (10 mL), and compound 24A (181 mg, 1.04 mmol) and acetic acid (1 mL) were added in sequence. The mixture was stirred at room temperature for half an hour, and then heated to reflux overnight. After the reaction mixture was cooled to room temperature, the reaction solution was removed by vacuum concentration, and the residue was separated by column chromatography (eluent ratio PE: EA = 20%-50%) to obtain compound 24B (196 mg, 78%).

[0982] LC-MS (ESI): m / z = 366.7 [M+H] + .

[0983] Step 2:

[0984] Compound 24B (196 mg, 0.54 mmol) was dissolved in methanol (5 mL), and a solution of sodium hydroxide (108 mg, 2.7 mmol) in water (0.5 mL) was added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain a crude compound 24C (320 mg).

[0985] LC-MS (ESI): m / z = 352.7 [M+H] + .

[0986] Step 3:

[0987] The crude compound 24C (320 mg) was dissolved in DMF (5 mL), and DIPEA (209 mg, 1.62 mmol), HATU (267 mg, 0.70 mmol), and intermediate 5 (130 mg, 0.59 mmol) were added in sequence, and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was separated by preparative HPLC to obtain compound 24 (180 mg, 64% total yield in 2 steps).

[0988] Preparative HPLC separation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm); Preparative chromatographic conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water; Gradient elution, mobile phase A content from 20%-75%; Flow rate 12mL / min. Elution time 20min. Peak time: 14.15min.

[0989] 1H NMR(400MHz,Chloroform-d)δ12.15(s,1H),7.13(t,1H),6.90(s,1H),6.02(s,1H),4.59(d,2H),3.10(d,2H),2.48( s,3H),2.32-2.27(m,3H),2.25(s,3H),2.18-2.05(m,3H),1.91-1.76(m,4H),1.60-1.41(m,4H),0.49-0.35(m,4H).

[0990] LC-MS (ESI): m / z = 546.2 [M+H] + .

[0991] Embodiment 25

[0992] 7-Chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 25)

[0993] 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[0994]

[0995]

[0996] Step 1: Methyl 2,3,4-tris(benzyloxy)benzoate (25A)

[0997] methyl 2,3,4-tris(benzyloxy)benzoate

[0998] Dissolve methyl 2,3,4-trihydroxybenzoate (1b) (9.5 g, 51.6 mmol) and benzyl bromide (26.5 g, 155 mmol) in DMF (76 mL), add potassium carbonate (22 g, 155 mmol), and react at room temperature for 20 hours. Pour the reaction solution into water (500 mL), extract with ethyl acetate (500 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1 to 4:1) to obtain the title compound methyl 2,3,4-tris(benzyloxy)benzoate (25A) as a white solid (16.0 g, yield 69%).

[0999] LCMS m / z=455.2[M+1] + .

[1000] Step 2: 3,4-bis(benzyloxy)-2-hydroxybenzoic acid methyl ester (25B)

[1001] methyl 3,4-bis(benzyloxy)-2-hydroxybenzoate

[1002] Add 2,3,4-tris(benzyloxy)benzoic acid methyl ester (25A) (16 g, 35.2 mmol) to acetic acid (95 mL), then add concentrated hydrochloric acid (9.5 mL), and heat to 40°C for 2 hours. Pour the reaction solution into water (500 mL), extract with ethyl acetate (500 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1 to 1:1) to obtain the title compound 3,4-bis(benzyloxy)-2-hydroxybenzoic acid methyl ester (25B) as a white solid (8.0 g, yield 62.5%).

[1003] LCMS m / z=365.2[M+1] + .

[1004] Step 3: Methyl 3,4-bis(benzyloxy)-2-(methoxy-d3)benzoate (25C)

[1005] methyl 3,4-bis(benzyloxy)-2-(methoxy-d3)benzoate

[1006] 3,4-bis(benzyloxy)-2-hydroxybenzoic acid methyl ester (25B) (7.5 g, 19.7 mmol) was added to acetone (80 mL), and then deuterated iodomethane (6.0 g, 39.4 mmol) and potassium carbonate (14.3 g, 98.4 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1 to 3:1) to obtain the title compound 3,4-bis(benzyloxy)-2-(methoxy-d3)benzoic acid methyl ester (25C), a white solid (6.0 g, yield 72.3%).

[1007] LCMS m / z=382.2[M+1] + .

[1008] Step 4: 3,4-dihydroxy-2-(methoxy-d3)benzoic acid methyl ester (25D)

[1009] methyl 3,4-dihydroxy-2-(methoxy-d3)benzoate

[1010] 3,4-bis(benzyloxy)-2-(methoxy-d3)benzoic acid methyl ester (25C) (5.5 g, 14.4 mmol) was added to methanol (55 mL), and then 10% palladium carbon (500 mg) was added, and hydrogen was replaced three times, and the reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1 to 1:2) to obtain the title compound 3,4-dihydroxy-2-(methoxy-d3)benzoic acid methyl ester (25D), a colorless oil (2.4 g, yield 82.7%).

[1011] LCMS m / z=202.1[M+1] + .

[1012] Step 5: 5-chloro-3,4-dihydroxy-2-(methoxy-d3)benzoic acid methyl ester (25E)

[1013] methyl 5-chloro-3,4-dihydroxy-2-(methoxy-d3)benzoate

[1014] Add methyl 3,4-dihydroxy-2-(methoxy-d3)benzoate (25D) (2.4 g, 12.0 mmol) to tetrahydrofuran (24 mL), protect with nitrogen, cool to -20°C, then add dichlorothionyl (1.78 g, 13.14 mmol) dropwise, and react at -20°C for 3 hours. The reaction solution was slowly poured into ice water, extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was separated and purified using a liquid phase preparation column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase acetonitrile (A), deionized water containing 5 mM ammonium acetate (B), gradient elution, A content = 20% to 70%, elution time 18 min, flow rate 15 mL / min, column temperature: 30°C); the title compound 5-chloro-3,4-dihydroxy-2-(methoxy-d3)benzoic acid methyl ester (25E) was obtained as a colorless oil (2.2 g, yield 78.6%).

[1015] LCMS m / z=236.1[M+1] + .

[1016] Step 6: 7-chloro-4-(methoxy-d3)-2-methyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25F)

[1017] methyl-7-chloro-4-(methoxy-d3)-2-methyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate

[1018] 5-Chloro-3,4-dihydroxy-2-(methoxy-d3)benzoic acid methyl ester (25E) (2.2 g, 9.36 mmol) was added to toluene (44 mL), and then Ru(CO) was added. 12 (300 mg, 0.468 mmol) and triphenylphosphine (260 mg, 0.94 mmol), nitrogen protection, heating to 110 ° C stirring reaction for 1 hour, then adding 4-ethynylcyclohexane-1-one (4.52 g, 28.1 mmol), after addition, reacting at 110 ° C for 16 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 8:1 to 2:1) to obtain the title compound 7-chloro-4-(methoxy-d3)-2-methyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25F) as a white solid (3.0 g, yield 89.8%).

[1019] LCMS m / z=358.2[M+1] + .

[1020] Step 7: 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25G)

[1021] methyl-7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxole-5-carboxylate

[1022] 7-Chloro-4-(methoxy-d3)-2-methyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25F) (1.5 g, 4.2 mmol) was added to dichloromethane (30 mL), and then 3-methoxyazetidine hydrochloride (700 mg, 5.5 mmol) and acetic acid (252 mg, 4.2 mmol) were added. The mixture was stirred at room temperature for 1 hour, and then sodium triacetylborohydride (1.8 g, 8.4 mmol) was added. After the addition was complete, the mixture was reacted at room temperature for 16 hours. The reaction solution was poured into water (100 mL), extracted with dichloromethane (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 8:1 to 1:1) to give the title compound 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25G) as a white solid (1.5 g, yield 83.8%).

[1023] LCMS m / z=429.2[M+1] + .

[1024] Step 8: 7-Chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxetan-5-carboxylic acid (25H)

[1025] 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxole-5-carboxylic acid

[1026] 7-Chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (25G) (1.0 g, 2.34 mmol) was added to methanol (16 mL), and 2 mol / L sodium hydroxide solution (4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxe-5-carboxylic acid (25H) as a white solid (0.9 g, yield 92.8%).

[1027] LCMS m / z=415.2[M+1] + .

[1028] Step 9: 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 25)

[1029] 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1030] 7-Chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2-methylbenzo[d][1,3]dioxetan-5-carboxylic acid (25H) (450 mg, 1.08 mmol) was added to DMF (10 mL), and then intermediate 5 (266 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol), N,N-diisopropylethylamine (418 mg, 3.24 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was separated and purified by liquid phase preparation column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase acetonitrile (A), deionized water containing 5 mM ammonium acetate (B), gradient elution, A content = 20% ~ 50%, elution time 18 min, flow rate 15 mL / min, column temperature: 30 ° C); the title compound 7-chloro-4-(methoxy-d3)-2-(4-(3-methoxyazetidine) was obtained. The cis-trans isomers 1 (retention time: 15.20 min, 300 mg, yield 47.5%) and cis-trans isomers 2 (retention time: 17.22 min, 160 mg, yield 25.4%) of 6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxetan-5-carboxamide (Compound 25) were chirally separated (Chiral separation preparation conditions: Analytical instrument: Waters UPC2 Analytical SFC (SFC-H) Column: ChiralPak IG, 150×4.6 mm inner diameter, 3 μm Mobile phase: A is CO 2 , B is methanol (0.05% DEA) Slope: B 50% Flow rate: 2.5 ml / min Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm. Preparative separation method Instrument: MGⅡ Preparative SFC (SFC-14) Chromatographic column: ChiralPak IG, 250×30 mm inner diameter, 10 μm Mobile phase: A is CO 2 , B is methanol (0.1% NH 3 H 2O) slope: B 50%, flow rate: 80 ml / min), cis-trans isomer 1 was separated by chiral HPLC to obtain isomer 1-1 of compound 25 (retention time: 4.696 min, 60 mg, yield 9.5%), isomer 1-2 of compound 25 (retention time: 5.739 min, 60 mg, yield 9.5%), cis-trans isomer 2 was separated by chiral HPLC to obtain isomer 2-1 of compound 25 (retention time: 4.894 min, 30 mg, yield 4.7%), isomer 2-2 of compound 25 (5.991 min, 30 mg, yield 4.7%).

[1031] Isomer 1-1 LCMS m / z=581.2[M+1] + .

[1032] Isomer 1-2 LCMS m / z=581.2[M+1] + .

[1033] Isomer 2-1 LCMS m / z=581.2[M+1] + .

[1034] Isomer 2-2 LCMS m / z=581.2[M+1] + .

[1035] Isomer 1-1 1 H NMR (400 MHz, CDCl 3 )δ11.90(s,1H),8.58-8.56(t,1H),7.74(s,1H),5.98(s,1H),4.64-4.63(d,2H),3.98(s,1H),3.55-3.53(m,2H) ,3.25(s,3H),2.75(s,1H),2.46(s,3H),2.33(s,3H),1.87-1.85(m,1H),1.68-1.56(m,11H),1.32-1.26(m,2H).

[1036] Isomer 1-2 1 H NMR (400 MHz, CDCl 3 )δ12.00(s,1H),8.58-8.56(t,1H),7.72(s,1H),6.03(s,1H),4.70-4.61(d,2H),4.38-4.36(m,1H),3.59(s,2H ),3.30(s,3H),3.25-3.23(m,1H),2.47(s,3H),2.34(s,3H),1.99-1.96(m,5H),1.86-1.71(m,6H),1.64(s,3H).

[1037] Isomer 2-1 1 H NMR (400 MHz, CDCl 3 )δ11.57(s,1H),8.60-8.57(t,1H),7.74(s,1H),5.98(s,1H),4.64-4.62(d,2H),3.97(s,1H),3.55-3.51(m,2H ),3.26(s,3H),2.74(m,1H),2.46(s,3H),2.32(s,3H),1.87-1.85(m,1H),1.73-1.55(m,11H),1.30-1.26(m,2H)

[1038] Isomer 2-2 1 H NMR (400 MHz, CDCl 3 )δ11.74(s,1H),8.56-8.54(t,1H),7.71(s,1H),6.00(s,1H),4.63-4.62(d,2H),4.16-3.98(m,3H),3.27(s,3H),3.15-3.12 (m,1H),2.75-2.70(m,1H),2.47(s,3H),2.33(s,3H),1.89–1.81(m,5H),1.70-1.66(m,3H),1.63(s,3H),1.47-1.40(s,2H).

[1039] Embodiment 26

[1040] 7-Chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(N-methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-amide (Compound 26)

[1041] 7-chloro-2,4-dimethyl-N-((6-methyl-4

[1042] -(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(N-methylsulfamoyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[1043]

[1044] Step 1: 7-chloro-2,4-dimethyl-2-(1-(N-methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-carboxylic acid methyl ester (26A)

[1045] Methyl 7-chloro-2,4-dimethyl-2-(1-(N-methyl sulfamoyl)piperidin-4–yl)benzo[d][1,3]dioxole-5-carboxylate

[1046] Intermediate 3 (0.20 g, 0.61 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.19 g, 1.80 mmol) and N-methylaminosulfonyl chloride (0.10 g, 0.74 mmol) were added. After the addition, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and saturated aqueous sodium chloride solution (30 mL) was added. The mixture was extracted with dichloromethane (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 4:1) to obtain the title compound 26A as a white solid (0.25 g, 97.0%).

[1047] LC-MS (ESI): m / z = 419.1 [M+H] + .

[1048] Step 2: 7-Chloro-2,4-dimethyl-2-(1-(N-methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-carboxylic acid (26B)

[1049] 7-chloro-2,4-dimethyl-2-(1-(N-methylsulfamoyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[1050] Dissolve 26A (0.25 g, 0.59 mmol) in methanol (10 mL), add water (2 mL) and sodium hydroxide (0.24 g, 5.9 mmol), and react at room temperature overnight. Add 2M dilute hydrochloric acid solution dropwise to adjust pH to 2-3, extract with ethyl acetate (25 mL×3), and dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 26B as a white solid (0.21 g, 86.9%).

[1051] LC-MS (ESI): m / z = 405.1 [M+H] + .

[1052] Step 3: 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(N-methylsulfonyl)piperidin-4-yl)benzo[d][1,3]dioxa-5-amide (Compound 26)

[1053] 7-chloro-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(1-(N-methylsulfamoyl)piperidin-4-yl)benzo[d][1,3]dioxole-5-carboxamide

[1054] 26B (0.21 g, 0.52 mmol) was dissolved in DMF (10 mL), and N,N-diisopropylethylamine (0.20 g, 1.56 mmol), HATU (0.26 g, 0.67 mmol), and intermediate 5 (0.11 g, 0.62 mmol) were added. After the addition, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, saturated aqueous sodium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by HPLC to obtain the product compound 26 (70 mg, 23.6%). Preparative HPLC separation conditions: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), the sample was dissolved in DMF, filtered with a 0.45 μm filter head, and the sample solution was prepared. Preparative chromatographic conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium acetate), gradient elution, mobile phase A content from 40% to 70%, flow rate 15 mL / min. Elution time 18 min. Retention time: 11.46 min.

[1055] 1 H NMR (400 MHz, CDCl 3 )δ6.89(s,1H),6.38(s,1H),4.61(d,2H),3.84-3.71(m,2H),2.81-2.66(m,5H) ,2.54(s,3H),2.45(s,3H),2.23(s,3H),2.01-1.86(m,3H),1.70-1.43(m,5H).

[1056] LC-MS (ESI): m / z = 571.2 [M+H] + .

[1057] Embodiment 27

[1058] 7-Chloro-2-(1-(cyclopropylmethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 27)

[1059] 7-chloro-2-(1-(cyclopropylmethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)benzo[d][1,3]dioxole-5-carboxamide

[1060]

[1061] 11D (180 mg, 0.47 mmol) and DMF (6 mL) were added to a 50 mL single-mouth bottle to dissolve, triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. 3-(aminomethyl-d2)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (intermediate 6) (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain compound 27 (50 mg, yield 20%).

[1062] LC-MS (ESI): m / z = 534.2 [M+H] + .

[1063] 1 H NMR (400 MHz, DMSO-d 6)δ11.49(s,1H),7.98(t,1H),6.86(s,1H),6.07(s,1H),3.01(d,2H),2.45(s,3H),2.17(s,3H),2.14(s,3H),2.12-2.16(m,2H), 1.82-1.87(m,3H),1.69-1.72(m,2H),1.62(s,3H),1.33-1.42(m,2H),0.78-0.81(m,1H),0.41-0.44(m,2H),0.00-0.05(m,2H).

[1064] Embodiment 28

[1065] 7-Chloro-2-(1-((3,3-difluorocyclobutyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)benzo[d][1,3]dioxacyclopentyl-5-carboxamide (Compound 28)

[1066] 7-chloro-2-(1-((3,3-difluorocyclobutyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl-d2)benzo[d][1,3]dioxole-5-carboxamide

[1067]

[1068] 10D (195 mg, 0.47 mmol) and DMF (6 mL) were added to a 50 mL single-mouth bottle to dissolve, triethylamine (127 mg, 1.26 mmol) and HATU (239 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. 3-(aminomethyl-d2)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (intermediate 6) (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain compound 28 (50 mg, yield 18%).

[1069] LC-MS (ESI): m / z = 584.2 [M+H] + .

[1070] 1H NMR (400 MHz, DMSO-d 6 )δ11.50(s,1H),7.97(s,1H),6.86(s,1H),6.07(s,1H),2.85-2.88(m,2H),2.58-2.64(m,2H),2.44(s,3H),2.36-2.38(m,2H),2.2 3-2.33(m,1H),2.20-2.22(m,1H),2.17(s,3H),2.14(s,3H),1.81-1.91(m,4H),1.67-1.70(m,2H),1.61(s,3H),1.30-1.39(m,2H).

[1071] Embodiment 29

[1072] 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylic acid methyl ester (Compound 29)

[1073] Methyl-4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate

[1074]

[1075] Step 1: 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)piperidine-1-carboxylic acid methyl ester (29A)

[1076] methyl-4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate

[1077] Intermediate 3 (0.4 g, 1.23 mmol) was dissolved in dichloromethane (10 mL), and DMAP (0.075 g, 0.61 mmol), DIEA (1.58 g, 12.28 mmol), and triphosgene (0.73 g, 2.46 mmol) were added in sequence, and the mixture was reacted in an ice bath for 2 hours. Anhydrous methanol (5 mL) was added, and the mixture was reacted at room temperature for 12 hours. Water (30 mL) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phases were combined, washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxin-2-yl)piperidine-1-carboxylic acid methyl ester (29A) as a yellow solid (0.2 g, yield 42%).

[1078] LCMS m / z=384.1[M+1] + .

[1079] Step 2: 7-Chloro-2-(1-(methoxycarbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (29B)

[1080] 7-chloro-2-(1-(methoxycarbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1081] 4-(7-chloro-5-(methoxycarbonyl)-2,4-dimethylbenzo[d][1,3]dioxa-2-yl)piperidine-1-carboxylic acid methyl ester (29A) (0.2 g, 0.52 mmol) was dissolved in a tetrahydrofuran / methanol / water (v / v / v=1 / 1 / 1) mixed solvent (12 mL), and sodium hydroxide (0.21 g, 5.21 mmol) was added and reacted at room temperature for 4 hours. Hydrochloric acid solution (6 mol / L) was added to the reaction solution until pH=2, and ethyl acetate was added for extraction (50 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2-(1-(methoxycarbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (29B) as a light yellow liquid (0.18 g, yield 93%).

[1082] LCMS m / z=370.1[M+1] + .

[1083] Step 3: 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylic acid methyl ester (Compound 29)

[1084] Methyl-4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylate

[1085] Compound 7-chloro-2-(1-(methoxycarbonyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (29B) (0.17 g, 0.45 mmol), intermediate 5 (0.10 g, 0.55 mmol), HATU (0.26 g, 0.68 mmol), and DIEA (0.18 g, 1.36 mmol) were dissolved in dichloromethane (12 mL) and reacted at room temperature for 12 hours. The reaction solution was diluted with water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 1:0 to 9:1) to give the title compound 4-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)piperidine-1-carboxylic acid methyl ester (Compound 29) (93 mg, yield 38%).

[1086] 1 H NMR (400MHz, CD 3 OD)δ6.90(s,1H),6.27(s,1H),4.49(s,2H),4.18(d,2H),3.67(s,3H),2.79(m,2H),2.5 2(s,3H),2.29(s,3H),2.19(s,3H),2.13(m,1H),1.83(m,2H),1.62(s,3H),1.33(m,2H).

[1087] LCMS m / z=536.2[M+1] + .

[1088] Embodiment 30

[1089] 7-Chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 30)

[1090] 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1091]

[1092] Step 1: 1-(Hydroxymethyl)cyclopropane-1-carbonitrile (30B)

[1093] 1-(hydroxymethyl)cyclopropane-1-carbonitrile

[1094] Dissolve 1-cyanocyclopropanecarboxylic acid ethyl ester (2g, 14.37mol) in tetrahydrofuran (20mL), add lithium borohydride (0.31g, 14.37mmol), and reflux for 1 hour. After the reaction solution is cooled to room temperature, add 1mol / L dilute hydrochloric acid to adjust the pH to about 3, extract with ether (50mL×3), collect the organic phase, dry over anhydrous sodium sulfate, concentrate, add methanol (30mL) to dissolve the crude product, and concentrate to obtain the title compound 1-(hydroxymethyl)cyclopropane-1-carbonitrile (30B), a colorless oil (1.4g, yield 100%).

[1095] LCMS m / z=98.1[M+1] + .

[1096] Step 2: 1-(Bromomethyl)cyclopropane-1-carbonitrile (30C)

[1097] 1-(bromomethyl)cyclopropane-1-carbonitrile

[1098] 1-(Hydroxymethyl)cyclopropane-1-carbonitrile (30B) (1.4 g, 14.4 mol) and carbon tetrabromide (7.17 g, 21.6 mmol) were dissolved in ether (15 mL), and a solution of triphenylphosphine (4.54 g, 17.3 mmol) in ether (8 mL) was added dropwise, and the mixture was reacted at room temperature for 30 minutes. The filtrate was collected by suction filtration, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1-(bromomethyl)cyclopropane-1-carbonitrile (30C) as a purple substance (1.8 g, yield 78%).

[1099] Step 3: 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (30D)

[1100] Methyl-7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1101] Intermediate 3 (3.7 g, 11 mmol), 1-(bromomethyl)cyclopropane-1-carbonitrile (30C) (1.8 g, 11 mmol), potassium carbonate (4.7 g, 34 mmol) and acetonitrile (20 mL) were mixed and refluxed overnight. After the reaction was cooled to room temperature, water (30 mL) was added to the reaction solution, and ethyl acetate (50 mL×3) was used for extraction. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (PE / EA=2 / 1) to obtain the title compound 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (30D) as a yellow solid (0.4 g, yield 9%).

[1102] LCMS m / z=405.2[M+1] + .

[1103] Step 4: 7-Chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (30E)

[1104] 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1105] Compound 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid methyl ester (30D) (0.33 g, 0.82 mmol) was dissolved in THF / MeOH / H 2 O (1 / 1 / 1) mixed solvent (12mL), sodium hydroxide (0.33g, 8.15mmol) was added, and the reaction was carried out at room temperature for 5 hours. Hydrochloric acid solution (6mol / L) was added to the reaction solution until pH = 2, and ethyl acetate was added for extraction (50mL×3), the organic phases were combined, washed with water (50mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (30E) as a light yellow solid (0.30g, yield 90%).

[1106] LCMS m / z=391.1[M+1] + .

[1107] Step 5: 7-Chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 30)

[1108] 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1109] Compound 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxazole-5-carboxylic acid (30E) (0.3 g, 0.77 mmol), intermediate 5 (0.21 g, 1.15 mmol), HATU (0.44 g, 1.15 mmol), and DIEA (0.30 g, 2.30 mmol) were dissolved in dichloromethane (12 mL) and reacted at room temperature for 12 hours. The reaction solution was diluted with water, separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 1:0 to 9:1) to obtain the title compound 7-chloro-2-(1-((1-cyanocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxazole-5-carboxamide (Compound 30), (157 mg, yield 37%).

[1110] 1 H NMR (400MHz, CD 3 OD)δ6.90(s,1H),6.27(s,1H),4.49(s,2H),3.14(m,2H),2.52(s,3H),2.45(s,2H),2.2 9(s,3H),2.20(s,3H),1.96(m,7H),1.63(s,3H),1.58(m,2H),1.26(m,2H),0.96(m,2H).

[1111] MS M / Z(ESI):557.2[M+1] + .

[1112] Embodiment 31

[1113] 7-Chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 31)

[1114] 7-chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1115]

[1116] Step 1: ((2,2-difluorocyclopropyl)methanol (31B)

[1117] (2,2-difluorocyclopropyl)methanol

[1118] 2,2-Difluorocyclopropanecarboxylic acid (31A) (0.5 g, 4.10 mmol) was dissolved in anhydrous THF (10 mL), cooled to 0 °C in an ice bath, and LiAlH 4 (234 mg, 6.15 mmol), after addition, slowly return to room temperature and stir for 2 hours. The reaction solution was cooled to 0°C, quenched with water and Mg 2 SO 4 (5 g), stirred for 10 minutes and then filtered, the filter cake was washed twice with THF, and the filtrate was concentrated under reduced pressure to give the title compound (31B) as a colorless oil (0.4 g, yield 90.9%).

[1119] Step 2: Methyl (2,2-difluorocyclopropyl)methanesulfonate (31C)

[1120] (2,2-difluorocyclopropyl)methyl methanesulfonate

[1121] ((2,2-Difluorocyclopropyl)methanol (31B) (0.4 g, 3.70 mmol) was dissolved in DCM (15 mL), and Et 3 N (1121 mg, 11.1 mmol), DMAP (45 mg, 0.37 mmol), the reaction solution was cooled to 0°C, MsCl (509 mg, 4.44 mol) was added dropwise, and the mixture was slowly returned to room temperature and stirred overnight. 30 mL of water was added to the reaction solution, and DCM was extracted three times. The organic phases were combined, washed twice with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (31C), a colorless oil (0.4 g, yield 58.1%).

[1122] Step 3: 7-chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (31D)

[1123] methyl 7-chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1124] Intermediate 3 (380 mg, 1.05 mmol) was placed in a 50 mL single-mouth bottle, and acetonitrile (20 mL), DIPEA (568 mg, 4.20 mmol), KI (183 mg, 1.05 mmol) and compound 31C (391 mg, 2.10 mmol) were added in sequence, and the mixture was heated to 60°C and stirred for 2 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to remove most of the reaction solvent, 30 mL of water was added to the residue, and EA was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=4 / 1) to obtain the title compound (31D) as a colorless oil (0.33 g, yield 75.7%).

[1125] Step 4: 7-Chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (31E)

[1126] 7-chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1127] Compound 31D (0.33 g, 0.79 mmol) was dissolved in THF / H 2 O (v / v = 2 / 1) 15 mL, add LiOH·H 2 O (166 mg, 3.95 mmol), the reaction temperature was raised to 60 ° C and stirred for 5 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to remove most of the organic solvent, 15 mL of water was added to the residue, and the pH was adjusted to 5 with 2N dilute hydrochloric acid, and EA was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (31E) as a white solid (0.30 g, yield 94.0%).

[1128] Step 5: 7-Chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 31)

[1129] 7-chloro-2-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1130] Compound 31E (0.20 g, 0.50 mmol) was dissolved in DMF (10 mL), HATU (285 mg, 0.75 mmol) was added, and DIPEA (193 mg, 1.50 mmol) and intermediate 5 (132 mg, 0.6 mmol) were added successively after stirring at room temperature for 15 minutes. After the addition, the mixture was stirred at room temperature overnight. 20 mL of water was added to the reaction solution, and EA was extracted 4 times. The organic phases were combined, washed twice with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound 31 (66 mg, yield 23.3%).

[1131] Preparative HPLC separation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm), the sample was dissolved in DMF, filtered with a 0.45μm filter head to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water); b. Gradient elution, mobile phase A content from 25% to 70%; c. Flow rate 12mL / min; d Elution time 20min; Retention time: 13.82min.

[1132] 1 H NMR (400 MHz, CDCl 3)δ11.50(s,1H),8.00(t,1H),6.85(s,1H),6.08(s,1H),4.27(d,2H),2.93(t,2H),2.56-2.53(m,1H),2.45(s,3H),2.31-2.26(m,1H), 2.17(s,3H),2.14(s,3H),1.99-1.84(m,3H),1.81-1.67(m,3H),1.62(s,3H),1.58-1.50(m,1H),1.44-1.33(m,2H),1.16-1.08(m,1H).

[1133] LCMS m / z=568.1[M+1] + .

[1134] Embodiment 32

[1135] 7-Chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 32)

[1136] 7-chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1137]

[1138] Step 1: (1-Fluorocyclopropyl)methanol (32B)

[1139] (1-fluorocyclopropyl)methanol

[1140] 1-Fluorocyclopropanecarboxylic acid (32A) (0.5 g, 4.8 mmol) was dissolved in anhydrous THF (10 mL), cooled to 0 °C in an ice bath, and LiAlH 4 (274 mg, 7.2 mmol), after addition, slowly return to room temperature and stir for 2 hours. The reaction solution was cooled to 0°C, quenched by adding water, and then Mg 2 SO 4(5 g), stirred for 10 minutes and then filtered, the filter cake was washed twice with THF, and the filtrate was concentrated under reduced pressure to give the title compound (32B) as a colorless oil (0.26 g, yield 60.5%).

[1141] Step 2: Methyl (1-fluorocyclopropyl)methanesulfonate (32C)

[1142] (1-fluorocyclopropyl)methyl methanesulfonate

[1143] (1-Fluorocyclopropyl)methanol (32B) (0.26 g, 2.9 mmol) was dissolved in DCM (10 mL), and Et 3 N (586 mg, 2.8 mmol), DMAP (35 mg, 0.29 mmol). MsCl (401 mg, 3.5 mol) was added dropwise at 0°C. After addition, the mixture was slowly returned to room temperature and stirred overnight. 20 mL of water was added to the reaction solution, and DCM was extracted three times. The organic phases were combined, washed twice with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (32C) as a colorless oil (0.37 g, yield 75.8%).

[1144] Step 3: 7-chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (32D)

[1145] methyl 7-chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1146] Intermediate 3 (400 mg, 1.10 mmol) was placed in a 50 mL single-mouth bottle, and acetonitrile (20 mL), DIPEA (568 mg, 4.40 mmol), KI (183 mg, 1.10 mmol) and compound 32C (370 mg, 2.20 mmol) were added in sequence, and the temperature was raised to 60°C and stirred for 2 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to remove most of the reaction solvent, 30 mL of water was added to the residue, and EA was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA=4 / 1) to obtain the title compound (32D) as a colorless oil (330 mg, yield 75.3%).

[1147] Step 4: 7-Chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (32E)

[1148] 7-chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1149] Compound 32D (330 mg, 0.83 mmol) was dissolved in THF / H 2 O (v / v = 2 / 1) 15 mL, add LiOH·H 2 O (174 mg, 4.15 mmol), after addition, stir at room temperature overnight. Concentrate under reduced pressure to remove most of THF, add 15 mL of water to the residue, add 2N dilute hydrochloric acid dropwise to adjust pH = 5, extract with EA 3 times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (32E) as a white solid (300 mg, yield 94.0%).

[1150] Step 5: 7-Chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 32)

[1151] 7-chloro-2-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1152] Compound 32E (200 mg, 0.52 mmol) was dissolved in DMF (10 mL), HATU (296 mg, 0.78 mmol) was added, and DIPEA (335 mg, 2.60 mmol) and intermediate 5 (137 mg, 0.62 mmol) were added successively after stirring at room temperature for 15 minutes. After the addition was completed, the mixture was stirred at room temperature overnight. 20 mL of water was added to the reaction solution, and EA was extracted 4 times. The organic phases were combined, washed twice with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound 32 (72 mg, yield 25.1%).

[1153] Preparative HPLC separation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm), the sample was dissolved in DMF, filtered with a 0.45μm filter head to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.05% ammonia water); b. Gradient elution, mobile phase A content from 25% to 70%; c. Flow rate 12mL / min; d. Elution time 20min; Retention time: 14.17min.

[1154] 1 H NMR (400 MHz, CDCl 3 )δ11.50(s,1H),8.00(t,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),3.02(d,2H),2.69(s,1H),2.63(s,1H),2.45(s,3H),2.17(s,3H),2.1 5(s,3H),2.03(t,2H),1.90-1.82(m,1H),1.73-1.70(m,2H),1.60(s, 3H),1.44-1.33(m,2H),0.98(t,1H),0.93(t,1H),0.65-0.59(m,2H).

[1155] LCMS m / z=550.2[M+1] + .

[1156] Embodiment 33

[1157] 7-Chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclic-5-amide (Compound 33)

[1158] 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1159]

[1160] Step 1: Methyl 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxacyclopentyl-5-amide (33A)

[1161] methyl 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1162] In a 50 mL single-mouth bottle, add intermediate 3 (250 mg, 0.77 mmol), dissolve in dichloromethane (10 mL), add 3-methoxycyclobutanone (120 mg, 1.20 mmol) and acetic acid (46 mg, 0.77 mmol), stir at room temperature for 1 h, add sodium triacetylborohydride (330 mg, 1.50 mmol), stir at room temperature for 16 h. The reaction solution was washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound methyl 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxacyclic-5-amide (33A), a yellow oil (280 mg, yield 89%).

[1163] LCMS m / z=410.2[M+1] + .

[1164] Step 2: 7-Chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (33B)

[1165] 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1166] 33A (280 mg, 0.68 mmol) was added to a 50 mL single-mouth bottle, methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL) were dissolved, sodium hydroxide (140 mg, 3.40 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 3-4 with hydrochloric acid (2 M), extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid (33B) as a white solid (230 mg, 85% yield).

[1167] LCMS m / z=396.1[M+1] + .

[1168] Step 3: 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclic-5-amide (Compound 33)

[1169] 7-chloro-2-(1-(3-methoxycyclobutyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1170] 33B (150 mg, 0.38 mmol) was added to a 50 mL single-mouth bottle, dissolved in DMF (5 mL), triethylamine (120 mg, 1.10 mmol) and HATU (170 mg, 0.45 mmol), and stirred at room temperature for 0.5 h. Intermediate 5 (100 mg, 0.57 mmol) was added, and stirred at room temperature for 16 h. Water (10 mL) was added to the reaction solution, and EA (10 mL × 2) was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by liquid phase preparation column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase is acetonitrile (A), water (containing 0.05% ammonia water) (B), gradient elution, A content = 20% to 70%, elution time 20 min, flow rate 15 mL / min, retention time: 13.0 min, column temperature: 30 ° C); the title compound 33 was separated (20 mg, 10% yield).

[1171] 1 H NMR (400 MHz, CDCl 3)δ12.47(s,1H),7.16(,1H),6.90(s,1H),6.07–6.01(m,1H),4.59(d,2H),3.60(t,1H),3.22(s,3H),3.0 0(d,2H),2.48(s,3H),2.43(ddt,2H),2.38–2.29(m,4H),2.25(s,3H),1.93–1.69(m,7H),1.61(brs,5H)

[1172] LCMS m / z=562.2[M+1] + .

[1173] Embodiment 34

[1174] 7-Chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxa-5-amide (Compound 34, Isomer 1 and Isomer 2)

[1175] 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1176]

[1177] Step 1: 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxa-5-carboxylic acid methyl ester (34A & 34B)

[1178] methyl 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1179] Dissolve intermediate 2 (0.50 g, 1.48 mmol) in 1,2-dichloroethane (5 mL), add trans-3-fluorocyclobutylamine hydrochloride (0.46 g, 3.69 mmol) and acetic acid (0.09 g, 1.48 mmol), and react at room temperature for 3 h. Add sodium triacetoxyborohydride (1.25 g, 5.90 mmol), and react at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 7-8, saturated aqueous sodium chloride solution (30 mL) was added, and the mixture was extracted with dichloromethane (25 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to give isomer 34A as a white solid (0.30 g, 49.1%), (petroleum ether: ethyl acetate (v / v) = 2:1, Rf = 0.45) to give isomer 34B as a white solid (0.30 g, 49.1%), (petroleum ether: ethyl acetate (v / v) = 2:1, Rf = 0.40).

[1180] LC-MS (ESI): m / z = 412.9 [M + H] + .

[1181] Step 2: 7-Chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxa-5-carboxylic acid (34C & 34D)

[1182] 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1183]

[1184] Dissolve 34A (0.30 g, 0.73 mmol) in methanol (10 mL), add water (2 mL) and sodium hydroxide (0.29 g, 7.3 mmol), and react at room temperature overnight. Add 2M dilute hydrochloric acid solution dropwise to adjust pH to 2-3, extract with ethyl acetate (25 mL×3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound, isomer 34C, as a white solid (0.30 g, 100%).

[1185] LC-MS (ESI): m / z = 398.9 [M+H] + .

[1186] Dissolve 34B (0.30 g, 0.73 mmol) in methanol (10 mL), add water (2 mL) and sodium hydroxide (0.29 g, 7.3 mmol), and react at room temperature overnight. Add 2M dilute hydrochloric acid solution dropwise to adjust pH to 2-3, extract with ethyl acetate (25 mL × 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound, isomer 34D, as a white solid (0.28 g, 96.6%).

[1187] LC-MS (ESI): m / z = 398.9 [M+H] + .

[1188] Step 3: 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxa-5-amide (Compound 34, Isomer 1 and Isomer 2)

[1189] 7-chloro-2-(4-((trans-3-fluorocyclobutyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1190] 34C (0.30 g, 0.75 mmol) was dissolved in DMF (10 mL), and N,N-diisopropylethylamine (0.29 g, 2.26 mmol), HATU (0.37 g, 0.98 mmol), and intermediate 5 (0.17 g, 0.90 mmol) were added. After the addition, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, saturated aqueous sodium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by preparative HPLC to obtain the product compound 34 isomer 1 (80 mg, 18.8%). Preparative HPLC separation conditions: instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), the sample was dissolved in DMF, filtered with a 0.45 μm filter head, and a sample solution was prepared. Preparative chromatographic conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium acetate), gradient elution, mobile phase A content from 40% to 70%, flow rate 15 mL / min. Elution time 18 min. Retention time: 11.97 min.

[1191] LC-MS (ESI): m / z = 564.2 [M+H] + .

[1192] 1 H NMR (400 MHz, CDCl 3 )δ6.86(s,1H),6.30(s,1H),5.28-5.07(m,1H),4.57(t,2H),4.00(d,1H),3.24(s,1H),2.87-2.68(m, 2H),2.62-2.47(m,5H),2.44(d,3H),2.20(d,3H),2.12-1.97(m,2H),1.97-1.59(m,7H),1.57(d,3H).

[1193] LC-MS (ESI): m / z = 564.2 [M+H] + .

[1194] 34D (0.28 g, 0.70 mmol) was dissolved in DMF (10 mL), and N,N-diisopropylethylamine (0.27 g, 2.11 mmol), HATU (0.35 g, 0.98 mmol), and intermediate 5 (0.15 g, 0.84 mmol) were added. After the addition, the mixture was reacted at room temperature overnight. Saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and saturated aqueous sodium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated aqueous sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by preparative HPLC to obtain the product compound 34 isomer 2 (280 mg, 70.5%). Preparative HPLC separation conditions: instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), the sample was dissolved in DMF, filtered with a 0.45 μm filter head, and a sample solution was prepared. Preparative chromatographic conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium acetate), gradient elution, mobile phase A content from 40% to 70%, flow rate 15 mL / min. Elution time 18 min. Retention time: 12.50 min.

[1195] 1 H NMR (400 MHz, CDCl 3 )δ6.87(s,1H),6.29(s,1H),5.36-5.03(m,1H),4.59(s,2H),4.01(s,1H),2.89(s,1H),2.83-2.63(m,2H),2.62-2.4 7(m,5H),2.43(s,3H),2.22(s,3H),2.12(d,2H),2.01(d,2H),1.88(t,1H),1.58(s,3H),1.49(dd,2H),1.28(q,2H).

[1196] LC-MS (ESI): m / z = 564.2 [M+H] + .

[1197] Embodiment 35

[1198] 7-Chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 35)

[1199] 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1200]

[1201]

[1202] Step 1: 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (35A)

[1203] Methyl 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1204] 7-Chloro-2-(4-((3,3-difluorocyclobutyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (4B) (500 mg, 1.16 mmol) and paraformaldehyde (157 mg, 1.74 mmol) were dissolved in 1,2-dichloroethane (10 mL), acetic acid (70 mg, 1.16 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Then, sodium triacetoxyborohydride (493 mg, 2.33 mmol) was slowly added and the mixture was reacted at room temperature for 4 hours. Water (100 mL) was slowly added to the reaction solution to quench the reaction. The mixture was separated and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 0:1 to 1:1) to give the title compound 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (35A) as a white powder solid (460 mg, yield 89%).

[1205] LCMS m / z=444.1[M+1] + .

[1206] Step 2: 7-Chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (35B)

[1207] 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[1208] 7-Chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (35A) (450 mg, 1.01 mmol) was dissolved in methanol (15 mL), and 2M sodium hydroxide aqueous solution (5 mL) was added dropwise, and the reaction was allowed to react at room temperature for 16 hours. Dilute hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to about 3, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL×5), and the organic phases were combined, washed with water (50 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid (35B) as a white powdery solid (420 mg, yield 96%).

[1209] LCMS m / z=430.2[M+1] + .

[1210] Step 3: 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxacyclo-5-carboxamide (Compound 35)

[1211] 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1212] 7-Chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid (35B) (420 mg, 1.047 mmol), 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 2) (277 mg, 1.26 mmol), and HATU (478 mg, 1.26 mmol) were dissolved in DMF (15 mL), and DIPEA (530 mg, 5.23 mmol) was added dropwise, and the reaction was carried out at room temperature for 8 hours. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL×5). The organic phases were combined, washed with water (50 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 0:1 to 10:1) to give the title compound 7-chloro-2-(4-((3,3-difluorocyclobutyl)(methyl)amino)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxe-5-carboxamide (Compound 35), (387 mg, yield 62%).

[1213] 1 H NMR (400MHz, DMSO) δ11.49(s,1H),8.01(t,1H),6.86(s,1H),6.07(s,1H),4.27(d,2H),3.15-3.04(m,1H),2.65-2.54(m,2 H),2.48-2.35(m,6H),2.16(d,6H),2.06(s,3H),2.03(d,1H),1.72(dd,4H),1.63(s,3H),1.52(dd,2H),1.41-1.31(m,2H).

[1214] LCMS m / z=596.2[M+1] + .

[1215] Embodiment 36

[1216] 8-(7-Chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxetane-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide (Compound 36)

[1217] 8-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide

[1218]

[1219]

[1220] Step 1: 3-Benzyl-8-ethynyl-3-azabicyclo[3.2.1]octane (36B)

[1221] 3-benzyl-8-ethynyl-3-azabicyclo[3.2.1]octane

[1222] 3-Benzyl-3-azabicyclo[3.2.1]octane-8-acetaldehyde (36A, synthesized by referring to the method of WO2007007282 using cyclopentanone as raw material) (3.4 g, 15 mmol) was dissolved in methanol (75 mL), potassium carbonate (6.1 g, 44 mmol) was added, and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (7.1 g, 37 mmol) was slowly added at 0°C under nitrogen protection. The reaction was allowed to react at room temperature for 3 hours. Ammonium chloride solution (10 mL) was slowly added to the reaction solution to quench, and the aqueous phase was extracted with ethyl acetate (150 mL×3). The organic phases were combined, washed with water (150 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 3-benzyl-8-ethynyl-3-azabicyclo[3.2.1]octane (36B) as a colorless oily liquid (2.3 g, yield 69%).

[1223] LCMS m / z=226.3[M+1] + .

[1224] Step 2: 2-(3-Benzyl-3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (36C)

[1225] methyl

[1226] 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1227] Dissolve 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (1b) (800 mg, 3.69 mmol) in toluene (10 mL), add triphenylphosphine (97 mg, 0.37 mmol) and dodecacarbonyl rhodium (5 mg, 0.04 mmol), and react at 120°C for 2 hours under nitrogen protection. Add a toluene (5 mL) solution of 3-benzyl-8-ethynyl-3-azabicyclo[3.2.1]octane (1.25 g, 5.54 mmol) dropwise, and react at 120°C for 2 hours. The reaction mixture was cooled to room temperature, and water was slowly added to the reaction solution. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with water (150 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 0:1 to 5:1) to give the title compound 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (36C) as a white powdery solid (520 mg, yield 34%).

[1228] LCMS m / z=442.21[M+1] + .

[1229] Step 3: 2-(3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxetan-5-carboxylic acid methyl ester (36D)

[1230] methyl 2-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate

[1231] 2-(3-Benzyl-3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (36C) (440 mg, 0.996 mmol) was dissolved in methanol (9 mL) and dioxane hydrochloride (3 mL), palladium carbon (62 mg, mass % = 0.4) was added, and the hydrogen was replaced at 120°C for 4 hours. The reaction solution was filtered through diatomaceous earth to remove the filter residue, and the filter residue was washed three times with methanol and concentrated to obtain the crude title compound 2-(3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (36D), a white powder solid (380 mg, yield 98%).

[1232] LCMS m / z=352.1[M+1] + .

[1233] Step 4: 7-Chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxane-5-carboxylic acid methyl ester (36E)

[1234] methyl 7-chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxole-5-carboxylate

[1235] Dissolve 2-(3-azabicyclo[3.2.1]octan-8-yl)-7-chloro-2,4-dimethylbenzo[d][1,3]dioxe-5-carboxylic acid methyl ester (36D) (100 mg, 0.284 mmol) in dichloromethane (15 mL), protect with nitrogen, slowly add triphosgene (30 mg, 0.1 mmol) at 0°C, add triethylamine (144 mg, 1.42 mmol) dropwise, and react at low temperature for 0.5 hours. Slowly add dichloromethane solution of methylamine hydrochloride (23 mg, 0.34 mmol) dropwise at 0°C, and react at room temperature for 1 hour. Ammonium chloride solution (10 mL) was slowly added to the reaction solution to quench the reaction. The mixture was separated and the aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with water (150 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 0:1 to 5:1) to give the title compound 7-chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxin-5-carboxylic acid methyl ester (36E) as a white powdery solid (47 mg, yield 34%).

[1236] LCMS m / z=410.1[M+1] + .

[1237] Step 5: 7-Chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxane-5-carboxylic acid (36F)

[1238] 7-chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxole-5-carboxylic acid

[1239] 7-Chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxin-5-carboxylic acid methyl ester (36E) (180 mg, 0.44 mmol) was dissolved in methanol (15 mL), and 2M sodium hydroxide aqueous solution (5 mL) was added dropwise, and the mixture was reacted at room temperature for 16 hours. Diluted hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to about 3, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL×5). The combined organic phases were washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7-chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxin-5-carboxylic acid (36F) as a white powdery solid (160 mg, yield 92%).

[1240] LCMS m / z=395.1[M+1] + .

[1241] Step 6: 8-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxetane-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide (Compound 36)

[1242] 8-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxol-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide

[1243] 7-Chloro-2,4-dimethyl-2-(3-(methylcarbamoyl)-3-azabicyclo[3.2.1]octan-8-yl)benzo[d][1,3]dioxin-5-carboxylic acid (36F) (160 mg, 0.63 mmol), 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 2) (168 mg, 0.76 mmol), and HATU (289 mg, 0.76 mmol) were dissolved in DMF (15 mL), and DIPEA (320 mg, 3.2 mmol) was added dropwise, and the reaction was carried out at room temperature for 8 hours. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL×5). The organic phases were combined, washed with water (50 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 0:1 to 10:1) to give the title compound 8-(7-chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxetane-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide (Compound 36), (220 mg, yield 95%).

[1244] LCMS m / z=561.3[M+1] + .

[1245] Resolution of compound 36

[1246] 8-(7-Chloro-2,4-dimethyl-5-(((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)benzo[d][1,3]dioxetane-2-yl)-N-methyl-3-azabicyclo[3.2.1]octane-3-carboxamide (Compound 36) (220 mg) was used for separation, and after separation, Isomer 1 of Compound 36 (retention time: 6.922 s, 96 mg) and Isomer 2 of Compound 36 (retention time: 9.746 s, 60 mg) were obtained.

[1247] Separation conditions: Instrument: MGⅡpreparative SFC (SFC-14); Column: ChiralPak AD, 250×30 mm I.D., 5 μm; Mobile phase: A for CO 2 and B for ethanol; gradient: B 50%; flow rate: 70 mL / min; back pressure: 100 bar; column temperature: 38°C; wavelength: 220 nm; cycle: ~8.2 min; sample preparation: dissolve the compound in 15 ml methanol / DCM; injection: 1 ml each time.

[1248] Isomer 1 of compound 36

[1249] 1 H NMR(400MHz,DMSO)δ11.50(s,1H),8.01(t,1H),6.86(s,1H),6.21(s,1H),6.08(s,1H),4.27(d,2H),3.65(d, 2H),2.79(d,2H),2.55-2.52(m,3H),2.45(s,3H),2.27(d,2H),2.20-2.10(m,7H),1.68(s,5H),1.36(d,2H).

[1250] LCMS m / z=561.3[M+1] + .

[1251] Isomer 2 of compound 36

[1252] 1 H NMR (400MHz, DMSO) δ11.50(s,1H),8.00(t,1H),6.86(s,1H),6.21(d,1H),6.07(s,1H),4.27(d,2H),3.65(d,J=11.6Hz,2 H),2.79(d,2H),2.54(d,3H),2.45(s,3H),2.27(d,2H),2.17(d,4H),2.13(s,3H),1.68(s,3H),1.36(d,2H),1.24(s,2H).

[1253] LCMS m / z=561.3[M+1] + .

[1254] Embodiment 37

[1255] 7-Chloro-2-(1-(cyclobutylmethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxo-5-carboxamide (Compound 37)

[1256] 7-chloro-2-(1-(cyclobutylmethyl)piperidin-4-yl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

[1257]

[1258] first step:

[1259] Intermediate 3 (200 mg, 0.55 mmol) was dissolved in DMF (6 mL), potassium carbonate (152 mg, 1.10 mmol) and bromomethylcyclobutane (164 mg, 1.10 mmol) were added thereto, and the mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and EA (20 mL) was used for extraction three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain a yellow solid 37A (190 mg, 88% yield).

[1260] LC-MS (ESI): m / z = 394.2 [M+H] + .

[1261] Step 2:

[1262] 37A (190 mg, 0.48 mmol) was dissolved in methanol (8 mL), and an aqueous solution of NaOH (201 mg, 5.00 mmol, 2 mL) was added. The reaction was stirred at 25°C and the reaction was completed by TLC monitoring. 2N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the solution was removed by concentration under reduced pressure to obtain a crude product. The crude product was soaked in a mixed solvent (DCM: MeOH = 10:1, 20 mL), and then filtered. The filtrate was concentrated to obtain 37B (180 mg, 95%).

[1263] LC-MS (ESI): m / z = 380.2 [M+H] + .

[1264] Step 3:

[1265] 37B (90 mg, 0.24 mmol) and DMF (6 mL) were added to a 50 mL single-mouth bottle to dissolve, triethylamine (64 mg, 0.63 mmol) and HATU (120 mg, 0.32 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 5 (186 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 5 h. Water (10 mL) was added to the reaction solution, and EA (20 mL × 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM: MeOH = 20: 1) to obtain compound 37 (30 mg, yield 23%).

[1266] LC-MS (ESI): m / z = 546.2 [M+H] + .

[1267] 1 H NMR (400 MHz, DMSO-d 6)δ11.50(s,1H),7.99(t,1H),6.85(s,1H),6.07(s,1H),4.27(d,2H),2.84(d,2H),2.45-2.48(m,1H),2.44(s,3H),2.28-2.30(m,2H), 2.17(s,3H),2.14(s,3H),1.95-2.01(...

Claims

1. A compound as shown below, its stereoisomers, and pharmaceutically acceptable salts, wherein the compound is selected from one of the following structures:

2. A pharmaceutical composition, characterized in that Containing the compound according to claim 1, its stereoisomers, pharmaceutically acceptable salts, and pharmaceutically acceptable excipients and / or carriers.

3. Use of the compound of claim 1, its stereoisomer, pharmaceutically acceptable salt, or the composition of claim 2 in the preparation of a medicament for treating an EZH2-mediated disease. The use according to claim 3, wherein the EZH2-mediated disease is a tumor or an autoimmune disease.

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