CYP11A1 inhibitors and their applications

Abstract

The present invention relates to CYP11A1 inhibitors and their uses. The present invention discloses compounds represented by formula (I), or their stereoisomers, deuterides, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutical compositions thereof, as well as their uses in the manufacture of pharmaceuticals for the treatment / prevention of CYP11A1-mediated diseases, where each group in formula (I) is as defined in the specification. [C1] TIFF2026514915000236.tif23156

Description

[Technical Field]

[0001] This invention relates to the pharmaceutical field, and more particularly to small molecule compounds having CYP11A1 selective inhibitory activity, their stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, and their uses in the manufacture of pharmaceuticals for treating related diseases. [Background technology]

[0002] Cytochrome p450 monooxygenase 11a1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is primarily involved in catalytic reactions related to drug metabolism and the synthesis of cholesterol, steroids, and other lipids. The CYP11A1 protein is localized in the inner mitochondrial membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in steroid hormone synthesis. This reaction takes place in adrenal cortical mitochondria and is catalyzed by cytochrome CYP11A1 (also known as P450scc), and functions in conjunction with CYP11A1, further including Adx and AdR. CYP11A1, Adx, and AdR belong to the cholesterol hydroxylase / lyase system (CH / L) and catalyze the initiation step of steroid synthesis in mammals, namely the process of producing pregnenolone from cholesterol. Pregnenolone is an important precursor of steroid hormones. The reaction process involves three consecutive monooxygenation reactions: the formation of 22R-hydroxycholesterol (22HC), the formation of 20R,22R-dihydroxycholesterol, and the cleavage of a C20-C22 bond. Each monooxygenation reaction requires the involvement of two electrons and one molecular oxygen. The electrons are supplied by NADPH and transferred to P450scc via NADPH-AdR and Adx. Adx and P450scc can form a complex and act as a mobile electron transporter.

[0003] CYP11A1 is primarily expressed in the placenta and responds to the synthesis of placental hormones such as progesterone and testosterone, while also being highly expressed in the adrenal glands and testes, and hardly expressed in other tissues. Inhibiting CYP11A1 (which is a key enzyme upstream of CYP17A1 in steroid biosynthesis) can achieve complete blockade of overall steroid biosynthesis. Therefore, CYP11A1 inhibitors have enormous potential to treat steroid hormone-dependent cancers, such as prostate cancer, even in the later stages of the disease, particularly in patients exhibiting hormone refractory disease. Recently, compounds with CYP11A1 inhibitory activity have been demonstrated to significantly inhibit tumor growth in vivo in a mouse CRPC xenograft model.

[0004] We have discovered a CYP11A1 inhibitor that exhibits high activity, high safety, and few side effects. This inhibitor has promising potential for clinical development and can be used to treat cancer or other proliferative disorders or conditions. [Overview of the Initiative] [Means for solving the problem]

[0005] The present invention provides small molecular weight compounds having CYP11A1 inhibitory activity, stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof, the compounds having structures as shown in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (II-a), (II-b), (II-c), (II-d), (II-e), (I-1), (I-2), (I-3), (I-4), and (I-5). [ka] X is selected from CH or N. X a It is selected from CH or N, A is a 4-14 member heterocyclic group, a 4-6 member heterocycloalkylene group, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4Selected from an alkyl group and a 5- to 6-membered cycloalkyl group, the heterocyclic group and heterocycloalkylene group contain 1 to 3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, heterocycloalkylene group, and alkyl group are optionally substituted with 1 to 4 Rs A substituted with In some embodiments, A is selected from a 4- to 14-membered heterocyclic group, a 5- to 6-membered cycloalkyl group, or a phenyl group. The heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S, and the heterocyclic group, cycloalkyl group, and phenyl group are optionally substituted with 1 to 4 Rs A substituted with In some embodiments, A is a 4- to 6-membered monocyclic heterocyclic group, a 5- to 6-membered heterocyclic group fused to a 5- to 6-membered heterocyclic group, a 5- to 6-membered heterocyclic group spiro-fused to a 5- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group fused to a 5- to 6-membered cycloalkyl group, a 4- to 6-membered heterocycloalkyl spiro-fused to a 5- to 6-membered heterocycloalkyl group, a 5- to 6-membered cycloalkyl fused to a 5- to 6-membered heterocycloalkyl group, a 5- to 6-membered cycloalkyl spiro-fused to a 5- to 6-membered heterocycloalkyl group, a 10- to 14-membered partially unsaturated tricyclic heterocycloalkyl group, cyclopropyl-NHSO2-C 1-2 alkyl group, -NHSO2-C 1-2 alkyl group, cyclohexyl group, or a 4-membered heterocycloalkylene group. The cycloalkyl group, heterocycloalkyl group, and heterocyclic group are optionally substituted with 1 to 4 Rs A substituted with In some embodiments, A is a 4- to 10-membered heterocycloalkyl group, a 4- to 6-membered heterocycloalkylene group, (C 3-4 cycloalkyl) 0-1 -NHSO2-C 1-2 alkyl group, or a 5- to 6-membered cycloalkyl group. The heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocycloalkyl group, and alkyl group are optionally substituted with 1 to 4 Rs A substituted with In some embodiments, A is a 4- to 8-membered heterocycloalkyl group, a 4- to 6-membered heterocycloalkylene group, (C3-4 Cycloalkyl) 0-1 -NHSO2-C 1-2 Selected from alkyl groups and 5-6 membered cycloalkyl groups, the heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocycloalkyl group, and alkyl group optionally contain 1-4 R A Replaced by, In some embodiments, A is a 4-6 member heterocycloalkyl group, a 4-6 member heterocycloalkylene group, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-2 Selected from alkyl groups and 5-6 membered cycloalkyl groups, the heterocycloalkyl group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocycloalkyl group, and alkyl group optionally contain 1-4 R A Replaced by, In some embodiments, A is a 4-6 member monocyclic heterocycloalkyl group, a 5-6 member heterocyclic group condensed into a 5-6 member heterocyclic group, a 5-6 member heterocyclic group spiro 5-6 member cycloalkyl group, a 5-6 member heterocyclic group condensed into a 5-6 member cycloalkyl group, a 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl condensed into a 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl spiro 5-6 member heterocycloalkyl group, a 10-14 member partially unsaturated tricyclic heterocycloalkyl group, or cyclopropyl-NHSO2-C 1-2 Alkyl alkyl group, -NHSO2-C 1-2 Selected from alkyl groups, cyclohexyl groups, and 4-membered heterocycloalkylene groups, the cycloalkyl group, heterocycloalkyl group, and heterocyclic group optionally have 1 to 4 R A Replaced by, In some embodiments, A is an azetidinyl group, an azacyclopentyl group, an azacyclohexyl group, epoxybutane, epoxypentane, epoxyhexane, a four-membered heterocycloalkylene group, or cyclopropyl-NHSO2-C 1-2 Alkyl alkyl, cyclobutyl-NHSO2-C 1-2Selected from alkyl groups, cyclopentyl groups, and cyclohexyl groups, the group contains 1 to 3 heteroatoms selected from N, O, and S, and the cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, epoxybutane, epoxypentane, epoxyhexane, heterocycloalkyl group, and alkyl group optionally contain 1 to 4 R A Replaced by, In some embodiments, A is selected from a 4- to 6-membered monocyclic heterocyclic group, and the heterocyclic group optionally has 1 to 4 R A Replaced by, In some embodiments, A is selected from a 7- to 9-membered bicyclic heterocyclic group, and the heterocyclic group is optionally comprised of 1 to 4 R A Replaced by, In some embodiments, A optionally comprises 1 to 4 R A Replaced with, [ka] One of the groups formed in this structure is selected, In some embodiments, A optionally comprises 1 to 4 R A Replaced with, [ka] One of the groups formed in this structure is selected, In some embodiments, A optionally comprises 1 to 4 R A Replaced with, [ka] One of the groups formed in this structure is selected, In some embodiments, A is [ka] One of the groups formed in this structure is selected, In some embodiments, ring A is [ka] One of the groups formed in this structure is selected, In some embodiments, A1 is [ka] Selected from the basis, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, In some embodiments, A1 is [ka] Selected from the basis, In some embodiments, A1 is [ka] Selected from the basis, In some embodiments, A1 is [ka] Selected from the basis, In some embodiments, A1 is [ka] Selected from the basis, R A2 is -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2)p -C(O)-(CH2) p -R a The alkyl group is selected from, and optionally, halogen, OH, NH2, CN, -O-haloC 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, A2 consists of 4-6 member monocyclic heterocycloalkyl groups, 5-6 member heterocyclic group condensation 5-6 member heterocyclic group, 5-6 member heterocyclic group spiro 5-6 member cycloalkyl groups, 5-6 member heterocyclic group condensation 5-6 member cycloalkyl groups, 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl groups, 5-6 member cycloalkyl condensation 5-6 member heterocycloalkyl groups, 5-6 member cycloalkyl spiro 5-6 member heterocycloalkyl groups, 10-14 member partially unsaturated tricyclic heterocycloalkyl groups, and cyclopropyl-NHSO2-C 1-2 Alkyl alkyl group, -NHSO2-C 1-2 Selected from alkyl groups and 4-membered heterocycloalkylene groups, the cycloalkyl group, heterocycloalkyl group, and heterocyclic group optionally have 1 to 4 R groups. A Replaced by, In some embodiments, the A2 ring optionally has 1 to 4 R A Replaced with, [ka] Selected from the basis, A3 can optionally have 1 to 4 R's. A Replaced with, [ka] Selected from the basis, In some embodiments, the above formula (Ia) [ka] In equation (I-2) [ka] In equation (Ib) [ka] Or in equation (II-a) [ka] Each of them operates independently. [ka] One of the groups formed in this structure is selected, B is selected from a phenyl group, a 6-12 membered bicyclic heterocyclic group, or a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R B Replaced by, In some embodiments, B is selected from a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocyclic group, or a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic group, heterocyclic group, and heteroaryl group optionally contain 1-4 R B Replaced by, In some embodiments, B is selected from a phenyl group, a 6-10 membered bicyclic heterocyclic group, or a 6-10 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R B Replaced by, In some embodiments, B is selected from a phenyl group, a 6-8 membered bicyclic heterocyclic group, or a 6-8 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R B Replaced by, In some embodiments, B is selected from a 6-membered heteroaryl group, a 5-6 member heterocyclic group condensed with a 5-6 member heteroaryl group, a 5-6 member carbon ring group condensed with a 5-6 member heteroaryl group, a 5-6 member heteroaryl group condensed with a 5-6 member heteroaryl group, a benzo-5-6 member heteroaryl group, a 5-6 member aryl group condensed with a 5-6 member aryl group, a 4-6 member heterocyclic spiro-5-6 member heteroaryl group, a phenyl group, a benzo-5-6 member heterocyclic group, and a 5-6 member heterocyclic group condensed with a 5-6 member heteroaryl group, wherein the heterocyclic group, heteroaryl group, carbon ring group, phenyl group, and aryl group are optionally composed of 1 to 4 R B Replaced by, In some embodiments, B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heteroaryl group, a 5-6 membered carbocyclic group condensed with a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, and a benzo-5-6 membered heteroaryl group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, and aryl group optionally have 1 to 4 R B Replaced by, In some embodiments, B is optionally 1 to 4 R B Replaced with, [ka] Selected from the basis, or [ka] Selected from, or [ka] Selected from, In some embodiments, B is optionally 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, B is optionally 1 to 4 R B Replaced with, [ka] One of the groups formed in this structure is selected, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, B1 can optionally contain 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, B1 is optionally 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, B2 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from the basis, or [ka] Selected from, In some embodiments, B2 is optionally 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, B2 is optionally 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, the B2 ring optionally has 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, the B2 ring optionally has 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, [ka] teeth, [ka] Selected from, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, B3 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from base B2, In some embodiments, B3 is optionally 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, the B3 ring optionally has 1 to 4 R B Replaced with, [ka] Selected from the basis, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, In some embodiments, the B4 ring optionally has 1 to 4 R B Replaced with, [ka] Selected from the basis, The B5 ring can optionally contain 1 to 4 R rings. B Replaced with, [ka] This is the basis, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, B6 can optionally contain 1 to 4 R's. B Replaced with, [ka] Selected from the basis, In some embodiments, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the following base, where ~~~ represents being connected to L1, and * represents being connected to L2, C is selected from a phenyl group, a 6-12 member partially unsaturated bicyclic heterocyclic group, an 8-14 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-10 member heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered partially unsaturated bicyclic heterocyclic group, or an 8-14 membered tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, and phenyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 6-10 member partially unsaturated bicyclic heterocyclic group, an 8-11 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-8 member heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 6-8 membered partially unsaturated bicyclic heterocyclic group, an 8-10 membered tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-7 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 6-7 membered partially unsaturated bicyclic heterocyclic group, an 8-10 membered tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-6 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 5-7 member heterocyclic condensed phenyl group, a 5-6 member carbocyclic condensed phenyl group, a 5-6 member heterocyclic condensed 5-6 member heteroaryl group, a 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl group, a 9-12 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-6 member heteroaryl group, wherein the heterocyclic group, heterocycloalkyl group, and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the phenyl group, heterocyclic group, carbocyclic group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 5-7 member heterocyclic condensed phenyl group, a 5-6 member carbocyclic condensed phenyl group, and a 5-6 member heterocyclic condensed 5-6 member heteroaryl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the phenyl group, heterocyclic group, and carbocyclic group optionally contain 1-4 R C Replaced by, In some embodiments, C is selected from a phenyl group, a 5-7 member heterocyclic condensed phenyl group, and a 5-6 member carbocyclic condensed phenyl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the phenyl group, heterocyclic group, and carbocyclic group optionally contain 1-4 R C Replaced by, In some embodiments, C is optionally 1 to 4 R C Replaced with, [ka] Selected from the basis, In some embodiments, C is optionally 1 to 4 R C Replaced with, [ka] Selected from the basis, In some embodiments, the C ring optionally has 1 to 4 R rings. C Replaced with, [Chemistry] selected from one of the following groups: C1 is optionally substituted with 1 to 4 R C and is selected from the following groups: [Chemistry] selected from the following group: In some embodiments, R C1 is -O-C 3-5 cycloalkyl group, C 3-5 cycloalkyl group, C 2-4 alkynyl group, -SCF3, -SF5, =O, -P(O)(C 1-4 alkyl)2, -NH-P(O)(C 1-4 alkyl)2, -CH2-O-C 1-4 alkyl group, and is selected from: In some embodiments, R C1 is -O-C 3-5 cycloalkyl group, C 3-5 cycloalkyl group, C 2-4 alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-4 alkyl)2, -(CH2) p -O-C 1-4 alkyl group, and is selected from: In some embodiments, R C1 is selected from cyclopropyl group, -O-cyclopropyl group, acetylene, -SCF3, -SF5, -NH-P(O)(CH3)2, -P(O)(CH3)2, -CH2-O-CH3. In some embodiments, the C1 ring is optionally substituted with 1 to 4 R C and is selected from the following groups: [Chemistry] selected from the following group: R A are each independently H, halogen, CN, OH, COOH, C 1-4 alkyl group, C 2-6 alkenyl group, C 2-6Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2,-NHC(O)-C 1-4 Alkyl alkyl groups, 3-6 member heterocycloalkyl groups, or -NHR a Selected from the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group, halogen, OH, NH2, CN, -O-haloC 1-4 Alkyl alkyl groups, deuterium, or C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, In some embodiments, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2 or -NHC(O)-C 1-4Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group may optionally be halogen, OH, NH2, CN, or -O-haloC. 1-2 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, In some embodiments, R A is -S(O)2-(CH2) p -R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group, -NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2 or -NHC(O)-C 1-2 Selected from alkyl groups, the alkyl group is optionally a halogen, OH, NH2, CN, -O-haloC 1-2 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, In some embodiments, R A is -S(O)2-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group, -C(O)-OR a -C(O)-CH2-R a ,-NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2 or -NHC(O)-C 1-2 Selected from alkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, CN, or D. In some embodiments, R A These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-C1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a or -C(O)N(C 1-4 Selected from alkyl)2, the alkyl group, alkenyl group, and alkynyl group can optionally be halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, In some embodiments, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-2 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are COOH and -OC, respectively, independently. 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are COOH and -OC, respectively, independently. 1-2 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are, independently, COOH, -OCH3, -OCH2CH3, -NH-S(O)2-CH3, -NH-S(O)2-CH2CH3, -S(O)2-CH3, -S(O)2-CH2CH3, and -S(O)2-CH3-R a -S(O)2-CH2CH3-R a , -P(O)-(CH2CH3)2, -P(O)-(CH3)2, -C(O)-OR a -CH2-C(O)-R a -C(O)-CH2-R a or -NHC(O)-R a Selected from, In some embodiments, R A These are, independently, -P(O)-(C 1-4Alkyl)2,-NH-S(O)2-C 1-4 Alkyl, -COOH, -C 1-4 Alkyl-C(O)-4~6 member heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-4 to 6-membered heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-C 3-6 Cycloalkyl groups, -C 1-4 Alkyl-C(O)-O-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-C 2-4 Alkynyl group, -S(O)2-C 1-4 Alkyl-C 3-5 Cycloalkyl groups, -S(O)2-C 1-4 Alkyl-5~6 member heteroaryl group, -S(O)2-C 1-4 Alkyl-O-Halo C 1-4 Alkyl alkyl group or -NHC(O)-C 3-5 Selected from cycloalkyl groups, In some embodiments, R A These are, independently, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-C 3-5 Selected from cycloalkyl groups, the alkyl group is optionally a halogen, OH, NH2, CN, -O-haloC 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are, independently, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2 or -NHC(O)-C 3-5Selected from cycloalkyl groups, the alkyl group is optionally a halogen, OH, NH2, CN, -O-haloC 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A is -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group or -NHC(O)-C 3-5 Selected from cycloalkyl groups, the alkyl group is optionally a halogen, OH, NH2, CN, -O-haloC 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A is -S(O)2-C 1-2 Alkyl-R a -S(O)2-C 1-2 Alkyl alkyl group, -C(O)-OR a -C(O)-CH2-R a or -NHC(O)-C 3-5 Selected from cycloalkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, and CN. In some embodiments, R A is -S(O)2-C 1-2 Alkyl-R a -S(O)2-C 1-2 Selected from alkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, and CN. In some embodiments, R A is -S(O)2-C 1-2 Selected from alkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, and CN. In some embodiments, R A is -NHC(O)-R a Selected from, In some embodiments, R A These are, independently, -S(O)2-CH3 and -P(O)-(CH3)2. [ka] Selected from, or [ka] -NHS(O)2-CH3, [ka] Selected from, In some embodiments, R A teeth, [ka] Selected from, In some embodiments, R A These are, independently, -CF3, -S(O)2CH3, -COCD3, -CON(CH3)2, -COCH2CN, -CH2CH2OH, -NHCOCD3, -NHCOCH3, -NHS(O)2CH3, -NHCOCF2CH3, -NHCOCH2CN, -NHCOCH2CF3, [ka] Selected from, In some embodiments, R A1 These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-2 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Selected from alkyl groups, the alkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and alkoxy group may optionally be halogens, C 1-4 Alkyl, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, 6-membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH, -S(O)2-CH3, or =CH2, =CHF, or =CF2, the alkyl group is further substituted with 1 to 3 groups selected from OH or CN, and the heterocycloalkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S. In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Alkyl alkyl group, C 1-2 Selected from alkyl groups, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 The alkyl group is further substituted with an alkyl group, an OH group, or a -S(O)2-CH3 group, and the alkyl group is further substituted with 1 to 3 groups selected from OH and CN. In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 The group is selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, -CHD2, methyl groups, and ethyl groups, and the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 The alkyl group is further substituted with an alkyl group, an OH group, or a -S(O)2-CH3 group, and the methyl group and ethyl group are further substituted with 1 to 3 groups selected from OH and CN. In some embodiments, R a The group is selected from ethynyl, propynyl, cyclopropyl, cyclobutyl, 4-6 member heterocycloalkyl, pyrazolyl, methoxy, ethoxy, -O-cyclopropyl, -CD3, methyl, and ethyl groups, and the cyclopropyl, cyclobutyl, heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups are optionally further substituted with groups F, Cl, Br, methyl, ethyl, -CD3, -CH2D, -CHD2, OH, and -S(O)2-CH3, and the methyl and ethyl groups are further substituted with 1-3 groups selected from OH and CN. In some embodiments, R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4Selected from alkyl groups, the alkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, alkyl group, and alkoxy group may optionally be halogens, C 1-4 Alkyl, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, 6-membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH groups, and -S(O)2-CH3 groups, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Selected from alkyl groups, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, and -CHD2, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R aThe group is selected from ethynyl group, propynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, methoxy group, ethoxy group, -O-cyclopropyl group, and -CD3, and the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group are optionally further substituted with groups F, Cl, Br, methyl group, ethyl group, -CD3, -CH2D, -CHD2, OH, and -S(O)2-CH3. In some embodiments, R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4 Selected from alkyl groups, the alkyl group is optionally a 6-membered heterocycloalkyl group, a 5-6 membered heteroaryl group, or C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH groups, and -S(O)2-CH3 groups, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Selected from alkyl groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4Selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, and -CHD2, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R a The group is selected from ethynyl group, propynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, methoxy group, ethoxy group, -O-cyclopropyl group, and -CD3, and the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group are optionally further substituted with groups of F, Cl, Br, methyl group, ethyl group, OH, and -S(O)2-CH3. In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, and a 5-6 membered heteroaryl group, wherein the heterocycloalkyl group and heteroaryl group are optionally a 6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, and C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH, or -S(O)2-CH3, and the heterocycloalkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, and a 5-6 membered heteroaryl group, wherein the heterocycloalkyl group and heteroaryl group are optionally a 6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, and C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-2 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH, or -S(O)2-CH3, and the heterocycloalkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with an alkyl group, OH or -S(O)2-CH3 group, In some embodiments, R a The group is selected from an ethynyl group, a propynyl group, a butynyl group, a cyclopropyl group, a 4-6 member heterocycloalkyl group, and a pyrazolyl group, and the ethynyl group, propynyl group, butynyl group, cyclopropyl group, heterocycloalkyl group, and pyrazolyl group may be optionally C 1-2 Further substituted with alkyl groups and OH groups, In some embodiments, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with alkyl groups and OH groups, In some embodiments, R a The group is selected from ethynyl, propynyl, cyclopropyl, 4-6 member heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups, and the cyclopropyl, heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups are optionally further substituted with F, Cl, Br, methyl, ethyl, or OH groups. In some embodiments, R a The group is selected from cyclopropyl, cyclobutyl, pyrazolyl, and -CD3, and the cyclopropyl, cyclobutyl, and pyrazolyl groups are optionally further substituted with F, Cl, Br, methyl, ethyl, -CD3, -CH2D, and -CHD2 groups. R BThese are H, halogen, CN, =O, OH, NO2, -SF5, and C, respectively, independently. 1-4 Alkyl, -P(O)-(CH3)2, -S(O)2-CH3, -S(O)2-CH2R a -, NH2, -C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-5 membered cycloalkyl group, halo C 1-2 A 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from alkyl, N, O, and S, or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein the alkoxy group, cycloalkyl group, heteroaryl group, and heterocycloalkyl group are optionally C 1-2 Further substituted with an alkyl group, In some embodiments, R B These are H, halogen, CN, =O, OH, -SF5, and C, respectively, independently. 1-2 Alkyl, -P(O)-(CH3)2, -S(O)2-CH3, -S(O)2-CH2R a -, NH2, -C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, halo C 1-2 A 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from alkyl, N, O, and S, or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein the alkoxy group, cycloalkyl group, heteroaryl group, and heterocycloalkyl group are optionally C 1-2 Further substituted with an alkyl group, In some embodiments, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, In some embodiments, R B These are F, Cl, Br, CN, =O, -SF5, CH3, CH2CH3, -S(O)2-CH3, -S(O)2-CH2CH3, NH2, -OCH3, -OCH2CH3, C 2-4 Alkenyl group, C 2-4 Selected from alkynyl groups, cyclopropyl groups, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CHClCH2Cl, -CHClCHCl2, -CHClCCl3, -CCl2CH2Cl, -CCl2CHCl2, -CCl2CCl3, and 5-6 membered heteroaryl groups, wherein the CH, CH2, CH3, CH2CH3, alkenyl groups, alkynyl groups, cyclopropyl groups, and heteroaryl groups are optionally C 1-2 Further substituted with an alkyl group, In some embodiments, R B Each of these groups is independently selected from F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, ethoxy group, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, cyclopropyl group, -CF3, -CHF2, -CH2F, 5-membered heteroaryl group, and 6-membered heteroaryl group, and the methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, and heteroaryl group are optionally further substituted with methyl or ethyl groups. In some embodiments, R BEach of these groups is independently selected from F, Cl, Br, =O, methyl group, ethyl group, methoxy group, ethoxy group, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, cyclopropyl group, -CF3, -CHF2, -CH2F, 5-membered heteroaryl group, and 6-membered heteroaryl group, and the methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, and heteroaryl group are optionally further substituted with methyl or ethyl groups. In some embodiments, R B These are, independently, a methoxy group, an ethoxy group, a cyclopropyl group, [ka] Selected from acetylene, propyne, -CH3, F, Cl, Br, ethylene, propylene, CN, CF3, =O, SF5, In some embodiments, R B Each of these groups is independently selected from F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, and ethoxy group, and the methyl group, ethyl group, methoxy group, and ethoxy group are optionally further substituted with methyl or ethyl groups. R C These are H, halogen, CN, =O, OH, NO2, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, -OC 3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Selected from alkyl groups, In some embodiments, R C These are H, halogen, CN, =O, OH, and C, respectively, independently. 1-2 Alkyl, halo C 1-2 alkyl group, -OC 3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C2-4 Alkenyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-2 Alkyl)2,-(CH2) p -OC 1-2 Selected from alkyl groups, In some embodiments, R C These are, independently, CN, OH, and C. 1-2 Alkyl group, =O, -O-cyclopropyl group, cyclopropyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) 0-1 -P(O)(C 1-2 Alkyl)2, C 1-2 C substituted with an alkoxy group 1-2 Selected from alkyl groups, In some embodiments, R C These are, independently, CN, OH, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Selected from alkynyl groups, In some embodiments, R C Each of these groups is independently selected from methyl, ethyl, -CF3, -CHF2, -CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, vinyl, propenyl, ethynyl, and propynyl groups, or selected from -O-cyclopropyl and cyclopropyl groups. In some embodiments, R C These are, independently, F, Cl, Br, CN, OH, -CH3, -CH2CH3, =O, -O-cyclopropyl group, cyclopropyl group, C 2-4 The group is selected from alkynyl group, -SCF3, -SF5, -NH-P(O)(CH3)2, -NH-P(O)(CH2CH3)2, -P(O)(CH3)2, -P(O)(CH2CH3)2, -CH2-O-CH3, and -CH2-O-CH2CH3.

[0006] In some embodiments, R CEach of these is independently selected from H, CN, OH, -CH3, -CH2CH3, =O, -O-cyclopropyl group, cyclopropyl group, acetylene, propyne, -SCF3, -SF5, -NH-P(O)(CH3)2, -NH-P(O)(CH2CH3)2, -P(O)(CH3)2, -P(O)(CH2CH3)2, -CH2-O-CH3, and -CH2-O-CH2CH3. In some embodiments, R C Each of these is independently selected from -CF3, -CHF2, -CH2CH2F, and cyclopropyl groups. Each Y1 is independently of the NHC. 1-4 Alkylene group, N(C) 1-4 Alkyl)C 1-4 An alkylene group is selected, and the alkylene group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. In some embodiments, Y1 is independently NHC 1-2 Alkylene group, N(C) 1-2 Alkyl)C 1-2 An alkylene group is selected, and the alkylene group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. In some embodiments, Y1 is independently selected from -NHCH2-, -NHCH2CH2-, -N(CH3)CH2-, -N(CH3)CH2CH2-, -N(CH2CH3)CH2CH2-, and the alkyl group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. L1 and L2 are independent of each other, W1-R L - Selected from W2, the left side of L1 is connected to A, the left side of L2 is connected to B, and L1 and L2 are not connected simultaneously. R L is a bond, C 1-4 Alkylene group, C 2-4 Selected from alkenylene groups, the alkylene group, alkenylene group optionally has 1 to 4 R L1 It is further replaced by, In some embodiments, RL is a bond, C 1-2 Alkylene group, C 2-4 Selected from an alkenylene group and a 3-6 membered cycloalkyl group, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1-4 R1s. L1 It is further replaced by, In some embodiments, R L The group is selected from -CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group, and the CH3, CH2, CH, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group can optionally have 1 to 4 R groups. L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 An alkoxy group is selected from a 3-6 membered cycloalkyl group, and the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 An alkoxy group is selected from a 3-6 membered cycloalkyl group, and the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. In some embodiments, R L1 These are F, Cl, Br, =O, -CH2-, -CH2CH2-, and C, respectively, independently. 2-4The group is selected from an alkenyl group, -O-CH2-, -O-CH2CH2-, and a cyclopropyl group, and the CH2, alkenyl group, and cyclopropyl group are optionally further substituted with 1 to 4 substituents selected from halogens, CN, OH, and NH2. In some embodiments, R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. W1 and W2 are independent of each other, and are bounded by -O-, -S-, and -NR. W1 -, -CONR W1 -, -NR W1 Selected from CO-, -C(=O)O-, and -OC(=O)-, In some embodiments, W1 and W2 are independently -O-, -S-, and -NR, respectively. W1 -, -CONR W1 -, -NR W1 Selected from CO-, -C(=O)O-, and -OC(=O)-, In some embodiments, W1 and W2 are independently selected from -O-, -S-, -NH-, -N(CH3)-, -CON(CH3)-, -N(CH3)CO-, -C(=O)O-, and -OC(=O)-, R W1 H, C 1-4 Selected from alkyl groups and halogens, In some embodiments, R W1 H, C 1-2 Selected from alkyl groups and halogens, In some embodiments, R W1 It is selected from H, -CH3, -CH2CH3, F, Cl, Br, In some embodiments, L1 is bonded to C 1-2 Alkylene-O,C 1-2 Alkylene group, N(C) 1-2 Alkylene)-C 1-2 Alkylene group, -O-, C 2-4Selected from alkenylene groups, the alkylene group optionally comprises 1 to 3 R groups. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, In some embodiments, L1 is selected from bonded, -CH2-O-, -CH2CH2-O-, -CH2-, -O-, -CH2CH2-, -N(CH3)-CH2-, ethylene, propylene, and the -CH2- is optionally composed of 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. In some embodiments, L1 is bonded to Halo C 1-4 Alkoxy group, C 1-4 Alkyl, -C(O)-O-, -O-CH2-CH=C-, -CH2-N(CH3)-, -N(CH3)-C(O)-, -O-, -SC 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, -CH(C 3-4 Selected from cycloalkyl)-O-, In some embodiments, L1 is bonded to C 1-2 Alkylene-O,C 1-2 Alkylene group, C 1-2 Alkylene-S,C 1-2 Alkylene-N(C) 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene group, -OC 1-3 Alkylene group, C 2-4 Alkenylene group, -N(C) 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2Selected from alkylene, -O-, -C(=O)-O-, and 3- to 6-membered cycloalkyl-O, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, In some embodiments, L1 is bonded to C 1-2 Alkylene-O,C 1-2 Alkylene group, N(C) 1-2 Alkylene)-C 1-2 An alkylene group is selected from -O-, and the alkylene group can optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, In some embodiments, L1 is selected from the bonds -CH2-O-, -CH2CH2-O-, -CH2-, -O-, -CH2CH2-, and -N(CH3)-CH2-, where the -CH2- is optionally composed of 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. In some embodiments, L1 is selected from bonded, -CH2-O-, -CH2CH2-O-, ethylene, and propylene, and the -CH2- is optionally 1 to 3 R L1 Further substitutions are made with R L1Each of these is independently selected from F, Cl, Br, methyl group, ethyl group, cyclopropyl group, and cyclobutyl group. In some embodiments, L2 is bonded, -C 1-4 Alkyl-NH-C(C 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C (HALO C) 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C(O)-,-CH2-N(CH3)-C 1-4 alkyl group - -CH2-C 3-4 Selected from cycloalkyl groups, or selected from -N(CH3)-, In some embodiments, L2 is bonded to C 1-2 Selected from alkylene group, -C(=O)-, 3- to 6-membered cycloalkyl group, -NH-, -O-, or -N(CH3)-, and the alkylene group, alkenylene group, and cycloalkyl group optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, In some embodiments, L2 is bonded to C 1-2 Selected from alkylene groups or selected from -N(CH3)-, the alkylene group optionally has 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, In some embodiments, L2 is selected from bond, -CH2-, -CH(CH3)-, or -N(CH3)-, and the -CH2-, -CH(CH3)- are optionally selected from 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. In some embodiments, L2 is selected from -CH2-, and the -CH2- is optionally selected from 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, methyl group, ethyl group, cyclopropyl group, and cyclobutyl group. In some embodiments, L 1A teeth, [ka] Selected from, L 1A The left end is connected to a piperidine ring, L 2A NH, O, [ka] Selected from, L 2A The left end is connected to a pyranone ring, p is selected from 0, 1, 2, 3, 4; n1, n2, n3, n4 are each independently selected from 0, 1, 2, 3; and m1, m2, m3, m4 are each independently selected from 0, 1, 2, 3. In some embodiments, n1 is selected from 1, 2, or 3. In some embodiments, n3 is selected from 0, 1, 2, and 3. In some embodiments, n1 is selected from 1 or 2. In some embodiments, n3 is selected from 0, 1, or 2. In some embodiments, p is selected from 0, 1, 2, and 3; in some embodiments, p is selected from 0, 1, and 2; in some embodiments, p is selected from 0 and 1; and in some embodiments, p is selected from 0. As options, B, L2, and C form tetracyclic heterocyclic groups with the atoms linked to them, and optionally, H, halogen, CN, OH, NO2, =O, COOH, and C. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with an alkyl group, Optionally, the compound satisfies at least one of the following conditions: A can choose 1 to 4 R A Replaced with, [ka] One of the groups formed in this structure is selected, 2) B can choose 1 to 4 R B Replaced with, [ka] One of the groups formed in this structure is selected, 3) The C ring can optionally contain 1 to 4 R rings. C Replaced with, [ka] Selected from one of the following bases, 4) B, L2, and C, together with the atoms linked to them, form a tetracyclic heterocycloalkyl group, and optionally, H, halogen, CN, OH, NO2, =O, COOH, C 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with an alkyl group, 5) At least one R A is -P(O)-(C 1-4 Alkyl)2,-NH-S(O)2-C 1-4 Alkyl, -COOH, -C 1-4 Alkyl-C(O)-4~6 member heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-4 to 6-membered heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-C 3-6 Cycloalkyl groups, -C 1-4 Alkyl-C(O)-O-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-C 2-4 Alkynyl group, -S(O)2-C 1-4 Alkyl-C 3-5 Cycloalkyl groups, -S(O)2-C 1-4 Alkyl-5~6 member heteroaryl group, -S(O)2-C 1-4 Alkyl-O-Halo C 1-4 Selected from alkyl groups, 6) At least one R B C 1-4 Alkyl, halogen, -C 1-4 Alkoxy group, CN, halo C 1-4 Alkyl alkyl group, SF5, -P(O)-(C 1-4 Alkyl)2, C 2-4 Alkynyl group, C 2-4 Alkenyl group, C 3-5 Cycloalkyl groups, C 5-6 Selected from heteroaryl groups, 7) At least one R C C 1-4 Alkyl, halogen, CN, C 2-4 Alkynyl group, SCF3, SF5, =O, -(NH) p -P(O)(C 1-4 Alkyl)2,-CH2-OC 1-4 Alkyl alkyl group, C 3-5 Cycloalkyl groups, -OC 3-5 Selected from cycloalkyl groups, 8) L1 is bonded, halo C 1-4Alkoxy group, C 1-4 Alkyl, -C(O)-O-, -O-CH2-CH=C-, -CH2-N(CH3)-, -N(CH3)-C(O)-, -O-, -SC 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, -CH(C 3-4 Selected from cycloalkyl)-O-, 9) L2 is a bond, -C 1-4 Alkyl-NH-C(C 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C (HALO C) 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C(O)-,-CH2-N(CH3)-C 1-4 alkyl group - -CH2-C 3-4 Selected from cycloalkyl groups.

[0007] As a specific technical example of the present invention, the present invention provides a compound represented by formula (I), its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts. [ka] A is selected from a 4-14 membered heterocyclic group, a 5-6 membered cycloalkyl group, and a phenyl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, cycloalkyl group, and phenyl group optionally contain 1-4 R A Replaced by, B is selected from a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocyclic group, or a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic group, heterocyclic group, and heteroaryl group optionally contain 1-4 R B Replaced by, C is selected from a phenyl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered partially unsaturated bicyclic heterocyclic group, and an 8-14 membered tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, and phenyl group optionally contain 1-4 R CReplaced by, L1 and L2 are independent of each other, W1-R L - Selected from W2, the left side of L1 is connected to A, the left side of L2 is connected to B, and L1 and L2 are not connected simultaneously. R L is a bond, C 1-4 Alkylene group, C 2-4 Selected from an alkenylene group and a 3-6 membered cycloalkyl group, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1-4 R1s. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 An alkoxy group is selected from a 3-6 membered cycloalkyl group, and the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are bounded by -O-, -S-, and -NR. W1 -, -CONR W1 -, -NR W1 Selected from CO-, -C(=O)O-, and -OC(=O)-, R W1 H, C 1-4 Selected from alkyl groups and halogens, As options, B, L2, and C form tetracyclic heterocyclic groups with the atoms linked to them, and optionally, halogen, CN, OH, NO2, =O, COOH, and C 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with 1 to 4 groups selected from alkyl groups, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2 or -NHC(O)-C 1-4 Alkyl alkyl groups, 3-6 member heterocycloalkyl groups, or -NHR a Selected from the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group, halogen, OH, NH2, CN, -O-haloC 1-4 Alkyl alkyl groups, deuterium, or C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, wherein the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S, or R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a or -C(O)N(C 1-4 Alkyl)2,-NHC(O)-(C 1-4 Selected from alkyl)2, the alkyl group, alkenyl group, and alkynyl group can optionally be halogen, OH, NH2, CN, and -O-haloC. 1-4Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Selected from alkyl groups, the alkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and alkoxy group may optionally be halogens, C 1-4 Alkyl, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, 6-membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH, -S(O)2-CH3, or =CH2, =CHF, or =CF2, the alkyl group is further substituted with 1 to 3 groups selected from OH or CN, and the heterocycloalkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O, or S, or R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4 Selected from alkyl groups, the alkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, alkyl group, and alkoxy group may optionally be halogens, C 1-4 Alkyl, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl group, 6-membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4The group is further substituted with 1 to 4 groups selected from alkyl groups, OH groups, and -S(O)2-CH3 groups, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. Or, R a C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-4 Selected from alkyl groups, the alkyl group is optionally a 6-membered heterocycloalkyl group, a 5-6 membered heteroaryl group, or C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH groups, and -S(O)2-CH3 groups, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. R B These are H, halogen, CN, =O, OH, NO2, -SF5, and C, respectively, independently. 1-4 Alkyl, -P(O)-(CH3)2, -S(O)2-CH3, -S(O)2-CH2R a -, NH2, -C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-5 membered cycloalkyl group, halo C 1-2 A 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from alkyl, N, O, and S, or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein the alkoxy group, cycloalkyl group, heteroaryl group, and heterocycloalkyl group are optionally C 1-2 Further substituted with an alkyl group, R C These are H, halogen, CN, =O, OH, NO2, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 alkyl group, -OC3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Selected from alkyl groups, p is selected from 0, 1, 2, 3, and 4.

[0008] Furthermore, the compound shown in formula (I), its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, wherein, A is a 4-14 member heterocyclic group, a 4-6 member heterocycloalkylene group, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 Selected from alkyl groups and 5-6 membered cycloalkyl groups, the heterocyclic group and heterocycloalkylene group contain 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, heterocycloalkylene group and alkyl group optionally contain 1-4 R A Replaced by, B is selected from a phenyl group, a 6-12 membered bicyclic heterocyclic group, or a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R B Replaced by, C is selected from a phenyl group, a 6-12 member partially unsaturated bicyclic heterocyclic group, an 8-14 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-10 member heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, heteroaryl group, and phenyl group optionally contain 1-4 R C Replaced by, Each Y1 is independently of the NHC. 1-4 Alkylene group, N(C) 1-4 Alkyl)C 1-4An alkylene group is selected, and the alkylene group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. L1 and L2 are independent of each other, W1-R L - Selected from W2, the left side of L1 is connected to A, the left side of L2 is connected to B, and L1 and L2 are not connected simultaneously. R L is a bond, C 1-4 Alkylene group, C 2-4 Selected from an alkenylene group and a 3-6 membered cycloalkyl group, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1-4 R1s. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 An alkoxy group is selected from a 3-6 membered cycloalkyl group, and the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are bounded by -O-, -S-, and -NR. W1 -, -CONR W1 -, -NR W1 Selected from CO-, -C(=O)O-, and -OC(=O)-, R W1 H, C 1-4 Selected from alkyl groups and halogens, As options, B, L2, and C form tetracyclic heterocyclic groups with the atoms linked to them, and optionally, H, halogen, CN, OH, NO2, =O, COOH, and C. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with an alkyl group, R A These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, and a 5-6 membered heteroaryl group, wherein the heterocycloalkyl group and heteroaryl group are optionally a 6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, and C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups and OH groups, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. R B These are H, halogen, CN, =O, OH, NO2, -SF5, and C, respectively, independently. 1-4 Alkyl, -P(O)-(CH3)2, -S(O)2-CH3, -S(O)2-CH2R a -, NH2, -C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-5 membered cycloalkyl group, halo C 1-2A 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from alkyl, N, O, and S, or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein the alkoxy group, cycloalkyl group, heteroaryl group, and heterocycloalkyl group are optionally C 1-2 Further substituted with an alkyl group, R C These are H, halogen, CN, =O, OH, NO2, and C, respectively, independently. 1-4 alkyl group, -OC 3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Selected from alkyl groups, p is selected from 0, 1, 2, 3, 4. The compound satisfies at least one of the following conditions: A can choose 1 to 4 R A Replaced with, [ka] One of the groups formed in this structure is selected, 2) B can choose 1 to 4 R B Replaced with, [ka] One of the groups formed in this structure is selected, 3) The C ring can optionally contain 1 to 4 R rings. C Replaced with, [ka] Selected from one of the following bases, 4) B, L2, and C, together with the atoms linked to them, form a tetracyclic heterocycloalkyl group, and optionally, H, halogen, CN, OH, NO2, =O, COOH, C 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with an alkyl group, 5) At least one R A is -P(O)-(C 1-4 Alkyl)2,-NH-S(O)2-C 1-4 Alkyl, -COOH, -C 1-4 Alkyl-C(O)-4~6 member heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-4 to 6-membered heterocycloalkyl groups, -C(O)-C 1-4 Alkyl-C 3-6 Cycloalkyl groups, -C 1-4 Alkyl-C(O)-O-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-4~6 member heterocycloalkyl groups, -S(O)2-C 1-4 Alkyl-C 2-4 Alkynyl group, -S(O)2-C 1-4 Alkyl-C 3-5 Cycloalkyl groups, -S(O)2-C 1-4 Alkyl-5~6 member heteroaryl group, -S(O)2-C 1-4 Alkyl-O-Halo C 1-4 Selected from alkyl groups, 6) At least one R B C 1-4 Alkyl, halogen, -C 1-4 Alkoxy group, CN, halo C 1-4 Alkyl alkyl group, SF5, -P(O)-(C 1-4 Alkyl)2, C 2-4 Alkynyl group, C 2-4 Alkenyl group, C 3-5 Cycloalkyl groups, C 5-6 Selected from heteroaryl groups, 7) At least one R C C 1-4Alkyl, halogen, CN, C 2-4 Alkynyl group, SCF3, SF5, =O, -(NH) p -P(O)(C 1-4 Alkyl)2,-CH2-OC 1-4 Alkyl alkyl group, C 3-5 Cycloalkyl groups, -OC 3-5 Selected from cycloalkyl groups, 8) L1 is bonded, halo C 1-4 Alkoxy group, C 1-4 Alkyl, -C(O)-O-, -O-CH2-CH=C-, -CH2-N(CH3)-, -N(CH3)-C(O)-, -O-, -SC 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, -CH(C 3-4 Selected from cycloalkyl)-O-, 9) L2 is a bond, -C 1-4 Alkyl-NH-C(C 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C (HALO C) 1-4 Alkyl)-, -C 1-4 Alkyl-NH-C(O)-,-CH2-N(CH3)-C 1-4 alkyl group - -CH2-C 3-4 Selected from cycloalkyl groups.

[0009] As a specific technical example of the present invention, we provide a compound represented by formula (I), its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, where, A is selected from a 4-6 member monocyclic heterocyclic group, a 7-9 member bicyclic heterocyclic group, a 5-6 member cycloalkyl group, and a phenyl group, and the heterocyclic group, cycloalkyl group, and phenyl group optionally have 1-4 R A Replaced by, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2an alkyl group, -S(O)2-C 1-2 an alkyl group, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-2 alkyl)2, -C(O)-OR a 、-(CH2) p -C(O)-(CH2) p -R a 、-NHC(O)-R a 、-C(O)N(C 1-4 alkyl)2 or -NHC(O)-C 1-4 an alkyl group or a 3- to 6-membered heterocycloalkyl group, -NHR a selected from, the alkyl group, alkenyl group, alkynyl group, and heterocycloalkyl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-haloC 1-2 an alkyl group, deuterium, or C 1-4 an alkyl group, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S, or, R A each independently is H, halogen, CN, OH, COOH, C 1-4 an alkyl group, C 2-4 an alkenyl group, C 2-4 an alkynyl group, -OC 1-4 an alkyl group, -NH-S(O)2-C 1-2 an alkyl group, -S(O)2-C 1-2 an alkyl group, -S(O)2-C 1-2 an alkyl-R a 、-P(O)-(C 1-2 alkyl)2, -C(O)-OR a 、-(CH2) p -C(O)-(CH2) p -R a 、-NHC(O)-R a or -C(O)N(C 1-4 alkyl)2, -NHC(O)-(C 1-4 alkyl)2 selected from, the alkyl group, alkenyl group, and alkynyl group are optionally halogen, OH, NH2, CN, -O-haloC 1-2Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Alkyl alkyl group, C 1-2 Selected from alkyl groups, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 The alkyl group is further substituted with an alkyl group, OH, -S(O)2-CH3 or =CH2, =CHF, =CF2 group, and the alkyl group is further substituted with 1 to 3 groups selected from OH, CN, or R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Selected from alkyl groups, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, Or, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Alkoxy group, -OC 3-6 Cycloalkyl groups, deuterated C 1-2 Selected from alkyl groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, p is selected from 0, 1, or 2. B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered carbocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, and a benzo-5-6 membered heterocyclic group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, and aryl group optionally have 1 to 4 R B Replaced by, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, C is selected from a phenyl group, a 5-7 member heterocyclic condensed phenyl group, a 5-6 member carbocyclic condensed phenyl group, and a 5-6 member heterocyclic condensed 5-6 member heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the phenyl group, heterocyclic group, carbocyclic group, and heteroaryl group optionally contain 1-4 R C Replaced by, R C These are, independently, CN, OH, and C. 1-2 Alkyl, halo C 1-2 Alkyl group, -O-cyclopropyl group, cyclopropyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) 0-1 -P(O)(C 1-2 Alkyl)2, C 1-2 C substituted with an alkoxy group1-2 selected from an alkyl group, L1 is a bond, C 1-2 alkylene - O, C 1-2 an alkylene group, N(C 1-2 alkylene)-C 1-2 an alkylene group, - O -, C 2-4 selected from an alkenylene group, and the alkylene group is optionally further substituted with 1 to 3 R L1 s, and R L1 are each independently halogen, =O, C 1-2 an alkyl group, haloC 1-2 an alkyl group, C 2-4 an alkenyl group, C 1-2 an alkoxy group, haloC 1-2 an alkoxy group, a 3 - to 6 - member cycloalkyl group, or, L1 is a bond, C 1-2 alkylene - O, C 1-2 an alkylene group, N(C 1-2 alkylene)-C 1-2 an alkylene group, - O - selected from, and the alkylene group is optionally further substituted with 1 to 3 R L1 s, and R L1 are each independently halogen, =O, C 1-2 an alkyl group, haloC 1-2 an alkyl group, C 2-4 an alkenyl group, C 1-2 an alkoxy group, haloC 1-2 an alkoxy group, a 3 - to 6 - member cycloalkyl group, L2 is a bond, C 1-2 an alkylene group, selected from - N(CH3)-, and the alkylene group is optionally further substituted with 1 to 3 R L1 s, and R L1 are each independently halogen, =O, C 1-2 an alkyl group, haloC 1-2 an alkyl group, C 2-4 an alkenyl group, C 1-2 an alkoxy group, haloC 1-2 an alkoxy group, a 3 - to 6 - member cycloalkyl group, and is selected from.

[0010] Furthermore, the compound shown in formula (I), its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, wherein, A is selected from a 4-14 membered heterocyclic group, a 5-6 membered cycloalkyl group, or a phenyl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, cycloalkyl group, and phenyl group optionally contain 1-4 R A Replaced by, B is selected from a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocyclic group, or a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic group, heterocyclic group, and heteroaryl group optionally contain 1-4 R B Replaced by, C is selected from a phenyl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered partially unsaturated bicyclic heterocyclic group, and an 8-14 membered tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, and phenyl group optionally contain 1-4 R C Replaced by, L1 and L2 are independent of each other, W1-R L - Selected from W2, the left side of L1 is connected to A, the left side of L2 is connected to B, and L1 and L2 are not connected simultaneously. R L is a bond, C 1-4 Alkylene group, C 2-4 Selected from an alkenylene group and a 3-6 membered cycloalkyl group, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1-4 R1s. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 An alkoxy group is selected from a 3-6 membered cycloalkyl group, and the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are bounded by -O-, -S-, and -NR. W1 -, -CONR W1 -, -NR W1 Selected from CO-, -C(=O)O-, and -OC(=O)-, R W1 H, C 1-4 Selected from alkyl groups and halogens, As options, B, L2, and C form tetracyclic heterocyclic groups with the atoms linked to them, and optionally, halogen, CN, OH, NO2, =O, COOH, and C 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl, -O-halo C 1-4 Substituted with 1 to 4 groups selected from alkyl groups, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a or -C(O)N(C 1-4 Alkyl)2,-NHC(O)-(C 1-4 Selected from alkyl)2, the alkyl group, alkenyl group, and alkynyl group can optionally be halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, R a C 2-4The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, and a 5-6 membered heteroaryl group, wherein the heterocycloalkyl group and heteroaryl group are optionally a 6 membered heterocycloalkyl group, a 5-6 membered heteroaryl group, and C 2-4 Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, OH, or -S(O)2-CH3, and the heterocycloalkyl group or heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S. R B These are H, halogen, CN, =O, OH, NO2, -SF5, and C, respectively, independently. 1-4 Alkyl, -P(O)-(CH3)2, -S(O)2-CH3, -S(O)2-CH2R a -, NH2, -C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-5 membered cycloalkyl group, halo C 1-2 A 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from alkyl, N, O, and S, or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein the alkoxy group, cycloalkyl group, heteroaryl group, and heterocycloalkyl group are optionally C 1-2 Further substituted with an alkyl group, R C These are H, halogen, CN, =O, OH, NO2, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 alkyl group, -OC 3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) p -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Selected from alkyl groups, p is selected from 0, 1, 2, 3, and 4.

[0011] As a specific technical proposal 3 of the present invention, the compound described in technical proposal 1, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, A is a 4-6 member monocyclic heterocycloalkyl group, a 5-6 member heterocyclic group condensed with a 5-6 member heterocyclic group, a 5-6 member heterocyclic group spiro 5-6 member cycloalkyl group, a 5-6 member heterocyclic group condensed with a 5-6 member cycloalkyl group, a 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl condensed with a 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl spiro 5-6 member heterocycloalkyl group, a 10-14 member partially unsaturated tricyclic heterocycloalkyl group, and cyclopropyl-NHSO2-C 1-2 Alkyl alkyl group, -NHSO2-C 1-2 Selected from alkyl groups, cyclohexyl groups, and 4-membered heterocycloalkylene groups, the cycloalkyl group, heterocycloalkyl group, and heterocyclic group optionally have 1 to 4 R A Replaced by, R A These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with alkyl groups and OH groups, p is selected from 0, 1, or 2.

[0012] As a specific technical proposal 4 of the present invention, the compound described in technical proposal 1, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered carbocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, a phenyl group, a benzo-5-6 membered heterocyclic group, and a 5-6 membered heterocyclic group condensed with a 5-6 membered heteroaryl group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, phenyl group, and aryl group are optionally given 1 to 4 R B Replaced by, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 It is further substituted with an alkyl group.

[0013] As a specific technical proposal 5 of the present invention, the compound described in technical proposal 1, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, C is selected from a phenyl group, a phenyl group formed by the condensation of a 5-7 member heterocyclic group, a phenyl group formed by the condensation of a 5-6 member carbocyclic group, a 5-6 member heteroaryl group formed by the condensation of a 5-6 member heterocyclic group, a 3-6 member cycloalkyl group formed by the condensation of a 5-6 member heterocycloalkyl group, a 9-12 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-6 member heteroaryl group. The heterocyclic group, heterocycloalkyl group, and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S. The phenyl group, heterocyclic group, carbocyclic group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group optionally contain 1-4 R atoms. C Replaced by, Each Y1 is independently of the NHC. 1-2 Alkylene group, N(C) 1-2 Alkyl)C 1-2 An alkylene group is selected, and the alkylene group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. R C These are, independently, CN, OH, and C. 1-2 Alkyl group, =O, -O-cyclopropyl group, cyclopropyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) 0-1 -P(O)(C 1-2 Alkyl)2, C 1-2 C substituted with an alkoxy group 1-2 Selected from alkyl groups.

[0014] As a specific example of the present invention, Technical Proposal 6 is a compound described in Technical Proposal 1, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, L1 is bond, C 1-2 Alkylene-O,C 1-2 Alkylene group, C 1-2 Alkylene-S,C 1-2 Alkylene-N(C) 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene group, -OC 1-3 Alkylene group, C 2-4 Alkenylene group, -N(C) 1-2Alkylene)-C(=O), -C(=O)-N(C 1-2 Selected from alkylene, -O-, -C(=O)-O-, and 3- to 6-membered cycloalkyl-O, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, L2 is a bond, C 1-2 The alkylene group, alkenylene group, and cycloalkyl group are selected from -C(=O)-, 3- to 6-membered cycloalkyl groups, -NH-, and -O-, and the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1 to 3 R groups. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups.

[0015] As a specific example of the present invention, Technical Proposal 7 is a compound described in Technical Proposal 1, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, A is a 4-6 member monocyclic heterocyclic group, a 5-6 member heterocyclic group condensed into a 5-6 member heterocyclic group, a 5-6 member heterocyclic spiro 5-6 member cycloalkyl group, a 5-6 member heterocyclic group condensed into a 5-6 member cycloalkyl group, a 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl condensed into a 5-6 member heterocycloalkyl group, a 5-6 member cycloalkyl spiro 5-6 member heterocycloalkyl group, a 10-14 member partially unsaturated tricyclic heterocycloalkyl group, and cyclopropyl-NHSO2-C 1-2 Alkyl alkyl group, -NHSO2-C 1-2Selected from alkyl groups, cyclohexyl groups, and 4-membered heterocycloalkylene groups, the cycloalkyl group, heterocycloalkyl group, and heterocyclic group optionally have 1 to 4 R A Replaced by, R A These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with alkyl groups and OH groups, p is selected from 0, 1, or 2. B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered carbocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, a phenyl group, a benzo-5-6 membered heterocyclic group, and a 5-6 membered heterocyclic group condensed with a 5-6 membered heteroaryl group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, phenyl group, and aryl group are optionally given 1 to 4 R B Replaced by, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, C is selected from a phenyl group, a phenyl group formed by the condensation of a 5-7 member heterocyclic group, a phenyl group formed by the condensation of a 5-6 member carbocyclic group, a 5-6 member heteroaryl group formed by the condensation of a 5-6 member heterocyclic group, a 3-6 member cycloalkyl group formed by the condensation of a 5-6 member heterocycloalkyl group, a 9-12 member tricyclic heterocyclic group, a Y1-phenyl group, and a Y1-5-6 member heteroaryl group. The heterocyclic group, heterocycloalkyl group, and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S. The phenyl group, heterocyclic group, carbocyclic group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group optionally contain 1-4 R atoms. C Replaced by, Each Y1 is independently of the NHC. 1-2 Alkylene group, N(C) 1-2 Alkyl)C 1-2An alkylene group is selected, and the alkylene group is optionally substituted with 1 to 4 groups selected from halogen, =O, OH, and CN. R C These are, independently, CN, OH, and C. 1-2 Alkyl group, =O, -O-cyclopropyl group, cyclopropyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) 0-1 -P(O)(C 1-2 Alkyl)2, C 1-2 C substituted with an alkoxy group 1-2 Selected from alkyl groups, L1 is bond, C 1-2 Alkylene-O,C 1-2 Alkylene group, C 1-2 Alkylene-S,C 1-2 Alkylene-N(C) 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene group, -OC 1-3 Alkylene group, C 2-4 Alkenylene group, -N(C) 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 Selected from alkylene, -O-, -C(=O)-O-, and 3- to 6-membered cycloalkyl-O, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, L2 is a bond, C 1-2 The alkylene group, alkenylene group, and cycloalkyl group are selected from -C(=O)-, 3- to 6-membered cycloalkyl groups, -NH-, and -O-, and the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1 to 3 R groups. L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups.

[0016] As a specific example of the present invention, Technical Proposal 8 is a compound described in Technical Proposal 2, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, A is selected from a 4-6 member monocyclic heterocyclic group, or a 7-9 member bicyclic heterocyclic group, or a 5-6 member cycloalkyl group or phenyl group, and the heterocyclic group, cycloalkyl group or phenyl group is optionally fitted with 1-4 R A Replaced by, R A These are H, halogen, CN, OH, COOH, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a or -NHC(O)-R a or -C(O)N(C 1-4 Alkyl)2,-NHC(O)-(C 1-4 Selected from alkyl)2, the alkyl group, alkenyl group, and alkynyl group can optionally be halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with an alkyl group, OH or -S(O)2-CH3 group, p is selected from 0, 1, or 2. B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered carbocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, and a benzo-5-6 membered heterocyclic group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, and aryl group optionally have 1 to 4 R B Replaced by, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, C is selected from a phenyl group, a phenyl group formed by the condensation of a 5-7 member heterocyclic group, or a phenyl group formed by the condensation of a 5-6 member carbocyclic group, or from a 5-6 member heteroaryl group formed by the condensation of a 5-6 member heterocyclic group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the phenyl group, heterocyclic group, carbocyclic group, and heteroaryl group optionally contain 1-4 R C Replaced by, R C These are, independently, CN, OH, and C. 1-2 Alkyl, halo C 1-2 Alkyl group, -O-cyclopropyl group, cyclopropyl group, C2-4 Alkenyl group, C 2-4 Alkynyl group, -SCF3, -SF5, -(NH) 0-1 -P(O)(C 1-2 Alkyl)2, C 1-2 C substituted with an alkoxy group 1-2 Selected from alkyl groups, L1 is bond, C 1-2 Alkylene-O,C 1-2 Alkylene group, N(C) 1-2 Alkylene)-C 1-2 An alkylene group is selected from -O-, and the alkylene group can optionally have 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, L2 is a bond, C 1-2 Selected from alkylene groups or selected from -N(CH3)-, the alkylene group optionally has 1 to 3 R L1 Further substitutions are made with R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups.

[0017] As a specific technical proposal 9 of the present invention, a compound described in any one of technical proposals 1, 3 to 7, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, having the structure of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), [ka] A1 can optionally contain 1 to 4 R A1Replaced with, [ka] Selected from the basis, X is selected from CH or N. R A2 is -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-(CH2) p -R a ,-P(O)-(C 1-4 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a The alkyl group is selected from, and optionally, halogen, OH, NH2, CN, -O-haloC 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, A2 consists of 4-6 member monocyclic heterocycloalkyl groups, 5-6 member heterocyclic group condensation 5-6 member heterocyclic group, 5-6 member heterocyclic group spiro 5-6 member cycloalkyl groups, 5-6 member heterocyclic group condensation 5-6 member cycloalkyl groups, 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl groups, 5-6 member cycloalkyl condensation 5-6 member heterocycloalkyl groups, 5-6 member cycloalkyl spiro 5-6 member heterocycloalkyl groups, 10-14 member partially unsaturated tricyclic heterocycloalkyl groups, and cyclopropyl-NHSO2-C 1-2 Alkyl alkyl group, -NHSO2-C 1-2 Selected from alkyl groups and 4-membered heterocycloalkylene groups, the cycloalkyl group, heterocycloalkyl group, and heterocyclic group optionally have 1 to 4 R groups. A Replaced by, B1 can optionally contain 1 to 4 R B Replaced with, [ka] Selected from the basis, B2 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from the basis, [ka] teeth, [ka] Selected from, B3 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from base B2, C1 can optionally contain 1 to 4 R C Replaced with, [ka] Selected from the basis, R C1 is, -OC 3-5 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 2-4 Alkynyl group, -SCF3, -SF5, =O, -P(O)(C 1-4 Alkyl)2,-NH-P(O)(C 1-4 Alkyl)2,-CH2-OC 1-4 Selected from alkyl groups, R A These are, independently, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a The alkyl group is selected from, and optionally, halogen, OH, NH2, CN, -O-haloC 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R A1 These are H, halogen, CN, OH, NO2, COOH, and C, respectively, independently. 1-2 Alkyl alkyl group, C 2-4Alkenyl group, C 2-4 Alkynyl group, -OC 1-2 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2 Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with alkyl groups and OH groups, n1, n2, n3, and n4 are each independently selected from 0, 1, 2, and 3. L 1A teeth, [ka] Selected from, L 1A The left end is connected to a piperidine ring, and the right end is connected to a pyranone ring. L 2A NH, O, [ka] Selected from, L 2A The left end is connected to a pyranone ring.

[0018] As a specific technical proposal 10 of the present invention, a compound described in any one of technical proposals 1, 3 to 7, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, having the structure of formula (II-a), (II-b), (II-c), (II-d), (II-e), [ka] X is selected from CH or N. A3 can optionally have 1 to 4 R's. A Replaced with, [ka] Selected from the basis, B4 can optionally contain 1 to 4 R's. B Replaced with, [ka] Selected from the basis, B5 can optionally contain 1 to 4 R's. B Replaced with, [ka] Selected from the basis, L 1A teeth, [ka] Selected from, L 1AThe left end is connected to a piperidine ring, and the right end is connected to a benzene ring. L 2A NH, O, [ka] Selected from, L 2A The left end is connected to a benzene ring, m1, m2, m3, and m4 are each independently selected from 0, 1, 2, and 3.

[0019] As a specific technical proposal 11 of the present invention, a compound described in any one of technical proposals 2 and 8, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt having the structure of formulas (I-1), (I-2), (I-3), and (I-4), [ka] X a It is selected from CH or N, A1 is [ka] Selected from the basis, B2 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] From this basis, or arbitrarily, 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the basis, B6 can optionally contain 1 to 4 R's. B Replaced with, [ka] Selected from the basis, B1 can optionally contain 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the above, or arbitrarily selected from 1 to 4 R B Replaced with, [ka] Selected from the basis, As an option, [ka] teeth, [ka] Selected from, R A is -S(O)2-(CH2) p -R a,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group, -NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2 or -NHC(O)-C 1-2 Alkyl alkyl groups or 3-6 member heterocycloalkyl groups, -NHR a The alkyl group and heterocycloalkyl group are selected from the following, and optionally the halogen, OH, NH2, CN, and -O-haloC. 1-2 Alkyl alkyl groups, deuterium, or C 1-2 Further substituted with 1 to 4 groups selected from alkyl groups, wherein the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S, or R A is -S(O)2-C 1-2 Alkyl-R a ,-P(O)-(C 1-2 Alkyl)2,-C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group or -NHC(O)-R a or -C(O)N(C 1-4 Selected from alkyl)2, the alkyl group is optionally halogen, OH, NH2, CN, -O-haloC 1-2 Further substituted with 1 to 4 groups selected from alkyl groups or deuterium, R B These are, independently, halogen, CN, and -P(=O)(C). 1-2 Alkyl)2,=O,-SF5,C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, cyclopropyl group, halo C 1-2Selected from alkyl groups and 5-6 membered heteroaryl groups, wherein the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group are optionally C 1-2 Further substituted with an alkyl group, R C These are, independently, CN, OH, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Selected from an alkynyl group, or selected from an -O-cyclopropyl group, a cyclopropyl group, or selected from -SF5, R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 The group is selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, -CHD2, methyl groups, and ethyl groups, and the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 The methyl group and ethyl group are further substituted with alkyl groups, OH groups, -S(O)2-CH3 groups, or =CH2, =CHF, =CF2 groups, and the methyl group and ethyl group are further substituted with 1 to 3 groups selected from OH and CN, or R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, and -CHD2, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with alkyl groups, OH groups, -S(O)2-CH3 groups, or R a C 2-4 Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4Selected from alkoxy groups, -O-cyclopropyl groups, -CD3, -CH2D, and -CHD2, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, Or, R a C 2-4 Alkynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C 1-4 Selected from alkoxy groups, the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C 1-2 Further substituted with an alkyl group, OH or -S(O)2-CH3 group, n1 is selected from 1, 2, or 3. n3 is selected from 0, 1, 2, and 3.

[0020] As a specific technical proposal 12 of the present invention, the compound described in technical proposal 11, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, R A is -S(O)2-(CH2) p -R a -S(O)2-C 1-2 Alkyl alkyl group, -C(O)-OR a -C(O)-CH2-R a ,-NHC(O)-R a , -C(O)N(C 1-4 Alkyl)2,-NHC(O)-(C 1-4 Alkyl)2 or -NHC(O)-C 1-2 Alkyl alkyl groups or 3-6 member heterocycloalkyl groups, -NHR a The alkyl group, heterocycloalkyl group is selected from, and the alkyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, CN or D or -CH3 or -CH2CH3, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, S, or, R A is -S(O)2-C 1-2 Alkyl-R a -S(O)2-C 1-2 Selected from alkyl groups, or -C(O)-OR a -C(O)-CH2-R a or -NHC(O)-R a or -C(O)N(C 1-4 Alkyl)2,-NHC(O)-(C 1-4 A alkyl group is selected from 2, and the alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, OH, NH2, CN, or D. R B Each of these groups is independently selected from F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, ethoxy group, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, cyclopropyl group, -CF3, -CHF2, -CH2F, 5-membered heteroaryl group, and 6-membered heteroaryl group, and the methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, and heteroaryl group are optionally further substituted with a methyl group or an ethyl group, or R B Each of these groups is independently selected from F, Cl, Br, =O, methyl group, ethyl group, methoxy group, ethoxy group, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, cyclopropyl group, -CF3, -CHF2, -CH2F, 5-membered heteroaryl group, and 6-membered heteroaryl group, and the methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, and heteroaryl group are optionally further substituted with methyl or ethyl groups. R C Each of these groups is independently selected from methyl, ethyl, -CF3, -CHF2, -CH2CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, vinyl, propenyl, ethynyl, and propynyl groups, or selected from -O-cyclopropyl, cyclopropyl, or -SF5. R aThe group is selected from ethynyl, propynyl, cyclopropyl, cyclobutyl, 4-6 member heterocycloalkyl, pyrazolyl, methoxy, ethoxy, -O-cyclopropyl, -CD3, methyl, and ethyl groups, and the cyclopropyl, cyclobutyl, heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups are optionally further substituted with groups of F, Cl, Br, methyl, ethyl, -CD3, -CH2D, -CHD2, OH, -S(O)2-CH3 or =CH2, =CHF, or =CF2, and the methyl and ethyl groups are further substituted with 1-3 groups selected from OH and CN, or R a The group is selected from ethynyl group, propynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, methoxy group, ethoxy group, -O-cyclopropyl group, and -CD3, and the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group are optionally further substituted with groups F, Cl, Br, methyl group, ethyl group, -CD3, -CH2D, -CHD2, OH, and -S(O)2-CH3. Or, R a The group is selected from ethynyl group, propynyl group, cyclopropyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, methoxy group, ethoxy group, -O-cyclopropyl group, and -CD3, and the cyclopropyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group are optionally further substituted with groups F, Cl, Br, methyl group, ethyl group, OH, and -S(O)2-CH3, or R a The group is selected from ethynyl, propynyl, cyclopropyl, 4-6 member heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups, and the cyclopropyl, heterocycloalkyl, pyrazolyl, methoxy, and ethoxy groups are optionally further substituted with F, Cl, Br, methyl, ethyl, OH, or -S(O)2-CH3 groups. n1 is selected from 1 or 2. n3 is selected from 0, 1, or 2. L1 is selected from bond, -CH2-O-, -CH2CH2-O-, -CH2-, -O-, -CH2CH2-, -N(CH3)-CH2-, ethylene, and propylene, and the -CH2- is optionally composed of 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. Alternatively, L1 is selected from the bonds -CH2-O-, -CH2CH2-O-, -CH2-, -O-, -CH2CH2-, and -N(CH3)-CH2-, and the -CH2- is optionally composed of 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group. L2 is selected from a bond, -CH2-, -CH(CH3)-, or -N(CH3)-, and the -CH2- and -CH(CH3)- are optionally selected from 1 to 3 R L1 Further substitutions are made with R L1 Each of these groups is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, and cyclobutyl group.

[0021] As a specific example of the present invention, Technical Proposal 13 is a compound described in Technical Proposal 11 or Technical Proposal 12, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein A1 is [ka] Selected from the basis, B2 can optionally select 1 to 4 R's.B Replaced with, [ka] Selected from the basis, R A is -NHC(O)-R a Selected from, R B Each of these groups is independently selected from F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, and ethoxy group, and the methyl group, ethyl group, methoxy group, and ethoxy group are optionally further substituted with methyl or ethyl groups. R C Each of these is independently selected from -CF3, -CHF2, -CH2CH2F, and cyclopropyl groups. R a The group is selected from cyclopropyl, cyclobutyl, pyrazolyl, and -CD3, and the cyclopropyl, cyclobutyl, and pyrazolyl groups are optionally further substituted with F, Cl, Br, methyl, ethyl, -CD3, -CH2D, and -CHD2 groups. n3 is selected from 1 or 2. L1 is selected from bond, -CH2-O-, -CH2CH2-O-, ethylene, and propylene, and the -CH2- is optionally composed of 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, methyl group, ethyl group, cyclopropyl group, and cyclobutyl group. L2 is selected from -CH2-, and -CH2- is optionally selected from 1 to 3 R L1 Further substitutions are made with R L1 Each of these is independently selected from F, Cl, Br, methyl group, ethyl group, cyclopropyl group, and cyclobutyl group.

[0022] As a specific technical example 14 of the present invention, a compound described in the present invention, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt having the structure of formula (I-5), [ka] Here, X a It is selected from CH or N, R A These are, independently, halogen, CN, OH, COOH, and C. 1-4 alkyl group, -OC 1-4 Alkyl alkyl group, -NH-S(O)2-C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -C(O)N(C 1-4 Alkyl)2,-NHC(O)-C 1-4 Alkyl alkyl group, -C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a , -NHR a Selected from 3-6 member heterocycloalkyl groups, wherein the alkyl group and heterocycloalkyl group are optionally halogens, OH, NH2, CN, and -O-haloC. 1-4 Alkyl alkyl groups, deuterium, or C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, and in some embodiments, R A These are, independently, halogen, CN, OH, COOH, and C. 1-2 alkyl group, -OC 1-2 Alkyl alkyl group, -NH-S(O)2-C 1-2 Alkyl group, -S(O)2-C 1-2 Alkyl group, -C(O)N(C 1-2 Alkyl)2,-NHC(O)-C 1-2 Alkyl alkyl group, -C(O)-OR a ,-(CH2) p -C(O)-(CH2) p -R a ,-NHC(O)-R a , -NHR a Selected from 3-4 member heterocycloalkyl groups, wherein the alkyl group and heterocycloalkyl group are optionally halogens, OH, NH2, CN, and -O-haloC. 1-2Alkyl alkyl groups, deuterium, or C 1-2 Further substitution with 1 to 4 groups selected from alkyl groups, R a C 1-4 Alkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -OC 3-6 Selected from cycloalkyl groups, the cycloalkyl group, heterocycloalkyl group, heteroaryl group can optionally be OH, -S(O)2-CH3, halogen, or C 1-4 Alkyl, halo C 1-4 Alkyl groups, deuterated C 1-4 Alkyl, -O-halo C 1-4 The group is further substituted with 1 to 4 groups selected from alkyl groups, the alkyl group is further substituted with 1 to 3 groups selected from OH and CN, the heterocycloalkyl group, the heteroaryl group contains 1 to 3 heteroatoms selected from N, O, and S, and in some embodiments, R a C 1-2 Alkyl groups, deuterated C 1-2 Alkyl alkyl group, C 1-2 Alkoxy group, 3-4 membered cycloalkyl group, 3-4 membered heterocycloalkyl group, 5 membered heteroaryl group, -OC 3-4 Selected from cycloalkyl groups, the cycloalkyl group, heterocycloalkyl group, heteroaryl group can optionally be OH, -S(O)2-CH3, halogen, or C 1-2 Alkyl, halo C 1-2 Alkyl groups, deuterated C 1-2 Alkyl, -O-halo C 1-2 The alkyl group is further substituted with 1 to 4 groups selected from alkyl groups, and the alkyl group is further substituted with 1 to 3 groups selected from OH and CN. R C These are H, halogen, CN, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 alkyl group, -OC 3-5 Cycloalkyl groups, C 3-5Selected from cycloalkyl groups, in some embodiments, R C These are, independently, H or halo C. 1-2 It is an alkyl group, and in some embodiments, R C These are, independently, H or CF3, B2 can optionally select 1 to 4 R's. B Replaced with, [ka] Selected from the basis, R B These are, independently, halogen, CN, =O, and C. 1-2 Alkyl alkyl, NH2, C 1-2 Alkoxy group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, Halo C 1-2 Selected from alkyl groups, n3 is selected from 0, 1, or 2. p is selected from 0, 1, or 2.

[0023] As a specific technical proposal 15 of the present invention, the compound described in technical proposal 14, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein, [ka] This involves selecting 1 to 4 R's arbitrarily. B Replaced with, [ka] Selected from the base, where ~~~ indicates that it is connected to the ring on the left.

[0024] The present invention relates to a compound, its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, wherein the compound is selected from, but is not limited to, the structures shown in Table 1 below.

[0025] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0026] The present invention further provides a pharmaceutical composition or pharmaceutical preparation comprising a compound described in any one of the above-mentioned technical proposals, its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0027] Furthermore, the present invention provides a composition or pharmaceutical preparation comprising 1 to 1500 mg of any one of the aforementioned technical proposals, its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a carrier and / or excipient.

[0028] The present invention further provides applications for the compound described in any one of the aforementioned technical proposals, its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, or composition described in any one of the aforementioned technical proposals, in the manufacture of pharmaceuticals for the treatment / prevention of CYP11A1-mediated diseases, wherein the CYP11A1-mediated disease is a steroid hormone-dependent cancer, and more preferably a prostate cancer.

[0029] The present invention further provides a method for treating a disease in a therapeutic mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the aforementioned technical proposals, its stereoisomer, deuteride, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount being preferably 1 to 1500 mg, and the disease being preferably prostate cancer. In some embodiments, the mammal described in the present invention includes humans.

[0030] The “effective dose” or “therapeutic effective dose” as described in this application comprises administering a sufficient amount of the compound disclosed herein that alleviates, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include 1-1500mg, 1-1400mg, 1-1300mg, 1-1200mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 1-500mg, 1-400mg, 1-300mg, 1-250mg, 1-200mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, and 5-1 500mg, 5~1000mg, 5~900mg, 5~800mg, 5~700mg, 5~600mg, 5~500mg, 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~150mg, 5~1 25mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10~1500mg, 10~1000mg, 10 ~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 1 0~125mg, 10~100mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20~1500mg, 20~1000 mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500mg, 20~400mg, 20~350mg, 20~300mg, 20~250mg, 20~200mg, 20~15 0mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40mg, 20~30mg, 50~1500mg, 50~1000mg,This includes, but is not limited to, the following dosage ranges: 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg, 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, and 100-200mg.

[0031] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit formulation (the amount of the active ingredient in the unit formulation is also called the "formulation specification"). In some embodiments, the pharmaceutical composition is available in doses of 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, and 21 mg. This includes, but is not limited to, 0 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg of the compound of the present invention or its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts.

[0032] A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention, its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is a CYP11A1-mediated disease, preferably prostate cancer.

[0033] A method for treating a disease in a mammal or a human, the method comprising administering to a subject a daily dose of a pharmaceutical compound of the present invention, its stereoisomers, deuterides, solvates, cocrystals or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient, the daily dose of which may be a single dose or divided dose, and in some embodiments, the daily dose is 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 7 This includes, but is not limited to, 5-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day, and in some embodiments, one The daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0034] The present invention relates to a kit, which may comprise a composition in the form of a single dose or multiple doses, the kit comprising the compound of the present invention or its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, the amount of the compound of the present invention or its stereoisomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts being the same as the amount in the pharmaceutical composition.

[0035] In the present invention, the amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt is, in each case, calculated in terms of the form of the free base.

[0036] "Formulation specifications" refer to the weight of the active ingredient contained in one unit formulation, one tablet formulation, or any other unit formulation.

[0037] Synthesis pathway Methods for producing CYP11A1 inhibitors are described in patent documents such as WO2018115591A1, and those skilled in the art can produce the compounds of the present invention by combining said documents with known organic synthesis techniques, the starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, including companies such as Taitan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Wuxing Kangde, and Bailingwei Technology.

[0038] Indexes of known chemical substances, compiled by the American Chemical Society's chemical information retrieval service, allow for the selective identification of specific and similar reactants. These indexes are available in many public and university libraries and online. For known chemicals not available in catalogs, it is optional to commission a custom chemical synthesizer to produce them, and many standard chemical suppliers offer custom synthesis services.

[0039] term Unless otherwise specified in this invention, the terms used in this invention have the following meanings.

[0040] In this specification, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0041] "Halogenation" or "halogen substitution" means that a hydrogen atom is substituted with one or more of the following selected from F, Cl, Br, I, or their isotopes, the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogens of the group being substituted, and unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and if the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens.

[0042] "Deuterated" or "deuterated product" refers to a situation in which a hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, or alkynyl group is substituted with at least one isotopic hydrogen atom. The upper limit of the number of deuterated groups is equal to the sum of the number of substituted hydrogen atoms in the group being substituted. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1 to 20 deuterium atom substitutions, more preferably 1 to 10 deuterium atom substitutions, even more preferably 1 to 6 deuterium atom substitutions, and even more preferably 1 to 3 deuterium atom substitutions.

[0043] "Alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group, which unless otherwise specified, is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, even more preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and various branched isomers thereof.

[0044] "Alkylene group" refers to a divalent linear and branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0045] "Cycloalkyl group" refers to a monovalent, non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, typically has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, [ka] or containing cycloheptyl, etc.

[0046] A "cycloalkylene group" is a divalent group of a "cycloalkyl group," and non-limiting examples include cyclopropylene groups, cyclobutylene groups, and the like.

[0047] A "heterocyclic ring" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from N, O, or S, and includes monocyclic heterocyclic rings, bridging bicyclic heterocyclic rings, fused bicyclic heterocyclic rings, spiro-dicyclic heterocyclic rings, etc. Unless otherwise specified, it is a 3 to 12-membered heterocyclic ring, more preferably a 4 to 12-membered heterocyclic ring, more preferably a 4 to 10-membered heterocyclic ring, and even more preferably a 4 to 7-membered heterocyclic ring. Its definition includes heterocycloalkyl groups and heteroaryl groups. The N and S in the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be linked to a heteroatom or carbon atom, and non-limiting examples include oxyranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrryl group, pyrimidinyl group, pyrazyl group, pyrazolyl group, pyridadinyl group, imidazolyl group, piperidinyl group, piperidinyl group, morpholino group, thiomorpholino group, 1,3-dithianyl group, and dihydrofuryl group. , dihydropyranyl group, dithiolanyl group, tetrahydrofuranyl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group and oxapiro[3.3]heptyl group, [ka] This includes, among others.

[0048] A "heterocyclylene group" is a divalent group corresponding to a "heterocyclic group," and non-limiting examples include imidazolyl groups, piperidinylene groups, and aziridinyl groups.

[0049] "Carbon ring" or "carbon ring group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbon ring group, including monocyclic carbon rings, bicyclic bridged rings, bicyclic parallel rings, bicyclic spiro rings, etc. Unless otherwise specified, it has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl groups and aryl groups. In non-limiting examples, monocyclic carbon rings include cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, or phenyl groups. [ka] The double-ring bridge includes, [ka] Including such as, a biring parallel ring is, [ka] The biring spiro ring includes, [ka] This includes, among others.

[0050] An "aryl group" refers to an aromatic carbon ring. Non-limiting examples include phenyl groups, naphthyl groups, and the like.

[0051] An "alkynyl group" refers to a linear or branched monounsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, and propargyl groups.

[0052] An "alkenyl group" refers to a linear or branched monounsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, an alkenyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include vinyl groups, propenyl groups, allyl groups, 2-butenyl groups, and 1-butenyl groups.

[0053] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group, and unless otherwise specified, -OC 1-8 It is an alkyl group, preferably -OC 1-6 It is an alkyl group, more preferably -OC 1-4 It is an alkyl group, and more preferably -OC 1-2 It is an alkyl group. Non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group and cyclobutoxy group, etc. "Haloalkoxy group" refers to -O-haloalkyl groups, and unless otherwise specified, -O-haloC 1-8 It is an alkyl group, preferably -O-haloC 1-6 It is an alkyl group, more preferably -O-haloC 1-4 It is an alkyl group, and more preferably -O-haloC 1-2 It is an alkyl group. Non-limiting examples include monofluoromethoxy groups, difluoromethoxy groups, trifluoromethoxy groups, difluoroethyloxy groups, etc.

[0054] "C 1-4 The alkylacyl group is C 1-4 This refers to alkyl-C(O)-. Non-limiting examples include formyl groups, acetyl groups, and propionyl groups.

[0055] "C 1-4 The alkylsulfonyl group is C 1-4 This refers to alkyl-S(O)2-. Non-limiting examples include methylsulfonyl groups, ethylsulfonyl groups, and propylsulfonyl groups.

[0056] A "hetero-aromatic ring" or "heteroaryl group" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridyl, furyl, pyranone, and pyridone.

[0057] A "heterocycloalkyl group" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle that generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, the heterocycloalkyl group further comprises 1 to 3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include azetidinyl groups, morpholino groups, piperazinyl groups, piperidinyl groups, tetrahydropyranyl groups, oxetanyl groups, and the like.

[0058] The "heterocycloalkylene group" is [ka] It refers to, but is not limited to, that.

[0059] "Optionally" or "optionally" means that the event or environment described thereafter may occur, but does not necessarily occur, and the description includes both cases where the event or environment occurs and cases where it does not. For example, "optionally substituted alkyl group with F" means that the alkyl group may be substituted with F, but does not necessarily have to be substituted with F, and indicates that this includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0060] "Pharmacologically acceptable salt" refers to a salt obtained by the reaction of the compound of the present invention with a non-toxic inorganic base or organic base, or by the reaction of the free base with a non-toxic inorganic acid or organic acid, in which the compound maintains the biological efficacy and properties of the free acid or free base.

[0061] "Pharmaceutical composition" means one or more of the compounds herein or their stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, or mixtures with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0062] A "carrier" refers to a system that does not cause significant irritation to the living body, does not cause the loss of the biological activity and properties of the administered compound, alters the method of drug administration to the human body and its distribution within the body, controls the rate of drug release, and delivers the drug to the target organ. Non-limited examples include microcapsules and microspheres, nanoparticles, and liposomes.

[0063] "Excipients" are substances that are not therapeutic agents themselves, but are added to pharmaceutical compositions as diluents, excipients, adhesives and / or mediators to improve their treatment and preservation properties, or to allow or facilitate the formation of a dosage form for administration. As is known to those skilled in the art, medicinal excipients can provide a variety of functions and may be described as wetting agents, buffers, suspension aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of medicinal excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa (9) Fat, suppository wax, (10) Oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, olive oil, corn oil and soybean oil, (11) Glycols, such as propylene glycol, (12) Polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (13) Esters, such as ethyl oleate and ethyl laurate, (14) Agar, (15) Buffers, such as magnesium hydroxide and aluminum hydroxide, (16) Alginic acid, (17) Water for endotoxin testing, (18) Isotonic saline solution, (19) Ringer's solution, (20) Ethanol, (21) pH buffer solution, (22) Polyesters, polycarbonates and / or polyanhydrides, and (23) Other non-toxic and suitable substances used in pharmaceutical formulations, but not limited to these.

[0064] "Stereoisomers" refer to isomers that arise from different arrangements of atoms in a molecule, and include cis-trans isomers, enantiomers, and conformational isomers.

[0065] A "solvate" refers to a substance formed when the compound or salt thereof of the present invention forms intermolecular non-covalent bonds with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0066] A "cocrystal" refers to a crystalline body formed when an active pharmaceutical ingredient (API) and a cocrystal compound (CCF) are bonded together by hydrogen bonds or other non-covalent bonds, where the pure states of the API and CCF are both solids at room temperature, and a fixed stoichiometric ratio exists between each component. Cocrystals are multi-component crystalline bodies, including not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate. [Modes for carrying out the invention]

[0067] The present invention will be described in detail below with reference to examples. Unless specific conditions are specified in the examples, the experiments were carried out according to general experimental methods. The examples given are for the purpose of better illustrating the present invention, and it should be understood that the present invention is not limited to the examples given. Non-essential improvements and adjustments made to the embodiments by those skilled in the art based on the above description of the invention are still within the scope of protection of the present invention.

[0068] Dess-Martin reagent, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one DIPEA: N,N-diisopropylethylamine NMP, N-methylpyrrolidine TBDMSCl:tert-butyldimethylchlorosilane DMAP: 4-dimethylNH2pyridine HATU:2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate T3P: Tricyclopropyl Phosphate Anhydride Intermediate 1: 2-(chloromethyl)-5-hydroxy-(4H)-pyran-4-one (Intermediate 1) [ka]

[0069] Kojic acid (20.0 g, 140.7 mmol) was dissolved in 40 ml of thionyl chloride and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was beaten with 100 ml of petroleum ether, filtered, and the filter cake was dried to obtain intermediate 1 (29.8 g, 90%).

[0070] LCMS(ESI): m / z = 161.2[M+H] 1 H NMR (400MHz,DMSO) δ 8.12 (s,1H),6.57(s,1H),4.66 (s,2H). Intermediate 2: 1-(methylsulfonyl)piperidine-4-yl)methanesulfonate methyl (Intermediate 2) [ka]

[0071] 4-hydroxymethylpiperidine (20.0 g, 175.4 mmol) was dissolved in 200 ml of acetonitrile, potassium carbonate (53.6 g, 386.0 mmol) was added, and the mixture was stirred mechanically at room temperature for 16 hours to allow it to react. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and then beaten with 100 ml of ethyl acetate:petroleum ether = 1:1 mixed solvent. The mixture was filtered, the filter cake was washed with water, and then dried to obtain intermediate 2 (47 g, 40%).

[0072] LCMS(ESI): m / z = 272.3[M+H] 1 H NMR (400MHz,CDCl3) δ 4.10 (d,2H),3.95 - 3.78 (m,2H),3.03 (s,3H),2.79 (s,3H),2.71-2.67 (m,2H),1.95 - 1.80 (m,3H),1.51 - 1.34 (m,2H). Intermediate 3: 5-hydroxy-2-(isoindole-2-ylmethyl)-4H-pyran-4-one (Intermediate 3) [ka]

[0073] Intermediate 1 (9.8 g, 61.0 mmol) and isoindole hydrochloride (19.0 g, 122.1 mmol) were dissolved in 200 ml of acetonitrile, and DIPEA (30.8 g, 244.2 mmol) was added. The mixture was stirred mechanically at room temperature for 16 hours to allow the reaction to proceed. After the reaction was complete, the reaction solution was filtered, and the filtered cake was beaten sequentially with 100 ml of water and 50 ml of ethyl acetate, filtered, and the filtered cake was dried to obtain intermediate 3 (47 g, 40%).

[0074] LCMS(ESI): m / z = 244.1[M+H] 1 H NMR (400MHz,DMSO) δ 9.06 (s,1H),8.06 (s,1H),7.39 - 7.04 (m,4H),6.41 (s,1H),3.95 (s,4H),3.78 (s,2H). Intermediate 4: 6-(isoindole-2-ylmethyl)-4-oxo-4H-pyran-3-yltrifluoromethanesulfonic acid ester [ka]

[0075] Step 1: At room temperature, the starting substrate intermediate 3 (1.0 g, 4.12 mmol) and triethylamine (1.26 g, 12.36 mmol) were dissolved in super-dehydrated DCM (10 mL), cooled to 0°C under nitrogen gas protection, and a solution of trifluoromethanesulfonic acid anhydride (1.75 g, 6.18 mmol) in super-dehydrated DCM (10 mL) was added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted for 1 hour. The reaction was quenched with 30 mL of saturated sodium bicarbonate, extracted with DCM (50 mL x 3), the organic phases were combined and washed with water (50 mL x 3), washed with saturated sodium chloride (50 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then column chromatography (ethyl acetate:petroleum ether = 0:1~1:1) was performed to obtain intermediate 4 (1.0 g, 65%). LC-MS (ESI): m / z = 376.1 [M+H] + . Example 1: [ka]

[0076] Step 1: Kojic acid (10.0 g, 70.4 mmol) and benzyl bromide (13.1 g, 77.4 mmol) were dissolved in 85 ml of methanol, and 85 ml of aqueous sodium hydroxide solution (3.38 g, 84.4 mmol, approximately 1 M solution) was added. The mixture was reacted at 80°C for 16 hours. After the reaction was complete, the reaction solution was added dropwise to 100 ml of ice water and extracted with dichloromethane (200 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound 1B (7.2 g, 41%). LCMS(ESI): m / z = 233.3[M+H]

[0077] Step 2: Compound 1B (7.20 g, 31.0 mmol) was suspended in 30 mL of aqueous methylamine solution, stirred overnight at 100°C under reflux, reacted for 16 hours, filtered, the filtered cake was suspended in 10 mL of ethyl acetate, stirred for 0.5 hours, filtered, and the filtered cake was dried to obtain the target compound 1C (5.12 g, 67%). LCMS(ESI): m / z = 246.2[M+H]

[0078] Step 3: Compound 1C (5.12 g, 20.9 mmol) was dissolved in 50 mL of ethyl acetate, and IBX (17.5 g, 62.6 mmol) was added. The mixture was reacted at 80°C for 16 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated and stirred at room temperature for 0.5 hours. The mixture was separated by silica gel column chromatography (PE:EA = 2:1) to obtain the target compound 1D (3.41 g, 51%). LCMS(ESI): m / z = 262.1[M+H]

[0079] Step 4: Compound 1D (2.71 g, 11.1 mmol) and isoindole (1.46 g, 12.3 mmol) were dissolved in 15 mL of tetrahydrofuran, acetic acid (1.02 g, 22.2 mmol) was added, and the mixture was reacted at 50°C for 3 hours. After the reaction, the mixture was cooled to room temperature, and sodium triacetoxyborohydride (4.70 g, 22.2 mmol) was added while stirring, and the mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was added dropwise to 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL x 3). The organic phases were combined, concentrated, and separated by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound 1E (1.36 g, 35%). LCMS(ESI): m / z = 347.5[M+H]

[0080] Step 5: Compound 1E (1.36 g, 3.92 mmol) was dissolved in 50 mL of methanol, 680 mg of palladium-carbon was added, and the mixture was purged three times with hydrogen gas. The reaction was carried out at atmospheric pressure and room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated and dried to obtain the target compound 1F (PE:EA=2:1) ​​(765 mg, 76%). LCMS(ESI): m / z = 257.2[M+H]

[0081] Step 6: Compound 1F (400 mg, 1.56 mmol) and intermediate 2 (466 mg, 1.72 mmol) were dissolved in 2 mL of DMF, cesium carbonate (1.02 g, 3.12 mmol) was added, and the mixture was reacted at 90°C for 2 hours. After monitoring the completion of the reaction by TLC, the reaction mixture was added dropwise to ice water and filtered. The filtered cake was purified by HPLC to obtain target compound 1 (152 mg, 22%).

[0082] LCMS(ESI): m / z = 432.1[M+H] 1H NMR (400MHz,DMSO) δ 7.53 (s,1H),7.28 - 7.14 (m,4H),6.25 (s,1H),3.88 (s,4H),3.78 (s,2H),3.77-3.75 (m,2H),3.72 (s,3H),3.62-3.56 (m,2H),2.86 (s,3H),2.77-2.68 (m,2H),1.89-1.80 (m,3H),1.35 - 1.22 (m,2H). Example 2: [ka]

[0083] Step 1: Dissolve 2A (7.00 g, 22.4 mmol) (synthesized according to patent CN114685415) and triethylamine (3.42 g, 33.6 mmol) in dichloromethane (50 mL). Add dropwise to a dichloromethane solution of methanesulfonic anhydride (4.68 g, 26.9 mmol) [trifluoromethanesulfonic anhydride dissolved in dichloromethane (20 mL)] at room temperature. After the dropwise addition is complete, stir at room temperature for 2 hours to allow the reaction to proceed. Monitor the reaction by LC-MS. After the reaction is complete, add water (20 mL) to the reaction mixture, stir at room temperature for 10 minutes, and then allow to stand to form stratification. Separate the organic phase, dry the organic phase over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (eluent:PE:EA = 1:1) to obtain compound 2B (6.64 g, yield: 76%). LCMS m / z=389.3[M+1] +

[0084] Step 2: Compound 2B (6.64 g, 17.0 mmol) and DIPEA (6.61 g, 51.2 mmol) were dissolved in acetonitrile (25 mL), and 2,3-dihydroisoindole hydrochloride (3.97 g, 25.5 mmol) was added. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. After monitoring the cessation of the reaction by LC-MS, the reaction mixture was filtered, the filter cake was beaten in water (25 mL), filtered, and the filter cake was further beaten with ethyl acetate / petroleum ether mixture (25 mL) (PE:EA = 1:1), filtered, and the filter cake was dried to obtain compound 2C (3.88 g, yield: 55%). 1 H NMR (400MHz,DMSO) δ 7.48 - 7.42 (m,2H),7.42 - 7.32 (m,3H),7.31 - 7.15 (m,4H),6.51 (s,1H),5.12 (s,2H),3.97 (s,4H),3.82 (s,2H).

[0085] Step 3: Under nitrogen gas protection, compound 2C (0.412 g, 1.0 mmol), potassium vinyltrifluoroborate (0.16 g, 1.2 mmol), and sodium carbonate (0.21 g, 2.0 mmol) were weighed and added to 1,4-dioxane (10 mL) and water (2 mL). Then tetrakistriphenylphosphine palladium (0.12 g, 0.1 mmol) was added. After the addition was complete, the mixture was heated for 4 hours until reflux occurred, and the reaction was monitored by TLC. The starting materials disappeared at the reaction endpoint (eluent, petroleum ether:ethyl acetate = 1:1). After the reaction was complete, the mixture was cooled to room temperature, concentrated, and then directly purified by column chromatography (eluent, ethyl acetate:petroleum ether = 1:1) to obtain the target compound 2D (0.323 g, yield: 89.87%). LCMS m / z=360.4[M+1] +

[0086] Step 4: Compound 2D (0.313 g, 0.87 mmol) was weighed and dissolved in trifluoroacetic acid (5 mL), then heated to 30°C and reacted. The reaction was monitored by TLC (developing agent, ethyl acetate:petroleum ether = 1:1, starting material disappeared at the reaction endpoint). After the reaction was complete, the solvent was concentrated to obtain the residue. The residue was adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (50 mL * 2), combined with the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 2E (0.22 g, yield: 93.9%). This crude product was used directly in the reaction of the next step. LCMS m / z=270.1[M+1] +

[0087] Step 5: Compound 2E (0.200 g, 0.74 mmol) was weighed and dissolved in sulfolane (10 mL), then intermediate 2 (0.24 g, 0.89 mmol) and cesium carbonate (0.36 g, 1.11 mmol) were added. After adding the intermediates, the mixture was heated to 80°C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water and ethyl acetate (80 mL x 2) were added to the reaction mixture to combine the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified using a preparative plate (ethyl acetate:methanol = 15:1) to obtain the target compound 2 (41 mg, yield: 12.46%).

[0088] LCMS m / z=445.3[M+1] + 1 H NMR (400MHz,DMSO) δ 7.26 - 7.18 (m,4H),6.91 - 6.84 (m,1H),6.39 (s,1H),6.04 - 6.00 (m,1H),5.69 - 5.66 (m,1H),4.00 (s,4H),3.93 - 3.91 (m,2H),3.85 (s,2H),3.59 - 3.56 (m,2H),2.85 (s,3H),2.75 - 2.69 (m,2H),1.86 - 1.79 (m,3H),1.36 - 1.26 (m,2H). Example 3: [ka]

[0089] Step 1: 3A (1.0 g, 7.96 mmol), 4-(2-bromoethyl)piperidine-1-carboxylate tert-butyl (2.79 g, 9.55 mmol), and potassium carbonate (2.20 g, 15.92 mmol) were dissolved in N,N-dimethylformamide (20 mL) and reacted overnight at 100 °C. After the reaction was cooled to room temperature, water (100 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried and concentrated, and then separated by column chromatography (PE / EA = 80% / 20%) to obtain 3B (820 mg, 30%). LC-MS (ESI): m / z = 337.2[M+H] + .

[0090] Step 2: 3B (820 mg, 2.44 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (617 mg, 6.10 mmol) and methanesulfonyl chloride (559 mg, 4.88 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react overnight at room temperature. Water (20 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was dried to obtain crude product 3C. LC-MS (ESI): m / z = 359.3 [M + H] + .

[0091] Step 3: 3C (600 mg, 1.45 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (293 mg, 2.90 mmol) and 2,3-dihydroisoindole hydrochloride (270 mg, 1.74 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction was concentrated and then separated by column chromatography (PE / EA = 70% / 30%) to obtain 3D (250 mg, 39%). LC-MS (ESI): m / z = 438.2[M+H] + .

[0092] Step 4: 3D (250 mg, 0.57 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1.5 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After concentrating the reaction, crude product 3E was obtained. LC-MS (ESI): m / z = 338.5 [M + H] + .

[0093] Step 5: 3E (190 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (170 mg, 1.68 mmol) and methanesulfonyl chloride (128 mg, 1.12 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was reacted at room temperature for 2.5 hours. After concentrating the reaction, the residue was separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20%-70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 3. LC-MS (ESI): m / z = 416.2[M+H] + . Example 4: [ka]

[0094] Step 1: Compound 5-(chloromethyl)quinoline-8-ol hydrochloride (200 mg, 0.87 mmol) and potassium carbonate (720 mg, 5.21 mmol) were dissolved in acetonitrile (10 ml), and isoindoline hydrochloride (150 mg, 0.95 mmol) was added. The mixture was reacted at 70°C for 20 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated to obtain compound 4B (240 mg, 99.90%). LC-MS (ESI): m / z = 277.20 [M + H] + .

[0095] Step 2: Compound 4B (100 mg, 0.36 mmol), intermediate 2 (100 mg, 0.36 mmol), and cesium carbonate (180 mg, 0.54 mmol) were added to the reaction flask and dissolved in DMF (5 ml). The mixture was reacted at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (50 ml), and then extracted twice with ethyl acetate (50 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by pre-TLC (6 mg, 3.7%).

[0096] 1 H NMR (400MHz,CDCl3) δ 8.95 - 8.93 (m,1H),8.72 - 8.70 (m,1H),7.48 - 7.40 (m,2H),7.20 - 7.13 (m,4H),6.99 - 6.97 (m,1H),4.23 (s,2H),4.11 - 4.10 (m,2H),3.97 - 3.85 (m,6H),2.81 (s,3H),2.81 - 2.72 (m,2H),2.35 - 2.22 (m,1H),2.16 - 2.14 (m,2H),1.59 - 1.48 (m,2H). LC-MS (ESI): m / z = 452.30 [M + H] + . Example 5: [ka]

[0097] Step 1: Under nitrogen gas protection, compound 2C (0.618 g, 1.5 mmol) was weighed and added to a mixed solution of 1,4-dioxane and water (35 mL, 1,4-dioxane:water = 30:5). Then, methylboronic acid (0.885 g, 15 mmol), sodium carbonate (2.38 g, 15.0 mmol), and Pd(dppf)Cl2 (0.219 g, 0.3 mmol) were added in sequence. The mixture was then heated to 100°C and allowed to react for 5 hours. The reaction was monitored by LC-MS. The mixture was then cooled to room temperature after the reaction was complete, the solvent was concentrated, and ethyl acetate (100 mL) and water (50 mL) were added to separate the organic phase. The aqueous phase was further extracted once with ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1.5:1) to obtain the target compound 5A (0.40 g, 76.92%). LC-MS (ESI): m / z = 348.2 [M + H] + .

[0098] Step 2: Compound 5A (0.400 g, 1.15 mmol) was weighed and dissolved in trifluoroacetic acid (10 mL), then heated to 40°C and reacted. The reaction was monitored by TLC (developing agent, ethyl acetate:petroleum ether = 1:1.5, the starting material disappeared at the reaction endpoint), and after the reaction was complete, the solvent was concentrated to obtain the residue. The residue was adjusted to pH=8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (100 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 5B (0.29 g, yield: 97.97%), which was used directly in the reaction of the next step. LCMS m / z=258.2[M+1] +

[0099] Step 3: Compound 5B (0.290 g, 1.13 mmol) was weighed and dissolved in DMF (20 mL), then added to intermediate 2 (0.36 g, 1.13 mmol) and cesium carbonate (0.554 g, 1.70 mmol). After adding the compounds, the mixture was heated to 80°C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water and ethyl acetate (100 mL x 2) were added to the reaction solution to combine the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified using a preparative plate (ethyl acetate:methanol = 10:1) to obtain the target compound 5 (200 mg, yield: 40.98%).

[0100] LCMS m / z=445.3[M+1] + 1 H NMR (400MHz,DMSO-d6) δ 7.35 - 7.07 (m,4H),6.34 (s,1H),3.96 (s,4H),3.84 - 3.82 (m,2H),3.76 (s,2H),3.59- 3.56 (m,2H),2.85 (s,3H),2.75 - 2.69 (m,2H),2.29 (s,3H),1.86 - 1.77 (m,3H),1.35 - 1.25 (m,2H). Example 6: [ka]

[0101] Step 1: In a 500 mL single-necked flask, 6-bromochromone-2-carboxylic acid (6A) (12 g, 44.62 mmol) was dissolved in tetrahydrofuran (360 mL), and N,N'-carbonyldiimidazole (7.24 g, 44.62 mmol) was added under ice bath. After adding, the mixture was stirred at room temperature for 2 hours. Under ice bath, sodium borohydride (2.53 g, 66.93 mmol) was slowly added little by little, and after adding, the mixture was stirred at room temperature overnight to allow the reaction to proceed. After the reaction was complete, methanol was added under ice bath to quench the reaction, and the mixture was diluted with ethyl acetate (600 mL). The organic phase was washed three times with water (300 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6B (3.2 g, yield: 28%).

[0102] Step 2: In a 250 mL single-necked flask, compound 6B (3.2 g, 12.55 mmol) was dissolved in dry dichloromethane (128 mL). Triethylamine (4.44 g, 43.93 mmol) was added under ice bath conditions, and after the addition was complete, methanesulfonyl chloride (2.16 g, 18.83 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (200 mL), the organic phase was washed twice with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6C (3.4 g, yield: 81%), which was used directly in the next step.

[0103] Step 3: In a 250 mL single-necked flask, compound 6C (3.4 g, 10.21 mmol) was dissolved in dry dichloromethane (102 mL). Under ice bath, triethylamine (3.62 g, 35.73 mmol) was added, and after the addition was complete, isoindoline (1.28 g, 10.72 mmol) was slowly added under ice bath, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with dichloromethane (200 mL), the organic phase was washed twice with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain compound 6E (2.4 g, yield: 66%).

[0104] Step 4: Compound 6E (1.6 g, 4.49 mmol), bis(pinacolato)diborone (1.71 g, 6.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.66 g, 0.9 mmol), and potassium acetate (1.54 g, 15.71 mmol) were dissolved in 1,4-dioxane (80 mL), and the mixture was reacted at 80°C for 2 hours after being purged three times with nitrogen gas. After the reaction was complete, the mixture was cooled to room temperature and then used directly in the next step.

[0105] Step 5: To the above 6F (1.81 g, 4.49 mmol) reaction solution, water (20 mL) was added to quench the reaction from the previous step. Then, 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylate tert-butyl (6G) (2.23 g, 6.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.66 g, 0.9 mmol), and potassium carbonate (2.17 g, 15.71 mmol) were added, and the mixture was purged with nitrogen gas three times before being reacted overnight at 100°C. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (400 mL), the organic phase was washed three times with water (200 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:1) to obtain compound 6H (1.2 g, yield: 58%).

[0106] Step 6: Compound 6H (1.2 g, 2.62 mmol) was dissolved in methanol (120 ml), palladium-carbon hydroxide (0.18 g, 1.28 mmol) was added, and the mixture was substituted three times with hydrogen gas. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, diatomaceous earth was placed over the reaction solution, and the solution was filtered. The filtrate was concentrated to obtain compound 6I (1.15 g, yield: 95%).

[0107] Step 7: 6I (500 mg, 1.09 mmol) and dichloromethane (8 ml) were added to a 25 ml single-necked flask, and trifluoroacetic acid (4 ml) was added. The mixture was reacted at room temperature for 1 hour. After complete reaction, the reaction mixture was concentrated to obtain compound 6J (390 mg, yield: 99%).

[0108] Step 8: In a 100 mL single-necked flask, compound 6 J (390 mg, 1.08 mmol) was dissolved in dry dichloromethane (20 mL), and triethylamine (382 mg, 3.78 mmol) was added under an ice bath. After the addition was complete, methanesulfonyl chloride (186 mg, 1.62 mmol) was slowly added under an ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (100 mL), the organic phase was washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then separated and purified using a preparative solution (instrument: waters 2767 preparative solution, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 ammonium acetate), gradient: 30%~80% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 6 (25 mg, yield: 5%).

[0109] LCMS m / z = 439.2[M+H] + , 1 H NMR (400MHz,DMSO) δ 7.88 (d,1H),7.74 (d,1H),7.61 (d,1H),7.23 (d,J4H),6.41 (s,1H),4.03 (s,4H),3.93 (s,2H),3.70 (d,2H),2.91 (s,3H),2.83 (dd,3H),1.93 (d,2H),1.71 (td,2H). Example 7: [ka]

[0110] Step 1: Compound 4A (200 mg, 0.87 mmol) and potassium carbonate (720 mg, 5.21 mmol) were dissolved in acetonitrile (10 ml), and 5-trifluoromethylisoindoline hydrochloride (194 mg, 0.87 mmol) was added. The mixture was reacted at 70°C for 5 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, filtered, the filtered cake was washed once with methanol (10 ml), the filtrate was collected and concentrated to obtain the crude compound 7B (480 mg, 160%). LC-MS (ESI): m / z = 345.0 [M + H] + .

[0111] Step 2: Compound 7B (200 mg, 0.58 mmol), intermediate 2 (160 mg, 0.58 mmol), and cesium carbonate (290 mg, 0.87 mmol) were added to a reaction flask and dissolved in DMF (10 ml). The mixture was reacted at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 ml), and a grayish-white solid precipitated. The solid was then heated and beaten twice with methanol (40 ml), filtered, and the filter cake was collected to obtain compound 7 (80 mg, 26.52%).

[0112] 1H NMR (400MHz,DMSO) δ 8.88 - 8.87 (m,1H),8.68 - 8.64 (m,1H),7.58 (s,1H),7.56 - 7.39 (m,4H),7.17 - 7.10 (m,1H),4.22 (s,2H),4.08 - 4.07 (m,2H),3.92 - 3.76 (m,4H),3.65 - 3.63 (m,2H),2.88 (s,3H),2.82 - 2.77 (m,2H),2.01 - 1.96 (m,3H),1.52 - 1.40 (m,2H). LC-MS (ESI): m / z = 520.70 [M+H] + . Example 8: [ka]

[0113] Step 1: Cyclopropylacetic acid (1.0 g, 10 mmol) was weighed and dissolved in dichloromethane (40 mL). Then, EDCI-HCl (2.30 g, 12 mmol), HOBT (1.62 g, 12 mmol), and triethylamine (3.03 g, 30 mmol) were added in sequence. After adding these, the mixture was stirred at room temperature for 10 minutes. Then, piperidine-4-methanol (1.15 g, 10 mmol) was added. After adding this, the mixture was stirred at room temperature for 18 hours. After the reaction was complete, dichloromethane (100 mL) and water (100 mL) were added to the reaction mixture to separate the aqueous phase. The organic phase was dried over anhydrous ammonium sulfate and filtered to obtain the crude product. The crude product was then purified by column chromatography (eluent: EA, color development with phosphomolybdic acid) to obtain the target compound 8B (0.58 g, 29.43%). LC-MS (ESI): m / z = 198.20 [M + H] + .

[0114] Step 2: Compound 8B (0.58 g, 2.94 mmol) was weighed and dissolved in dichloromethane (10 mL), then triethylamine (0.89 g, 8.8 mmol) was added. After adding the triethylamine, the temperature was lowered to 0°C, then methanesulfonyl chloride (0.40 g, 3.49 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (EA, the starting material disappeared at the reaction endpoint, and color development occurred with phosphomolybdic acid). After the reaction was complete, dichloromethane (100 ml) was added to the reaction solution, and the mixture was washed sequentially with aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and water. It was dried over sodium sulfate-free solution, filtered, and then concentrated to obtain the crude product of the target compound 8C (0.90 g, >100%), which was used directly in the reaction of the next step. LC-MS (ESI): m / z = 276.2 [M + H] + .

[0115] Step 3: Compound 8C (0.237 g, crude) and Compound 4B (0.19 g, 0.69 mmol) were weighed and added to a reaction flask. Then, DMF (10 mL) and cesium carbonate (0.33 g, 1.72 mmol) were added. After the addition of these compounds, the mixture was heated to 100°C and reacted for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried again over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Pre-TLC (DCM:MeOH = 10:1) to obtain the target compound 8 (72 mg, 18.38%).

[0116] LC-MS (ESI): m / z = 456.7 [M + H] + . 1 H NMR (400MHz,DMSO) δ 8.87 - 8.75 (m,1H),8.68 - 8.66 (m,1H),7.54 - 7.49 (m,2H),7.19 - 7.11 (m,5H),4.49 - 4.45 (m,1H),4.19 (s,2H),4.06 - 4.00 (m,2H),3.93 - 3.89 (m,1H),3.81 (s,4H),3.10 - 3.04 m,1H),2.64 - 2.58 (m,1H),2.33 - 2.23 (m,2H),2.17 - 2.14 (m,1H),1.94 - 1.87 (m,2H),1.41 - 1.10 (m,2H),0.99 - 0.94 (m,1H),0.54 - 0.38 (m,2H),0.14 - 0.10 (m,2H). Example 9: [ka]

[0117] Step 1: Compound 7B (230 mg, 0.69 mmol), compound 8C (190 mg, 0.69 mmol), and cesium carbonate (330 mg, 1.03 mmol) were added to a reaction flask and dissolved in DMF (10 ml). The mixture was reacted at 100°C for 1 hour. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, diluted with water (100 ml), extracted twice with ethyl acetate (100 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by pre-TLC (DCM:MeOH = 10:1) to obtain the target compound 9 (70 mg, 19.41%).

[0118] 1H NMR (400MHz,CDCl3) δ 8.90 - 8.88 (m,1H),8.62 - 8.59 (m,1H),7.40 - 7.33 (m,3H),7.19 - 7.17(m,2H),6.93 - 6.90 (m,1H),4.69 - 4.66 (m,1H),4.17 - 4.12 (m,2H),4.09 - 4.02 (m,1H),3.99 - 3.94 (m,1H),3.90 - 3.83 (m,4H),3.07 - 3.01 (m,1H),2.62 - 2.55 (m,1H),2.40 - 2.28 (m,1H),2.24 - 2.22 (m,2H),2.12 - 2.09 (m,1H),1.95 - 1.92 (m,1H),1.33 - 1.23 (m,2H),1.23 - 1.16 (m,1H),1.04 - 0.93 (m,1H),0.52 - 0.47(m,2H),0.13 - 0.10 (m,2H). LC-MS (ESI): m / z = 524.70 [M+H] + . Example 10: [ka]

[0119] Step 1: 3A (1.0 g, 7.96 mmol), 4-(2-bromoethyl)piperidine-1-carboxylate tert-butyl (2.79 g, 9.55 mmol), and potassium carbonate (2.20 g, 15.92 mmol) were dissolved in N,N-dimethylformamide (20 mL) and reacted overnight at 100 °C. After the reaction was cooled to room temperature, water (100 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried and concentrated, and then separated by column chromatography (PE / EA = 80% / 20%) to obtain 10B (820 mg, 30%). LC-MS (ESI): m / z = 337.2[M+H] + .

[0120] Step 2: 10B (820 mg, 2.44 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (617 mg, 6.10 mmol) and methanesulfonyl chloride (559 mg, 4.88 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react overnight at room temperature. Water (20 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was dried to obtain crude product 10C. LC-MS (ESI): m / z = 359.3 [M + H] + .

[0121] Step 3: 10C (600 mg, 1.45 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (293 mg, 2.90 mmol) and 2,3-dihydroisoindole hydrochloride (270 mg, 1.74 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction was concentrated and then separated by column chromatography (PE / EA = 70% / 30%) to obtain 10D (250 mg, 39%). LC-MS (ESI): m / z = 438.2[M+H] + .

[0122] Step 4: 10D (250 mg, 0.57 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1.5 mL) was added dropwise at 0-5°C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After concentrating the reaction, crude product 10E was obtained. LC-MS (ESI): m / z = 338.5 [M + H] + .

[0123] Step 5: Compound 10E (190 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (170 mg, 1.68 mmol) and methanesulfonyl chloride (128 mg, 1.12 mmol) were added dropwise at 0-5°C. After the addition was complete, the mixture was reacted at room temperature for 2.5 hours. After concentrating the reaction, the residue was separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20%-70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 10 (130 mg, 55%).

[0124] LC-MS (ESI): m / z = 416.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.10-8.09 (d,1H),7.24 - 7.17 (m,4H),6.99-6.98 (d,1H),6.77 (s,1H),4.32-4.29 (t,2H),3.87-3.85 (m,6H),3.55-3.52 (d,2H),2.82 (s,3H),2.70-2.65 (m,2H),1.82-1.79 (d,2H),1.71-1.66 (q,2H),1.62-1.55 (m,1H),1.28-1.18 (m,2H). Example 11: [ka]

[0125] Step 1: Compound 10B (0.33 g, 0.98 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (3 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then directly spin-dried, and the residue was used directly in the next step. LC-MS (ESI): m / z = 237.3 [M+H] +

[0126] Step 2: Crude product 11B was dissolved in DCM (15 mL), and methanesulfonyl chloride (0.19 mL, 2.44 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain 11C (0.35 g, 90%). LC-MS (ESI): m / z = 393.5 [M + H] + .

[0127] Step 3: Compound 11C (350 mg, 0.89 mmol) and compound 5-trifluoromethylisoindoline hydrochloride (300 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (270 mg, 2.67 mmol) was added. The mixture was reacted at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 11 (95 mg, 22.07%).

[0128] LC-MS (ESI): m / z = 484.7 [M + H] + . 1H NMR (400MHz,CDCl3) δ 8.10 (d,1H),7.54 - 7.41 (m,2H),7.29 (d,1H),6.93 (d,1H),6.78 (s,1H),4.35 (t,2H),4.00 (s,4H),3.88 (s,2H),3.79 (d,2H),2.76 (s,3H),2.65 (td,2H),1.88 (d, 2H),1.77 (dd,2H),1.69 - 1.62 (m,1H),1.39 (ddd,2H). Example 12: [ka]

[0129] Step 1: Kojic acid (12.0 g, 84.42 mmol) was dissolved in tetrahydrofuran (100 mL), and NBS (30.0 g, 168.61 mmol) and NH4OAc (3.25 g, 42.21 mmol) were added in sequence. The reaction mixture was heated to 70°C and stirred for 6 hours. After the reaction was complete, 150 mL of water was added to quench the reaction, and the mixture was extracted with EA (100 mL x 3). The organic phases were combined and washed with saturated brine (200 mL x 1). After drying over anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 1:0~10:1) to obtain compound 12A (15.0 g, 80%). LC-MS (ESI): m / z = 221.10[M+H] + .

[0130] Step 2: At room temperature, compound 12A (5.0 g, 22.62 mmol), 1-Boc-4-ethynylpiperidine (4.73 g, 22.62 mmol), bis(triphenylphosphine)palladium dichloride (3.18 g, 4.52 mmol), and cuprous iodide (1.72 g, 9.05 mmol) were dissolved in tetrahydrofuran (100 mL). Under a nitrogen gas atmosphere, triethylamine (6.87 g, 67.86 mmol) was added, and the reaction mixture was heated to 40 °C and stirred for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 1:0~10:1) to obtain compound 12B (1.6 g, 20%). LC-MS (ESI): m / z=294.2[Mt-Bu+H] + .

[0131] Step 3: Compound 12B (1.6 g, 4.01 mmol) was dissolved in DCM (20 mL), trifluoroacetic acid (4 mL) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain compound 12C (1.0 g, crude product), which was used directly in the next step without purification. LC-MS (ESI): m / z = 250.2[M+H] + .

[0132] Step 4: Compound 12C (1.0 g, 4.01 mmol) and TEA (1.83 g, 4.50 mmol) were dissolved in DCM (20 mL), and methanesulfonyl chloride (1.48 g, 12.92 mmol) was added. The reaction was allowed to proceed at room temperature for 3 hours. After concentrating the reaction mixture, the residue was purified by column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:1) to obtain compound 12D (450 mg, 28%). LC-MS (ESI): m / z = 406.3 [M+H] + .

[0133] Step 5: Compound 12D (300 mg, 0.74 mmol) and isoindole hydrochloride (160 mg, 1.04 mmol) were dissolved in acetonitrile (20 mL), and DIPEA (290 mg, 2.22 mmol) was added. The reaction mixture was stirred overnight at room temperature, and after the reaction was complete, it was concentrated. The resulting crude product was purified by column chromatography (DCM:MeOH = 1:0~10:1) to obtain compound 12 (250 mg, 78%).

[0134] LC-MS (ESI): m / z = 429.5[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.42-7.30 (m,4H),6.89 (s,1H),6.68 (s,1H),4.75-4.45 (m,6H),3.68-3.58 (m,2H),3.07-2.96 (m,1H),2.94-2.84 (m,5H),2.16-2.05 (m,2H),1.80-1.64 (m,2H). Example 13: [ka]

[0135] Step 1: Compound 11C (350 mg, 0.89 mmol) and Compound 13A (280 mg, 0.97 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (270 mg, 2.67 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain Compound 13 (45 mg, 10.7%).

[0136] LC-MS (ESI): m / z = 472.7 [M + H] + . 1H NMR (400MHz,CDCl3) δ 8.09 (d,1H),7.08 (d,1H),6.93 (d,1H),6.88 (d,2H),6.78 (s,1H),4.34 (t,2H),3.91 (d,4H),3.85 (s,2H),3.79 (d,2H),3.70 (dt,1H),2.76 (s,3H),2.65 (td,2H),1.88 (d,2H),1.76 (q,2H),1.66 (ddd, 1H),1.39 (ddd,2H),0.75 (d,4H). Example 14: [ka]

[0137] Step 1: 3B (0.33 g, 0.98 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (3 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then directly spin-dried, and the residue was used directly in the next step. LC-MS (ESI): m / z = 237.3 [M+H] + .

[0138] Step 2: Compound 14B (0.23 g, 0.98 mmol) and TEA (0.45 g, 4.40 mmol) were dissolved in DCM (15 mL), and methanesulfonyl chloride (0.19 mL, 2.44 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain 14C (0.25 g, 65%). LC-MS (ESI): m / z = 393.5 [M + H] + .

[0139] Step 3: Compound 14C (250 mg, 0.64 mmol) and compound 5-trifluoromethylisoindoline hydrochloride (210 mg, 0.96 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (190 mg, 1.92 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 14 (105 mg, 33.93%).

[0140] LC-MS (ESI): m / z = 484.1 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.48 (d,1H),7.45 (s,1H),7.30 (d,1H),7.22 (d,1H),6.56 (s,1H),6.32 (dd,1H),4.03 - 3.94 (m,6H),3.80 (d,2H),3.73 (s,2H),2.77 (s,3H),2.66 (dd,2H),1.89 (d,2H),1.73 (dd,2H),1.54 - 1.31 (m,3H). Example 15: [ka]

[0141] Step 1: Compound 10C (350 mg, 0.84 mmol) and compound 5-cyclopropoxyisoindoline hydrochloride (290 mg, 1.01 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (340 mg, 3.36 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound 15B (350 mg, 84.41%). LC-MS (ESI): m / z = 494.6 [M + H] + .

[0142] Step 2: Compound 15B (350 mg, 0.71 mmol) was dissolved in dichloromethane (5 mL), and then dioxane hydrochloride solution (10 mL, 4.0 mmol / L) was added. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain compound 15C (250 mg, 84.41%). LC-MS (ESI): m / z = 394.4 [M + H] + .

[0143] Step 3: Compound 15C (250 mg, 0.64 mmol) and triethylamine (200 mg, 1.95 mmol) were dissolved in dichloromethane (15 mL). Cyclopropylacetyl chloride (150 mg, 1.27 mmol) was added dropwise under ice water bath, and the mixture was allowed to react at room temperature for 2 hours after the addition was complete. After the reaction was complete, the mixture was concentrated and purified by passing it through a silica gel column (dichloromethane:methanol = 20:1) to obtain compound 15 (50 mg, 16.4%).

[0144] LC-MS (ESI): m / z = 476.3 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 8.10 (d,1H),7.09 (d,1H),6.96 (d,1H),6.92 - 6.85 (m,2H),6.80 (s,1H),4.63 (d,1H),4.34 (t,2H),3.95 (d,2H),3.91 - 3.77 (m,2H),3.70 (ddd,1H),3.00 (dd,2H),2.55 (dd,2H),2.27 (d,2H),1.80-1.78 (m,5H),1.32 - 1.27 (m,2H),1.23 - 1.14 (m,2H),1.06-1.02 (m,2H),0.76 (dd,2H),0.58 - 0.52 (m, 2H), 0.17 (q, J=4.8 Hz, 2H). Example 16: [ka]

[0145] Step 1: Compound 14C (300 mg, 0.76 mmol) and compound 5-cyclopropylisoindoline hydrochloride (220 mg, 1.14 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (0.31 mg, 3.06 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound P0 (55 mg, 15.88%).

[0146] LC-MS (ESI): m / z = 456.5 [M + H] + 1 H NMR (400MHz,CDCl3) δ 7.20 (d,1H),7.06 (d,1H),6.93 (d,1H),6.90 (s,1H),6.54 (s,1H),6.36 (d,1H),4.01 - 3.94 (m,2H),3.91 (s,4H),3.79 (d,2H),3.71 (s,2H),2.76 (s,3H),2.65 (t,2H),1.93 - 1.83 (m,3H),1.72 (dd,3H),1.44 - 1.33 (m,2H),0.96 - 0.89 (m,2H),0.68 - 0.61 (m,2H). Example 17: [ka]

[0147] Step 1: Compound 3C (350 mg, 0.84 mmol) and compound 5-cyclopropylisoindoline hydrochloride (250 mg, 1.26 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (0.34 g, 3.36 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 17B (320 mg, 79.76%). LC-MS (ESI): m / z = 478.4[M+H] + .

[0148] Step 2: Compound 17B (320 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), and then dioxane hydrochloride solution (10 mL, 4.0 mmol / L) was added. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain compound 17C (260 mg, 100%). LC-MS (ESI): m / z = 378.6 [M + H] + .

[0149] Step 3: Compound 17C (250 mg, 0.69 mmol) and triethylamine (209 mg, 2.06 mmol) were dissolved in dichloromethane (15 mL). Cyclopropylacetyl chloride (160 mg, 1.38 mmol) was added dropwise under ice water bath, and the mixture was allowed to react at room temperature for 2 hours after the addition was complete. After the reaction was complete, the mixture was concentrated and purified by passing it through a silica gel column (dichloromethane:methanol = 20:1) to obtain compound 17 (50 mg, 15.7%).

[0150] LC-MS (ESI): m / z = 460.7 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.20 (d,1H),7.07 (d,1H),6.93 (d,1H),6.90 (s,1H),6.54 (s,1H),6.35 (d, 1H),4.64 (d, 1H),3.96 (td,2H),3.91 (s,4H),3.83 (d,1H),3.71 (s,2H),3.08 - 2.94 (m,1H),2.61 - 2.49 (m,1H),2.27 (d,2H),1.86 - 1.64 (m,5H),1.59 (ddd,1H),1.18 (dd,2H),1.10 - 0.99 (m,1H),0.97 - 0.91 (m,2H),0.70 - 0.61 (m,2H),0.61 - 0.51 (m,2H),0.17 (q,2H) Example 18: [ka]

[0151] Step 1: 18A (1 g, 4.42 mmol) and N-methylaniline (948 mg, 8.85 mmol) were dissolved in 1,4-dioxane (30 mL), RuPhos Pd G3 (370 mg, 0.44 mmol) and cesium carbonate (2.89 g, 8.85 mmol) were added, and the mixture was reacted at 100°C for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound 18B (620 mg, 55.5%). LCMS(ESI): m / z = 253.1[M+H] +

[0152] Step 2: Compound 18B (300 mg, 1.19 mmol) was dissolved in DMF (5 mL), sodium hydride (95 mg, 2.38 mmol, 40%) was added, and the mixture was stirred for 30 minutes. Then intermediate 2 (483 mg, 1.78 mmol) was added, the temperature was raised to 60°C, and the mixture was stirred for 3 hours. The complete reaction was monitored by TLC, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm x 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20%~70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 18 (100 mg, 19.7%).

[0153] LCMS(ESI): m / z = 428.2[M+H] + 1H NMR (400MHz,DMSO-d6) δ 7.66 (d,1H),7.45 - 7.35 (m,2H),7.24 - 7.13 (m,3H),6.74 - 6.67 (m,1H),6.63 (d,1H),3.59 - 3.51 (m,2H),3.48 (t,2H),3.34 (d,2H),3.32 - 3.29 (m,3H,overlapped with H2O peak),2.88 - 2.80 (m,5H),2.72 - 2.62 (m,2H),1.86 - 1.75 (m,3H),1.75 - 1.65 (m,2H),1.30 - 1.16 (m,2H). Example 19: [ka]

[0154] Step 1: 19A (2g, 9.3 mmol) was added to DMF-DMA (20 mL), the reaction was stirred at 100°C for 16 hours, and the complete reaction was monitored by TLC. After concentration, the crude product of the target compound 19B (2.5 g, 99.5%) was obtained and used directly in the next step of the reaction. LCMS(ESI):m / z=270.1&272.1[M+H]

[0155] Step 2: Compound 19B (2.5 g, 9.25 mmol) was dissolved in dichloromethane (50 mL), and m-CPBA (4.8 g, 27.76 mmol) was slowly added at 0°C. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the mixture was separated using a silica gel chromatography column (PE:EA = 1:1) to obtain the target compound 19C (1.1 g, 2-step yield 49%). LCMS(ESI):m / z=241.1&243.1[M+H]

[0156] Step 3: Compound 19C (1.1 g, 4.56 mmol) was dissolved in dichloromethane (20 mL), and TBSCl (1.0 g, 6.85 mmol) and imidazole (465 mg, 6.85 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was concentrated and separated using a silica gel chromatography column (PE:EA = 7:1) to obtain the target compound 19D (1.08 g, 66.6%). LCMS(ESI):m / z=355.1&357.1[M+H]

[0157] Step 4: 19D (880 mg, 2.34 mmol) and N-methylaniline (500 mg, 4.68 mmol) were dissolved in toluene (20 mL), and palladium acetate (87 mg, 0.23 mmol), BINAP (291 mg, 0.47 mmol), and cesium carbonate (1.5 g, 4.68 mmol) were added. The mixture was reacted at 100 °C for 5 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the target compound 19E (420 mg, 47.1%). LCMS(ESI): m / z = 382.2[M+H]

[0158] Step 5: Compound 19E (420 mg, 1.1 mmol) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1.7 mL, 1.7 mmol, 1 M) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was then concentrated to obtain the target compound 19F (260 mg, 88.4%). LCMS(ESI): m / z = 268.1[M+H]

[0159] Step 6: Compound 19F (240 mg, 0.90 mmol) and intermediate 2 (487 mg, 1.80 mmol) were dissolved in acetonitrile (10 mL), cesium carbonate (585 mg, 1.80 mmol) was added, and the mixture was reacted at 80°C for 16 hours. After monitoring the completion of the reaction by TLC, water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 ammonium bicarbonate), gradient: 20%~70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 19 (20 mg, 5.0%).

[0160] LCMS(ESI): m / z = 443.2[M+H] 1 H NMR (400MHz,DMSO-d6) δ 8.11 (s,1H),7.80 (d,1H),7.53 - 7.45 (m,2H),7.35 - 7.25 (m,3H),6.79 - 6.72 (m,1H),6.71 - 6.64 (m,1H),3.83 - 3.72 (m,2H),3.64 - 3.52 (m,2H),3.40 - 3.32 (m,3H,overlapped with H2O peak),2.86 (s,3H),2.79 - 2.68 (m,2H),1.94 - 1.80 (m,3H),1.38 - 1.21 (m,2H). Example 20: [ka]

[0161] Step 1: 20A (10g, 61.30 mmol), benzyl bromide (11.53g, 67.43 mmol), and potassium carbonate (16.94g, 122.6 mmol) were dissolved in N,N-dimethylformamide (60 mL), stirred at 70°C for 2 hours, and after the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, spin-dried, and beaten with petroleum ether to obtain product 20B (7.6g, 49%). LC-MS (ESI): m / z = 254.20 [M+H] +

[0162] Step 2: 20B (0.3g, 1.18 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1.03 g, 4.11 mmol) was added under an ice bath. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, adjusted to alkalinity with potassium carbonate, extracted three times with ethyl acetate, spin-dried, beaten with petroleum ether, and filtered to obtain product 20C (0.15 g, 53%). LC-MS (ESI): m / z = 240.30 [M+H] + .

[0163] Step 3: 20C (0.5g, 2.09 mmol), iodine (0.69g, 2.72 mmol), and sodium methanesulfinate (0.28g, 2.74 mmol) were dissolved in water (10 mL) and formic acid (2 mL), and the mixture was reacted at 110°C for 12 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, and the mixture was spin-dried. The product was then purified by normal phase (petroleum ether:ethyl acetate = 3:1) to obtain product 20D (0.2g, 30%). LC-MS (ESI): m / z = 318.30 [M+H] + .

[0164] Step 4: 20D (0.030 g, 0.095 mmol), methyl (1-methylsulfonylpiperidine-4-yl)methanesulfonate (0.036 g, 0.13 mmol), and potassium carbonate (0.033 g, 0.24 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 80°C for 3 hours. After the reaction was complete, the solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, spin-dried, and purified by HPLC. Separation method by preparative HPLC: 1. Instrument: waters2767 preparative liquid, chromatography column: SunFire@ PrepC18 (19 mm × 250 mm) 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.5% ammonium acetate). b. Gradient elution was performed, with mobile phase A content ranging from 30% to 90%. c. Flow rate was 20 mL / min. d. Elution time: 15 min. Retention time: 15 min. Compound 20 (7 mg, 15%) was obtained by lyophilization.

[0165] 1H NMR (400MHz,DMSO-d6) δ 7.39 - 7.30 (m,2H),7.27-7.21 (m,3H),6.94 (s,1H),6.86 (s,1H),4.45 (s,2H),3.92 (d,2H),3.58 (d,2H),3.36 (s,1H),3.12 (s,3H),2.85 (s,3H),2.84-2.79(m,2H),2.78-2.69 (m,2H),1.96 - 1.83 (m,5H),1.42-1.30 (m,2H),1.24 (s,1H). LC-MS (ESI): m / z = 493.30 [M+H] + . Example 21: [ka]

[0166] Step 1: Compound 21A (2.0 g, 17.7 mmol) was dissolved in DMF-DMA (40 mL), stirred at 90°C for 4 hours, and after the reaction was complete, the reaction mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 21B (2.4 g, 81%) was obtained by column chromatography (PE:EA = 2:1). LCMS (ESI): m / z = 169.2[M+H]

[0167] Step 2: Compound 21B (2.6 g, 15.46 mmol) was dissolved in ethanol (50 ml), and NH2NH2.H2O (773 mg, 15.46 mmol) was added to the reaction mixture. The mixture was stirred at 100°C for 16 hours. The target compound 21C (2.0 g, 94%) was obtained by column chromatography (MeOH:DCM = 10:1). LCMS (ESI): m / z = 138.1[M+H]

[0168] Step 3: Compound 21C (200.0 mg, 1.46 mmol) was dissolved in tetrahydrofuran (4 mL), and 60% sodium hydride (87.6 mg, 2.19 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 10 minutes, and benzyl bromide (299.6 mg, 1.75 mmol) was slowly added dropwise. After the addition was complete, the reaction was moved to 70°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 21D (120.0 mg, 36%) was obtained by column chromatography (MeOH:DCM = 15:1). LCMS (ESI): m / z = 228.3[M+H]

[0169] Step 4: 21D (120 mg, 0.53 mmol) was dissolved in tetrahydrofuran (4 mL), and 60% sodium hydride (32.0 mg, 1.51 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 10 minutes, and intermediate 2 (143.8 mg, 0.53 mmol) was slowly added. After the addition was complete, the reaction was transferred to 70°C and stirred for 16 hours. After the reaction was complete, the reaction was concentrated, and the residue was separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20%~70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain the target compound 21 (47 mg, 22%).

[0170] 1 H NMR (400MHz,CDCl3) δ 7.77 (s,1H),7.34 (t,3H),7.26 (d,2H),5.26 (s,2H),3.76 (d,2H),3.59 (t,2H),3.40 (d,2H),2.95 (t,2H),2.76 (s,3H),2.69 (t,2H),1.81 (d,3H),1.41 (dd,2H). LCMS (ESI): m / z = 403.2[M+H] + . Example 22: [ka]

[0171] Step 1: Compound 21C (200.0 mg, 1.46 mmol) was dissolved in tetrahydrofuran (4 mL), and 60% sodium hydride (87.6 mg, 2.19 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 10 minutes, and benzyl bromide (299.6 mg, 1.75 mmol) was slowly added dropwise. After the addition was complete, the reaction was moved to 70°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 22D (81.0 mg, 24%) was obtained by column chromatography (MeOH:DCM = 15:1). LCMS (ESI): m / z = 228.3[M+H] +

[0172] Step 2: 22D (81.0 mg, 0.36 mmol) was dissolved in tetrahydrofuran (4 mL), and 60% sodium hydride (21.7 mg, 0.54 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 10 minutes, and intermediate 2 (97.7 mg, 0.36 mmol) was slowly added. After the addition was complete, the reaction was transferred to 70°C and stirred for 16 hours. After the reaction was complete, the reaction was concentrated, and the residue was separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20% to 70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain the target compound 22 (29 mg, 14%).

[0173] 1 H NMR (400MHz,CDCl3) δ 7.90 (s,1H),7.37 - 7.28 (m,3H),7.15 (d,2H),5.29 (s,2H),3.76 (d,2H),3.56 (t,2H),3.37 (d,2H),2.79 (t,2H),2.76 (s,3H),2.69 (dd,2H),1.83 (d,3H),1.47 - 1.32 (m,2H). LCMS (ESI): m / z = 403.2[M+H] + . Example 23: [ka]

[0174] Step 1: Compound 23A (10.0 g, 49.5 mmol) was dissolved in pyridine (30 mL), cooled to 0°C, and 2-chloroacetaldehyde (4.7 g, 59.4 mmol) was added dropwise to the reaction mixture under an N2 atmosphere. After the addition was complete, the temperature was raised to 50°C and the reaction was allowed to proceed for 1.5 hours. After the reaction was complete, water was added to quench the reaction, the reaction mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 23B (5.7 g, 51%) was obtained by column chromatography (PE:EA = 4:1). LCMS (ESI): m / z = 227.2[M+H] +

[0175] Step 2: Compound 23B (5.6 g, 24.8 mmol) was added to acetonitrile (60 mL), and N-bromosuccinimide (5.3 g, 29.7 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the pH was adjusted to neutral with saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the target compound 23C (7.1 g, 94%) was obtained by column chromatography (PE:EA = 3:1). LCMS (ESI): m / z = 306.1[M+H] +

[0176] Step 3: Compound 23C (7.0 g, 22.9 mmol) was dissolved in ethanol (70 mL), and sodium borohydride (2.6 mg, 68.7 mmol) was slowly added under ice bath conditions. After 15 minutes, the reaction was transferred to 25°C and stirred for 3 hours. After the reaction was complete, the reaction was cooled to 0°C, the pH was adjusted to weakly acidic with 6 mol / L HCl, extracted with chloroform, and concentrated under reduced pressure. Compound 23D (4.3 g, 71%) was obtained by column chromatography (PE:EA = 2:1). LCMS (ESI): m / z = 262.9 [M + H] +

[0177] Step 4: 23D (4.1 g, 15.6 mmol), phthalimide (2.3 g, 15.6 mmol), and triphenylphosphine (4.1 g, 15.6 mmol) were dissolved in THF (40 mL), and the mixture was cooled to 0°C under N2 protection. Diisopropyl azodicarboxylate (3.2 g, 15.6 mmol) was added dropwise to the reaction mixture, and after the addition was complete, the reaction was transferred to 25°C and stirred for 1 hour. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The compound was separated and purified by column chromatography (DCM:MeOH) = 12:1 to obtain the target compound 23E (4.4 g, 72%). LCMS (ESI): m / z = 392.1[M+H] +

[0178] Step 5: Compound 23E (2.3 g, 5.8 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate (0.6 mL, 11.4 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was extracted with dichloromethane and methanol, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography (DCM:MeOH) = 10:1 to obtain 23F (1.4 g, 91%). LCMS (ESI): m / z = 262.1[M+H] +

[0179] Step 6: 1,5,7-Triazabicyclo(4.4.0)deca-5-ene (220.0 mg, 1.6 mmol) was added to a solution of 23F (1.4 g, 5.3 mmol) in THF (6 mL) and stirred at 75°C for 30 min. After the reaction was complete, water was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 23G (780.0 mg, 68%) was obtained by column chromatography (PE:EA = 1:1). LCMS (ESI): m / z = 216.0 [M + H] +

[0180] Step 7: Under N2 protection, 23G (200.0 mg, 0.93 mmol), manganese (112.4 mg, 2.05 mmol), and TFA (0.1) were dissolved in acetonitrile (6 mL), stirred for 10 minutes, then cobalt bromide (22.0 mg, 0.09 mmol) was added, and the mixture was stirred at 35°C for 4 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, the reaction solution was extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 23H (121.0 mg, 57%) was obtained by column chromatography (PE:EA = 1:1). LCMS (ESI): m / z = 228.3[M+H] +

[0181] Step 8: 23H (121.0 mg, 0.53 mmol) was dissolved in THF (3 mL), and 60% sodium hydride (25.0 mg, 0.63 mmol) was added to the reaction mixture at 0°C. After stirring for 15 minutes, intermediate 2 (140.0 mg, 0.53 mmol) was added. After the addition was complete, the reaction was transferred to 70°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction was concentrated, and the residue was separated and purified by preparative liquid purification (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 20%~70% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain target compound 23 (37.0 mg, 17%).

[0182] 1 H NMR (400MHz,CDCl3) δ 7.34 - 7.28 (m,2H),7.25 - 7.21 (m,3H),6.34 (s,1H),3.94 (s,2H),3.77 (d,2H),3.60 (t,2H),3.36 (d,2H),2.91 (t,2H),2.77 (s,3H),2.69 (td,2H),1.86 - 1.77 (m,3H),1.39 (dt,2H). LCMS (ESI): m / z = 403.2[M+H] + . Example 24: [ka]

[0183] Step 1: Compound 3C (1.2g, 2.89 mmol) and Compound 13A (0.92g, 3.18 mmol) were dissolved in DCM (20 mL), and triethylamine (0.73 g, 7.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 50 mL of water was added to quench the mixture, and the mixture was extracted with DCM (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain Compound 24F (0.75 g, 53%). LC-MS (ESI): m / z = 494.3 [M + H] + .

[0184] Step 2: Compound 24F (750 mg, 1.56 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain compound 24G (0.80 g, crude product), which was used directly in the next step without purification. LC-MS (ESI): m / z = 394.5 [M + H] + .

[0185] Step 3: Compound 24G (0.36 g, 0.91 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.28 g, 2.77 mmol) and methanesulfonyl chloride (0.16 g, 1.39 mmol) were added sequentially under ice water bath. The reaction mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, the mixture was concentrated, and the crude product was purified by high-performance liquid preparative fractionation to obtain compound 24 (15 mg, 3%).

[0186] Preparative method: Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 1‰ trifluoroacetic acid). Gradient elution was performed, with mobile phase A content ranging from 15% to 60%, and a flow rate of 12 mL / min. Elution time: 20 min.

[0187] LC-MS (ESI): m / z = 472.2[M+H] + . 1 H NMR (400MHz,DMSO) δ 7.82 (d,1H),7.30 (d,1H),7.13 (s,1H),7.02 (d,1H),6.58 (s,1H),6.37 (d,1H),4.80-4.35 (m,6H),3.93 (t,2H),3.86-3.80 (m,1H),3.55-3.51 (m,2H),2.84 (s,3H),2.69-2.62 (m,2H),1.86-1.76 (m,2H),1.64-1.54 (m,2H),1.40-1.30 (m,1H),1.27-1.16 (m,2H),0.80-0.74 (m,2H),0.66-0.60 (m,2H). Example 25: [ka]

[0188] Step 1: Compound 14C (100 mg, 0.25 mmol) and compound 5-pentafluorothioisoindoline hydrochloride (74 mg, 0.30 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (100 mg, 1.0 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 25 (8 mg, 5.9%).

[0189] LC-MS (ESI): m / z = 542.1 [M+H] + . 1 H NMR (400MHz,DMSO) δ 7.82 (d,1H),7.75 (dd,1H),7.65 (d,1H),7.47 (d,1H),6.35 (s,1H),6.25 (dd,1H),3.99 - 3.86 (m,6H),3.71 (s,2H),3.52 (d,2H),2.83 (s,3H),2.65 (dd,2H),1.81 (d,2H),1.58 (dd,2H),1.33 (d,1H),1.23 - 1.10 (m,2H). Example 26: [ka]

[0190] Step 1: 26A (2.0 g, 16.0 mmol) was dissolved in DCE (20 mL), and then 5-trifluoromethylisoindoline hydrochloride (3.5 g, 16.0 mmol) and sodium borohydride acetate (6.6 g, 32.0 mmol) were added. Glacial acetic acid (0.6 g, 10.0 mmol) was then added, and the mixture was allowed to react at room temperature for 12 hours until the reaction was complete. After complete reaction, saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 26B (4.0 g, 84.3%). LC-MS (ESI): m / z = 297.1 [M+H] + .

[0191] Step 2: N-Boc-4-hydroxypiperidine (0.8 g, 4.0 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.16 g, 4.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, then 26B (0.6 g, 2.0 mmol) was added. The mixture was reacted overnight at room temperature, a small amount of methanol was added to quench the mixture, and after concentration, the residue was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 26C (0.5 g, 50.1%). LC-MS (ESI): m / z = 478.2[M+H] + .

[0192] Step 3: Compound 26C (0.5 g, 1.0 mmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (3.0 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 26D (0.5 g, 96%), which was used directly in the next step. LC-MS (ESI): m / z = 378.2[M+H] + .

[0193] Step 4: 26D (0.5 g, 1.0 mmol) was dissolved in DMF (8.0 mL), cyclopropylacetic acid (121.2 mg, 1.2 mmol) and N-methylimidazole (327.8 mg, 4.0 mmol) were added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (336.0 mg, 1.1 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. After complete reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 26 (150.0 mg, 32%).

[0194] LC-MS (ESI): m / z = 460.2[M+H] + . 1H NMR (400MHz,CDCl3) δ 8.09 (d,1H),7.52 - 7.38 (m,2H),7.29 (d,1H),6.93 - 6.91 (m,1H),6.77 (s,1H),5.83 - 5.28 (m,1H),3.96 - 3.93 (m,5H),3.87 (s,2H),3.78 - 3.64 (m,1H),3.59 - 3.46 (m,1H),3.46 - 3.32 (m,1H),2.31 (d,2H),2.06 - 1.93 (m,2H),1.80 - 1.77 (m,2H),1.14 - 0.97 (m,1H),0.63 - 0.51 (m, 2H), 0.19 (q, 2H). 19 F NMR (377MHz,CDCl3) δ -60.02 (s). Example 27: [ka]

[0195] Step 1: 27A (1.2 g, 6.1 mmol) (synthesized according to patent EP2881384A1) was weighed and added to a 100 mL round-bottom flask, dissolved in 20 mL of DMF, cooled in an ice bath, then NaH (60% of kerosene) (480 mg, 12 mmol) was added, and the mixture was reacted at this temperature for 30 minutes. Then 5,8-dibromoimidazo[1,2-a]pyrazine (1.7 g, 6.0 mmol) was added, and the reaction was continued for 1 hour. After the starting material had completely disappeared, saturated ammonium chloride solution was added until the system became weakly acidic, filtered, the filtered cake was washed with water, and dried to obtain the target compound 27B (1.84 g, yield: 78.2%). LC-MS (ESI): m / z=393.3,393.5[M+H] + .

[0196] Step 2: Compound 27B (1.84 g, 4.7 mmol) was dissolved in 1,4-dioxane (30 mL), and (tributyltin)methanol (1.6 g, 5 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(Xphos-pd-G2) (390 mg, 0.5 mmol) were added. The mixture was then purged with nitrogen gas and reacted at 90°C for 4 hours. After cooling, the mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to obtain compound 27C (722 mg, yield: 44.5%). LC-MS (ESI): m / z = 345.4 [M + H] + .

[0197] Step 3: Compound 27C (344 mg, 1 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1 mL) and methanesulfonyl chloride (125 mg, 1.1 mmol) were added. The mixture was stirred at room temperature for 1 hour. The solution was directly concentrated, the resulting residue was redissolved in ethyl acetate, filtered, and the filtrate was concentrated to obtain the target compound 27D (185 mg, crude).

[0198] Step 4: Compound 27D (185 mg, crude) was dissolved in DMF (5 mL), and 5-(trifluoromethyl)isoindoline hydrochloride (112 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) were added. The mixture was reacted at 70°C for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The resulting residue was concentrated and purified by column chromatography (dichloromethane:anhydrous methanol (v:v) = 1:0~5:1) to obtain compound 27 (87 mg, yield: 33.8%).

[0199] 1H NMR (400MHz,CDCl3) δ7.97 - 7.94 (m,1H),7.67 - 7.65 (m,1H),7.50 - 7.46 (m,1H),7.44 (s,1H),7.33 (s,1H),7.30 - 7.26 (m,1H),4.76 - 4.66 (m,1H),4.49 - 4.32 (m,2H),4.13 - 4.09 (m,2H),4.03 - 3.98 (m,4H),3.93 - 3.86 (m,1H),3.12 - 3.03 (m,1H),2.68 - 2.58 (m,1H),2.34 - 2.20 (m,3H),2.12 - 1.90 (m,2H),1.40 - 1.27 (m,2H),1.13 - 0.99 (m,1H),0.62 - 0.50 (m,2H),0.27 - 0.15 (m,2H). LC-MS (ESI): m / z = 514.2[M+H] + Example 28: [ka]

[0200] Step 1: Compound 24G (0.36g, 0.91 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.37g, 3.64 mmol) and cyclopropylacetyl chloride (0.22g, 1.82 mmol) were added sequentially in an ice bath. The reaction mixture was heated to room temperature and stirred for 5 hours. After the reaction was complete, the mixture was concentrated, and the crude product was purified by high-performance liquid preparative fractionation to obtain compound 28 (20 mg, 4%).

[0201] Preparative chromatography method: Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 1‰ trifluoroacetic acid). Gradient elution was performed, with mobile phase A content ranging from 20% to 60%, and a flow rate of 12 mL / min. Elution time: 20 min.

[0202] LC-MS (ESI): m / z = 476.3 [M + H] + . 1 H NMR (400MHz,DMSO) δ 7.83 (d,1H),7.32 (d,1H),7.13 (s,1H),7.03 (d,1H),6.58 (s,1H),6.37 (d,1H),4.70-4.30 (m,7H),3.93 (t,2H),3.88-3.76 (m,3H),3.01-2.87 (m,1H),2.23 (d,2H),1.78-1.67 (m,2H),1.60-1.44 (m,3H),1.15-0.90 (m,3H),0.82-0.75 (m,2H),0.65-0.60 (m,2H),0.48-0.40 (m,2H),0.14-0.08 (m,2H). Example 29: [ka]

[0203] Step 1 Compound 29A (550 mg, 2.22 mmol), triethylamine (338 mg, 3.32 mmol), and methanesulfonic anhydride (579 mg, 3.32 mmol) were dissolved in 10 mL of DCM and reacted at 0°C for 0.5 hours. After monitoring the disappearance of the starting materials by LC-MS, 5-trifluoromethylisoindole hydrochloride (740 mg, 3.32 mmol) and triethylamine (676 mg, 6.64 mmol) were added. After monitoring the disappearance of the active ester by TLC, the reaction mixture was added dropwise to 20 mL of ice water, extracted three times with 20 mL of dichloromethane, the organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound 29B (230 mg, 25%). LCMS(ESI): m / z = 418.5[M+H] +

[0204] Step 2: Compound 29B (230 mg, 0.55 mmol) was dissolved in 4 mL of methanol, and 4 mL of 4N dioxane hydrochloride was added. The reaction was allowed to proceed for 3 hours. After monitoring the disappearance of the starting material by TLC, the reaction mixture was concentrated to obtain compound 29C (140 mg, 80%), which was used directly in the next step. LCMS(ESI): m / z = 318.1[M+H] +

[0205] Step 3: NaH (20 mg, 0.50 mmol, 60% inmineral oil) was suspended in 5 ml of anhydrous THF, and 29C (80 mg, 0.25 mmol) was added under ice bath conditions, and the reaction was carried out for 1 hour. The reaction solution was evaporated using a rotary evaporator to remove excess solvent, and 5 ml of anhydrous 1,4-dioxane and intermediate 2 (74 mg, 0.28 mmol) were added. The reaction was carried out at 80°C for 2 hours, and after monitoring the completion of the reaction by LC-MS, the mixture was purified by silica gel column chromatography (DCM:MeOH-20:1), and further fractionation by SFC yielded the target compound 29-1 (7.2 mg, 6%) and compound 29-2 (13.3 mg, 11%).

[0206] Analysis method: Instrument: SHIMADZU LC-30AD; Chiral column: Chiralcel AS column; Mobile phase: A for CO2, B for 0.05% DEA in IPA; Gradient: B 5~40%; Flow rate: 3 mL / min; Column pressure: 100 bar; Column temperature: 35℃ Detection wavelength: 220nm Cycle time: 3.0min Preparative method: Instrument: Waters 150 Prep-SFC A; Chiral column: Chiralcel AS column; Mobile phase: A for CO2, B for 0.1%NH3·H2O in IPA; Gradient: B 40%; Flow rate: 100 mL / min; Column pressure: 100 bar; Column temperature: 25°C; Detection wavelength: 220 nm; Cycle time: 3.8 min Compound 29-1: LCMS(ESI): m / z=493.8[M+H] + 7.2 mg, duration of action: 1.833 min. 1 H NMR (400MHz, DMSO) δ 8.18 (s,1H),7.67-7.58 (m,3H),7.57-7.53 (m,1H),7.47-7.43 (m,1H),7.24 (d,1H),4.21-4.18 (m,2H),4.01 (s,2H),3.93 (s,4H),3.54 (d,2H),2.85-2.78(s,3H),2.68-2.57 (m,2H),1.96 (s,1H),1.60-1.55(m,2H),1.40 ‐ 1.21 (m,2H). Compound 29-2: LCMS(ESI): m / z=493.8[M+H] + 13.3 mg, retention time: 2.175 min. 1 H NMR (400MHz, DMSO) δ 8.19 (s,1H),7.69- 7.59 (m,3H),7.57-7.53 (m,1H),7.47-7.43 (m,1H),7.30 (d,1H),4.21-4.18 (m,2H),3.98 (s,2H),3.92 (s,4H),3.55 (d,2H),2.85-2.78(s,3H),2.68-2.57 (m,2H),1.96 (s,1H),1.60-1.55(m,2H),1.40 ‐ 1.21 (m,2H). Example 30:

change

[0207] ステップ1: Compound 12D (100 mg, 0.25 mmol) and 5-trifluoromethylisoindoline hydrochloride (80 mg, 0.36 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (100 mg, 0.78 mmol) was added. The reaction mixture was stirred overnight at room temperature, and after the reaction was complete, it was concentrated. The resulting crude product was purified by column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 30 (35 mg, 28%).

[0208] LC-MS (ESI): m / z = 497.60 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.63 (s,1H),7.57 (d,1H),7.47 (d,1H),6.88 (s,1H),6.44 (s,1H),4.06 (s,4H),3.91 (s,2H),3.66-3.56 (m,2H),3.03-2.94 (m,1H),2.93-2.84 (m,5H),2.15-2.05 (m,2H),1.75-1.63 (m,2H). Example 31: [ka]

[0209] Step 1: 5-Hydroxyhexahydrocyclopenta[C]pyrrole-2(1H)-carboxylate tert-butyl (1.4 g, 6.0 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.24 g, 6.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, then 26B (0.9 g, 3.0 mmol) was added, and the mixture was reacted overnight at room temperature. A small amount of methanol was added to quench the mixture, and after concentration, the residue was separated and purified by silica gel column chromatography (PE / EA=4 / 1) to obtain 31A (1.3 g, 86.6%). LC-MS (ESI): m / z = 504.2[M+H] + .

[0210] Step 2: Compound 31A (1.3g, 2.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 31B (1.3g, 95%), which was used directly in the next step. LC-MS (ESI): m / z = 404.2[M+H] + .

[0211] Step 3: 31B (1.3g, 2.5 mmol) was dissolved in DMF (10 mL), cyclopropylacetic acid (303.0 mg, 3.0 mmol) and N-methylimidazole (819.6 mg, 10 mmol) were added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (840.0 mg, 2.85 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. After complete reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 31 (450.0 mg, 37%).

[0212] LC-MS (ESI): m / z = 486.2[M+H] + . 1 H NMR (400MHz,CDCl3) δ 8.24 (d,1H),7.64 (d,1H),7.56 (s,1H),7.43 (d,1H),7.11 (d,1H),6.75 (s,2H),5.62 - 5.43 (m,1H),4.74 - 4.65 (m,4H),4.54 - 4.28 (m,2H),3.86 - 3.50 (m,4H),3.06 - 2.76 (m,2H),2.47 - 2.33 (m,1H),2.31 (d,2H),2.28 - 2.12 (m,1H),1.96 - 1.83 (m,2H),1.26 (d,1H),1.05 - 0.98 (m,1H),0.62 - 0.47 (m,2H),0.18 (d,2H). 19 F NMR (377MHz,CDCl3) δ -60.59 (s),-73.88 (s). Example 32: [ka]

[0213] Step 1: N-BOC-4-piperidinemethanol (1.3 g, 6.0 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.24 g, 6.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, then 26B (0.9 g, 3.0 mmol) was added. The mixture was reacted overnight at room temperature, a small amount of methanol was added to quench the mixture, and after concentration, the residue was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 32A (1.4 g, 95.2%). LC-MS (ESI): m / z = 492.2[M+H] + .

[0214] Step 2: Compound 32A (1.4 g, 2.8 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 32B (1.4 g, 96%), which was used directly in the next step. LC-MS (ESI): m / z = 392.2[M+H] + .

[0215] Step 3: 32B (1.4 g, 2.8 mmol) was dissolved in DMF (15.0 mL), cyclopropylacetic acid (340.0 mg, 3.4 mmol) and N-methylimidazole (920.0 mg, 12.2 mmol) were added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (940.1 mg, 3.2 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. After complete reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1), and compound 32 (550.0 mg, 42%) was obtained by acidic HPLC preparative sampling.

[0216] LC-MS (ESI): m / z = 474.2 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 8.46 (s,2H),8.04 (d,1H),7.46 (d,1H),7.37 (s,1H),7.24 (d,1H),6.83 - 6.82 (m,1H),6.66 (s,1H),4.47 (d,5H),4.20 (s,2H),3.99 (d,2H),3.72 (d,1H),2.90 (t,1H),2.44 (t,1H),2.12 (d,2H),2.00 - 1.80 (m,1H),1.73 - 1.64 (m,2H),1.11 (s,2H),0.91 - 0.73 (m,1H),0.43 - 0.29 (m,2H),-0.01 (q, 2H). 19 F NMR (377MHz,CDCl3) δ -60.55 (s),-73.71 (s). Example 33: [ka]

[0217] Step 1: Compound intermediate 2 (0.77 g, 2.84 mmol) and compound 33A (0.50 g, 2.84 mmol) were weighed and added to a 100 mL single-necked flask. They were dissolved in DMF (10 mL), potassium carbonate (1.17 g, 8.44 mmol) was added, and after the addition was complete, the mixture was stirred at 80°C for 16 hours. The complete reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1), water (20 mL) was added, the mixture was stirred for 5 minutes, and the organic phase was extracted with ethyl acetate (20 mL) to separate it. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 33B (0.6 g, yield: 60%). LCMS m / z=352.1[M+1] +

[0218] Step 2: Compound 33B (600 mg, 1.71 mmol) was added to a 100 mL single-necked flask and dissolved in methanol (10 mL). Lithium hydroxide monohydrate (140 mg, 3.42 mmol) and water (5 mL) were added. After the addition was complete, the system was protected with nitrogen gas and stirred at 20 °C for 16 hours. The complete reaction of the starting materials was detected by LC-MS. The reaction solution was adjusted to acidity with 2 N hydrochloric acid, extracted with ethyl acetate (20 mL), and concentrated under reduced pressure to obtain the target compound 33C (0.4 g, yield: 69%). LCMS m / z=338.1[M+1] +

[0219] Step 3: Compound 33C (0.50 g, 1.48 mmol) and 5-trifluoromethylisoindoline hydrochloride (0.33 g, 1.48 mmol) were weighed and added to a 100 mL single-necked flask. They were dissolved in DMF (10 mL), and 1-propylphosphonic anhydride (1.41 g, 2.22 mmol) was added. After the addition was complete, the mixture was stirred at 20°C for 2 hours, and the complete reaction of the starting materials was detected by LC-MS. Water (20 mL) was added, the mixture was stirred for 5 minutes, and the mixture was extracted with ethyl acetate (20 mL) to separate the organic phase. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain the target compound 33D (0.4 g, yield: 53%). LCMS m / z=507.1[M+1] +

[0220] Step 4: Compound 33D (0.25 g, 0.49 mmol) was weighed and dissolved in THF (10 mL). Borane dimethyl sulfide complex (0.15 g, 2.97 mmol) was added, and after the addition was complete, the mixture was stirred at 50°C for 16 hours. Complete reaction of the starting materials was detected by LC-MS, methanol (10 mL) was added to the reaction solution to quench it, and then the mixture was concentrated under reduced pressure to obtain the crude product of the target compound. Compound 33 (6 mg, 2.5%) was obtained by preparative HPLC.

[0221] Preparative chromatography method: Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm), sample dissolved in DMF, filtered through a 0.45 μm filter to prepare sample solution, preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5 mM aqueous ammonia), b. Gradient elution, mobile phase A content 40%~80%, c. Flow rate 15 mL / min. d. Elution time 20 min, retention time: 10.20 min.

[0222] LCMS m / z=493.2[M+1] + 1H NMR (400 MHZ,DMSO) δ8.86 (s,1H),7.54-7.60 (m,4H),7.44-7.46 (m,1H),6.47 (d,1H),4.22 (d,2H),4.05 (s,2H),4.00 (s,4H),3.54 (d,2H),2.81 (s,3H),2.63 (t,2H),1.94-2.02 (m,1H),1.55 (d,2H),1.23-1.35 (m,2H). Example 34: [ka]

[0223] Step 1: Compound 3C (350 mg, 0.84 mmol) and compound 5-trifluoromethylisoindoline hydrochloride (282 mg, 1.26 mmol) were dissolved in dichloromethane (15 mL), and triethylamine (0.34 g, 3.36 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (EA / PE = 0-100%) to obtain compound 34B (350 mg, 82.43%). LC-MS (ESI): m / z = 506.3[M+H] + .

[0224] Step 2: Compound 34B (350 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain compound 34C (280 mg, 100%). LC-MS (ESI): m / z = 406.3 [M+H] + .

[0225] Step 3: 1-(methylsulfonyl)azetidine-3-ol (125 mg, 0.83 mmol) was dissolved in tetrahydrofuran (10 mL), CDI (135 mg, 0.83 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (254 mg, 2.49 mmol) was added, and the mixture was stirred for another 15 minutes at room temperature. Compound 34C (280 mg, 0.69 mmol) and a tetrahydrofuran (5 mL) solution of triethylamine (209 mg, 2.06 mmol) were then added to the reaction system, and the mixture was stirred overnight at 60°C. After the reaction was complete, the mixture was concentrated, and compound 34 (150 mg, 37.31%) was obtained by column chromatography (dichloromethane:methanol = 10:1).

[0226] LC-MS (ESI): m / z = 583.7 [M+H] + . 1 H NMR (400MHz,DMSO-D6) δ 7.64 (d,2H),7.56 (d,1H),7.46 (d,1H),6.35 (s,1H),6.25 (dd,1H),5.05-4.98(m,1H),4.18-4.10(m,2H),3.99 - 3.92 (m,6H),3.90 - 3.81 (m,4H),3.71(s, 2H),3.28(s, 2H),3.04(s, 3H),1.73(d, 2H),1.62 - 1.50 (m,2H), 1.48 - 1.37 (m,1H),1.15 - 1.02 (m,2H). Example 35: [ka]

[0227] Step 1: 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (1.5 g, 6.0 mmol) was dissolved in DMF (20 mL), and sodium hydride (0.24 g, 6.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, then 26B (0.9 g, 3.0 mmol) was added, and the mixture was reacted overnight at room temperature. A small amount of methanol was added to quench the mixture, and after concentration, the residue was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 35A (1.0 g, 64.5%). LC-MS (ESI): m / z = 518.2[M+H] + .

[0228] Step 2: Compound 35A (1.0 g, 1.9 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (6 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 35B (0.9 g, 91%), which was used directly in the next step. LC-MS (ESI): m / z = 418.2[M+H] + .

[0229] Step 3: 35B (0.6 g, 1.4 mmol) was dissolved in DMF (10 mL), cyclopropylacetic acid (170.0 mg, 1.7 mmol) and N-methylimidazole (459.2 mg, 5.6 mmol) were added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (470.04 mg, 1.6 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. After complete reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1), and compound 35 (210.0 mg, 30%) was obtained by acidic HPLC preparative sampling.

[0230] LC-MS (ESI): m / z = 500.2[M+H] +. 1 H NMR (400MHz,CDCl3) δ 8.49 (s,2H),8.26 (d,1H),7.68 (d,1H),7.58 (s,1H),7.45 (d,1H),7.00 (s,1H),6.83 (s,1H),5.29 - 5.09 (m,1H),4.68 (s,4H),4.37 (s,2H),3.61- 3.39 (m,4H),2.59 - 2.39 (m,2H),2.33 (d,2H),1.98 (s,2H),1.67 (s,4H),1.07 - 0.93 (m,1H),0.56 (d,2H),0.20 (d,2H). 19 F NMR (377MHz,CDCl3) δ -60.58 (s),-73.77 (s). Example 36: [ka]

[0231] Step 1: Compound 36A (5.0 g, 18.54 mmol) and tetramethylammonium fluoride (7.0 g, 74.16 mmol) were added to a reaction flask, and DMSO (50 ml) was added. The mixture was reacted at 80°C for 16 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, diluted with water (200 ml), extracted twice with ethyl acetate (150 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 36B (4.3 g, yield: 91.57%). LC-MS(ESI): m / z=254.1[M+H] + .

[0232] Step 2: Compound 36B (4.3 g, 16.98 mmol) was added to a reaction flask, methanol (100 ml) was added, followed by palladium / carbon (0.85 g, 20% wt), and a hydrogen gas balloon was inserted. The mixture was reacted at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was filtered, the filter cake was washed once with methanol (20 ml), the filtrate was collected, concentrated, and purified by silica gel column chromatography (PE:EA = 12:1) to obtain compound 36C (2.6 g, yield: 93.49%). LC-MS(ESI): m / z=164.20[M+H] + .

[0233] Step 3: Compound 36C (2.5 g, 15.32 mmol) was added to a reaction flask and dissolved in ACN (50 ml). Then, 1,3-dibromo-5,5-dimethylhydantoin (2.62 g, 9.20 mmol) was added, and the mixture was reacted at room temperature for 4 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and purified by silica gel column chromatography (PE:EA = 15:1) to obtain compound 36D (2.4 g, yield: 64.72%). LC-MS(ESI): m / z=243.90[M+H] + .

[0234] Step 4: Compound 36D (2.4 g, 9.92 mmol), intermediate 5 (2.9 g, 9.92 mmol), and cesium carbonate (4.84 g, 14.88 mmol) were added to a reaction flask, dissolved in DMF (50 ml), and reacted at 100°C for 1 hour. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, diluted with water (200 ml), extracted twice with ethyl acetate (100 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 15:1) to obtain compound 36E (2.14 g, yield: 49.10%). LC-MS(ESI): m / z=341.0[M+H] + .

[0235] Step 5: Compound 36E (2.1 g, 4.78 mmol), tri-n-butyltin methanol (1.70 g, 5.26 mmol), and Xphos Pd G2 (0.37 g, 0.48 mmol) were added to a reaction flask, dissolved in 1,4-dioxane (40 ml), and reacted at 90°C for 4 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 12:1) to obtain compound 36F (0.5 g, yield: 26.79%). LC-MS(ESI): m / z=291.2[M+H] + .

[0236] Step 6: Compound 36F (0.4 g, 1.02 mmol) was added to a reaction flask and dissolved in DCM (20 ml). Triethylamine (0.29 ml, 2.04 mmol) was then added, followed by methanesulfonyl chloride (132 mg, 1.12 mmol). The mixture was reacted at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain compound 36G (0.48 g, yield: 100.4%), and the next step was carried out directly.

[0237] Step 7: Compound 36G (0.48 g, 1.02 mmol), 5-trifluoromethylisoindoline hydrochloride (230 mg, 1.02 mmol), and potassium carbonate (0.56 g, 4.08 mmol) were added to a reaction flask, dissolved in acetonitrile (10 ml), and reacted at 70°C for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 1:2) to obtain compound 36H (0.4 g, yield: 70.08%). LC-MS(ESI) m / z=460.2[M+H] + .

[0238] Step 8: Compound 36H (0.4 g, 0.71 mmol) was added to the reaction flask, and then DCM (8 ml) and TFA (2 ml) were added. The mixture was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain compound 36I (0.31 g, yield: 95.02%). LC-MS(ESI) m / z=460.2[M+H] + .

[0239] Step 9: The compounds cyclopropanol (31 mg, 0.52 mmol) and CDI (91 mg, 0.56 mmol) were added to a reaction flask, dissolved in THF (10 ml), stirred at room temperature for 30 minutes, then triethylamine (0.5 ml, 3.5 mmol) was added, and finally compound 36I (160 mg, 0.35 mmol) was added, and the mixture was reacted at 70°C for 16 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:EA=1:1) to obtain compound 36 (38 mg, yield: 19.97%).

[0240] 1 H NMR (400MHz,DMSO-d6) δ 10.80 (s,1H),8.25 (d,1H),7.58 (s,1H),7.53 (d,1H),7.42 (d,1H),7.11 (d,1H),7.06 (d,1H),6.52 (d,1H),4.06 (s,2H),4.01 - 3.97 (m,1H),3.95 (d,2H),3.87 (s,4H),3.31 (s,2H),2.84 - 2.77 (m,2H),2.15 - 2.03 (m,1H),1.91 (d,2H),1.28 - 1.19 (m,2H),0.66 - 0.58 (m,4H). LC-MS(ESI) m / z=544.50[M+H] + . Example 37 [ka]

[0241] Step 1: Compound 37A (1.52 g, 10 mmol) was dissolved in DMF (30 mL), 1-BOC-4-bromomethylpiperidine (3.34 g, 12 mmol) was added, and then cesium carbonate (4.89 g, 15 mmol) was added. The mixture was heated to 80°C and reacted for 3 hours. After the reaction was complete, water (60 mL) was added, and the mixture was further extracted with EA (20 mL x 3). The organic phase was washed with saturated brine, and the organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (EA / PE = 0-50%) to obtain compound 37B (2.1 g, 62%). LC-MS (ESI): m / z=294.2[M- t [AD+H] + .

[0242] Step 2: Compound 37B (1.5 g, 4.29 mmol) was dissolved in dichloromethane (30 mL), cooled to -15°C, and SnCl4 (1.91 g, 7.33 mmol) was added. The mixture was reacted at -15°C for 15 minutes. 1,1-Dichlorodimethyl ether (493 mg, 4.29 mmol) was then added, and the reaction was continued for 30 minutes. The complete reaction was monitored by TLC, the reaction mixture was slowly added dropwise to ice water, silica gel was added to the system, the mixture was concentrated, spin-dried, and purified by column chromatography (MeOH / DCM = 0-30%) to obtain compound 37C (1 g, 84%). LC-MS (ESI): m / z = 278.1 [M+H] + .

[0243] Step 3: 1-(methylsulfonyl)azetidine-3-ol (382 mg, 2.52 mmol) was dissolved in tetrahydrofuran (15 mL), CDI (408 mg, 2.52 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (771 mg, 7.56 mmol) was added, and the mixture was stirred for another 15 minutes at room temperature. Compound 37C (500 mg, 1.80 mmol) and a solution of triethylamine (552 mg, 5.41 mmol) in tetrahydrofuran (15 mL) were then added to the reaction system, and the mixture was stirred overnight at 60°C. The reaction mixture was concentrated, and 37D (290 mg, 35%) was obtained by column chromatography (MeOH / DCM = 0-15%). LC-MS (ESI): m / z = 455.1 [M + H] +

[0244] Step 4: Compound 37D (50 mg, 0.11 mmol) and compound 5-trifluoromethylisoindoline hydrochloride (49 mg, 0.22 mmol) were dissolved in DCE (10 mL), glacial acetic acid (7 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then sodium triacetoxyborohydride (47 mg, 0.22 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-15%) to obtain compound 37 (9 mg, 13%).

[0245] LC-MS (ESI): m / z = 626.6 [M + H] + . 1H NMR (400MHz,DMSO-d6) δ 7.59 (s,1H),7.53 (d,1H),7.44 (d,1H),6.80 (d,1H),6.53 (d,1H),5.06-5.00(m,1H),4.28-4.20(m,4H),4.18 - 4.12 (m,2H),4.06 - 3.99 (m,2H),3.89(s, 4H),3.87-3.83(m, 2H),3.80(d, 2H),3.77(s, 2H),3.27(s, 2H),3.04(s, 3H),2.00 - 1.92 (m,1H),1.82 - 1.74 (m,2H),1.15 - 1.02 (m, 2H). Example 38: [ka]

[0246] Step 1: 1-Methylsulfonylazetidine-3-ol (220.0 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), and CDI (240.0 mg, 1.5 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of 35B (0.42 g, 1.0 mmol) in tetrahydrofuran (10 mL) and triethylamine (300.0 mg, 3.0 mmol) were added. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 38 (210.0 mg, 41%).

[0247] LC-MS (ESI): m / z = 595.2[M+H] + . 1H NMR (400MHz,CDCl3) δ 8.11 (s,1H),7.49 (d,2H),7.31 (s,1H),6.94 (s,1H),6.78 (s,1H),5.27 - 5.20 (m,1H),5.16 - 5.06 (m,1H),4.18 - 4.14 (m,2H),4.12 - 3.70 (m,7H),3.49 - 3.32 (m,4H),2.89 (s,3H),2.50 - 2.45 (m,2H),1.96 - 1.91 (m,2H),1.66 - 1.61 (m,4H). 19 F NMR (377MHz,CDCl3) δ -60.06 (s). Example 39: [ka]

[0248] Step 1: 39A (5.50 g, 22.62 mmol, synthesis reference: WO2022 / 56269, 2022, A1) was dissolved in dichloromethane (100 mL), and m-chloroperbenzoic acid (13.78 g, 67.86 mmol) was added at 0-5°C. After the addition was complete, the mixture was reacted overnight at room temperature. After complete reaction, the reaction mixture was filtered, the filtrate was concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, (v / v)) to obtain 39B (5.50 g, 88%). LC-MS (ESI): m / z = 275.0 [M+H] + .

[0249] Step 2: 39B (5.50 g, 19.99 mmol) was dissolved in 1,4-dioxane (100 mL), and (tributyltin)methanol (9.63 g, 29.98 mmol) was added at room temperature. After adding the methanol, the mixture was purged three times with nitrogen gas. Then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.57 g, 2.00 mmol) was added. After adding the methanol, the mixture was purged three times with nitrogen gas, and the mixture was reacted overnight at 100°C. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, (v / v)) to obtain 39C (2.50 g, 55%). LC-MS (ESI): m / z = 227.1[M+H] + .

[0250] Step 3: Compound 39C (1.60 g, 7.07 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (2.86 g, 28.28 mmol) and methanesulfonyl chloride (0.85 g, 7.42 mmol) were added at 0-5°C. After adding the compounds, the mixture was allowed to react at room temperature for 30 minutes, then 5-trifluoromethylisoindoline hydrochloride (1.90 g, 8.48 mmol) was added, and the mixture was allowed to react overnight at room temperature. After complete reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 7, (v / v)) to obtain compound 39D (1.5 g, 53%). LC-MS (ESI): m / z = 396.1[M+H] + .

[0251] Step 4: 39D (650 mg, 1.64 mmol) was dissolved in methanol (30 mL), and palladium carbon (175 mg, 0.16 mmol) was added at room temperature. After the addition, the mixture was purged three times with hydrogen gas and reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated to obtain the crude compound 39E. LC-MS (ESI): m / z = 398.1[M+H]+ .

[0252] Step 5: Compound 39E (530 mg, 1.33 mmol) was dissolved in dichloromethane (15 mL), and boron tribromide (1.00 g, 3.99 mmol) was added at 0-5°C. After the addition, the mixture was allowed to react overnight at room temperature. After the reaction was complete, the solvent in the reaction flask was discarded, and the black solid in the reaction flask was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 2), and the organic phase was concentrated. The residue was then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4, (v / v)) to obtain compound 39F (320 mg, 62%). LC-MS (ESI): m / z = 384.1 [M+H] + .

[0253] Step 6: 39F (0.37 g, 0.97 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 4-(bromomethyl)piperidine-1-carboxylate tert-butyl (0.32 g, 1.16 mmol), potassium carbonate (0.27 g, 1.95 mmol), and potassium iodide (16.10 mg, 0.097 mmol) were added at room temperature. The mixture was reacted overnight at 80°C. After complete reaction, the reaction was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain 39G (0.21 g, 37%). LC-MS (ESI): m / z=528.8[M-55] + .

[0254] Step 7: 39G (210 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added at 0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated to obtain the crude compound 39H, and the next step in the reaction was carried out directly.

[0255] Step 8: 1-Methylsulfonylazetidine-3-ol (47.62 mg, 0.32 mmol) was dissolved in tetrahydrofuran (4 mL), and N,N'-carbonyldiimidazole (51.08 mg, 0.32 mmol) was added at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (63.75 mg, 0.63 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 39H (100 mg, 0.21 mmol) was added dropwise at 0-5°C. After the addition, the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 39 (25 mg, 18%).

[0256] LC-MS (ESI): m / z = 658.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.60 - 7.54 (m,3H),7.5-7.434 (d,1H),7.09-7.07 (d,1H),5.06-5.00 (m,1H),4.17-4.13 (m,2H),4.03-3.98 (m,4H),3.92-3.86 (m,8H),3.53-3.49 (m,2H),3.37-3.28 (m,2H),3.04(s,3H),2.87-2.82 (m,2H),1.99 (s,1H),1.82-1.75 (m,2H),1.27-1.24 (m,2H). Example 40: [ka]

[0257] Step 1: N-BOC-4-piperidineethanol (1.37 g, 6.0 mmol) was dissolved in DMF (20 mL), sodium hydride (0.24 g, 6.0 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then, 26B (0.9 g, 3.0 mmol) was added, and the mixture was reacted overnight at room temperature. A small amount of methanol was added to quench the mixture, and after concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 (v / v)) to obtain 40A (1.5 g, 96%). LC-MS (ESI): m / z = 506.2[M+H] + .

[0258] Step 2: Compound 40A (1.5 g, 2.9 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 40B (1.4 g, 96%), which was used directly in the next step. LC-MS (ESI): m / z = 406.2[M+H] + .

[0259] Step 3: Cyclopropanol (220.0 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), and CDI (240.0 mg, 1.5 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of 40B (0.4 g, 1.0 mmol) in tetrahydrofuran (10 mL) and triethylamine (300.0 mg, 3.0 mmol) were added. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 40 (290.0 mg, 59%).

[0260] LC-MS (ESI): m / z = 490.2[M+H] + . 1H NMR (400MHz,CDCl3) δ 8.11 (d,1H),7.54 - 7.40 (m,2H),7.29 (d,1H),6.93 (s,1H),6.78 (s,1H),4.34 (t,2H),4.22 - 3.81 (m,9H),2.76 - 2.70 (m,2H),1.79 - 1.64 (m,5H),1.19 (s,2H),0.72 - 0.59 (m,4H). 19 F NMR (377MHz,CDCl3) δ -60.03 (s). Example 41: [ka]

[0261] Step 1: 41A (1.20 g, 6.63 mmol; see synthesis reference: Organic Letters, 2012, vol.14, #6, pp. 1508-1511) was dissolved in N,N-dimethylformamide (20 mL), and triphenylmethylamine (1.72 g, 6.63 mmol), potassium carbonate (2.75 g, 19.89 mmol), and potassium iodide (0.11 g, 0.66 mmol) were added at room temperature. After all additions were made, the mixture was reacted overnight at 85 °C. After the reaction was complete, water (70 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (70 mL x 2). The organic phase was washed with water (70 mL) and saturated brine (70 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 19 / 1, (v / v)) to obtain 41B (300 mg, 12%).

[0262] Step 2: 41B (300 mg, 0.82 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added at 0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated to obtain the crude compound 41C, and the next step in the reaction was carried out directly. LC-MS (ESI): m / z = 126.0 [M+H] + .

[0263] Step 3: 10C (0.25 g, 0.60 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (212.50 mg, 2.10 mmol) and 41C (0.11 g, 0.90 mmol) were added at 0-5°C. After the additions were complete, the mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain 41D (170 mg, 63%). LC-MS (ESI): m / z = 444.2[M+H] + .

[0264] Step 4: 41D (125 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added at 0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated to obtain the crude compound 41E, and the next step in the reaction was carried out directly.

[0265] Step 5: 1-Methylsulfonylazetidine-3-ol (63.50 mg, 0.42 mmol) was dissolved in tetrahydrofuran (6 mL), and N,N'-carbonyldiimidazole (68.10 mg, 0.42 mmol) was added at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (85.00 mg, 0.84 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 41E (96 mg, 0.28 mmol) was added dropwise at 0-5°C, and after the addition, the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 41 (12 mg, 8%).

[0266] LC-MS (ESI): m / z = 521.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ8.09-8.08 (d,1H),7.42-7.41 (d,1H),6.98-6.97 (d,1H),6.88-6.87 (d,1H),6.76 (s,1H),5.05 - 4.99 (m,1H),4.31-4.26 (m,2H),4.16 - 4.12 (m,2H),3.93-3.92 (m,6H),3.87 - 3.79 (m,4H),3.03 (s,3H),2.86-2.70 (m,2H),1.73-1.62 (m,5H),1.11-1.09 (s,2H). Example 42: [ka]

[0267] Step 1 Compound 12A (3.0 g, 13.57 mmol), 4-(propa-2-in-1-yl)piperidine-1-carboxylate tert-butyl (3.03 g, 13.57 mmol), bis(triphenylphosphine)palladium dichloride (0.95 g, 1.36 mmol), and cuprous iodide (0.52 g, 2.72 mmol) were dissolved in tetrahydrofuran (50 mL) and triethylamine (4.11 g, 40.71 mmol) was added under a nitrogen gas atmosphere. The reaction mixture was heated to 40 °C and stirred for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v / v)) was obtained to obtain the target compound 42A (0.76 g, yield: 15%). LC-MS (ESI): m / z=308.2[Mt-Bu+H] + .

[0268] Step 2: 42A (440 mg, 1.21 mmol) was dissolved in DCM (20 mL), and Dess-Martin oxidizing agent (617 mg, 1.45 mmol) was gradually added at room temperature. After the addition was complete, the mixture was reacted at room temperature for two hours. The mixture was quenched with saturated sodium thiosulfate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotated to obtain the target compound 42B (420 mg, yield: 96%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z=306.2[Mt-Bu+H] + .

[0269] Step 3: 42B (420 mg, 1.16 mmol) was dissolved in methanol (10 mL), and 5-trifluoromethyl group-2,3-dihydro-1H-isoindole hydrochloride (312 mg, 1.40 mmol) was added. The mixture was stirred at room temperature for 1 hour, then sodium borohydride cyanohydride (88 mg, 1.40 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain the target compound 42C (156 mg, yield: 25%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z=477.2[Mt-Bu+H] + .

[0270] Step 4: 42C (156 mg, 0.29 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 1 hour. After complete reaction, the reaction mixture was concentrated, and the crude product 42D was used directly in the next step without purification.

[0271] Step 5: The crude product 42D from the previous step was dissolved in DCM (20 mL), N,N-diisopropylethylamine (112 mg, 0.87 mmol) was added, and the mixture was stirred at room temperature for five minutes. Then 27B (129 mg, 0.58 mmol) was added, and the mixture was reacted at room temperature for one hour. The reaction mixture was quenched with water, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and the target compound 42 (40 mg, yield: 27%) was obtained by column chromatography (dichloromethane:methanol (v / v) = 10:1).

[0272] LC-MS (ESI): m / z = 517.6 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.49 (d,1H),7.46 (s,1H),7.31 (d,1H),6.46 (s,1H),6.32 (s,1H),4.11 (s,4H),4.08 - 4.03 (m,1H),3.88 (s,2H),2.77 - 2.67 (m,4H),2.05 - 1.90 (m,2H),1.74 - 1.60 (m,3H),1.26 - 1.10 (m,2H),0.72 - 0.62 (m,4H). Example 43: [ka]

[0273] Step 1: 16D (333.0 mg, 2.25 mmol) was dissolved in 1,2-dichloroethane (20 mL), then 13D (174.9 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After stirring, sodium triacetoxyborohydride (466.0 mg, 2.2 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotary evaporated to obtain 43A (300.0 mg, 63.0%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z = 477.2[M+H] + .

[0274] Step 2: Compound 43A (300.0 mg, 0.62 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (2.0 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 43B (310.0 mg, 97%), which was used directly in the next step. LC-MS (ESI): m / z = 377.2[M+H] + .

[0275] Step 3: Cyclopropanol (44.0 mg, 0.75 mmol) was dissolved in tetrahydrofuran (5.0 mL), and CDI (120.0 mg, 0.75 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of 43B (310.0 mg, 0.62 mmol) in tetrahydrofuran (5.0 mL) and triethylamine (191.0 mg, 1.9 mmol) were added. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain compound 43 (102.0 mg, 35%).

[0276] LC-MS (ESI): m / z = 461.2[M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.79 (s,1H),7.04 (s,2H),6.55 - 6.49 (m,1H),6.42 (d,1H),6.17 (d,1H),4.45 - 3.86 (m,7H),3.78 (d,2H),2.94 - 2.71 (m,6H),2.32 - 2.15 (m,1H),2.11 - 2.04 (m,2H),1.74 (d,2H),1.36 (d,2H),0.69 - 0.67 (m,4H). Example 44 [ka]

[0277] Step 1: Cyclopropanol (146 mg, 2.52 mmol) was dissolved in tetrahydrofuran (10 mL), CDI (408 mg, 2.52 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (771 mg, 7.56 mmol) was added, and the mixture was stirred for another 15 minutes at room temperature. Compound 37C (500 mg, 1.80 mmol) and a solution of triethylamine (552 mg, 5.41 mmol) in tetrahydrofuran (15 mL) were then added to the reaction system, and the mixture was stirred overnight at 60°C. The reaction mixture was concentrated, and 44A (140 mg, 21%) was obtained by column chromatography (MeOH / DCM = 0-15%). LC-MS (ESI): m / z = 362.40 [M+H] +

[0278] Step 2: Compound 44A (140 mg, 0.39 mmol) and compound 5-trifluoromethylisoindoline hydrochloride (173 mg, 0.78 mmol) were dissolved in DCE (10 mL), glacial acetic acid (23 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then sodium triacetoxyborohydride (164 mg, 0.79 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by column chromatography (MeOH / DCM = 0-15%) to obtain compound 44 (30 mg, 14%).

[0279] LC-MS (ESI): m / z = 533.3 [M + H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.58 (s,1H),7.52 (d,1H),7.43 (d,1H),6.79 (d,1H),6.52 (d,1H),4.27-4.18(m,4H),4.02-3.94(m,2H),3.89(s, 4H),3.81-3.75(m, 4H),3.28(s, 1H),2.85- 2.70 (m,2H),1.92- 1.87 (m,1H),1.77- 1.69 (m,2H),1.20- 1.11 (m,2H),0.65- 0.56 (m,4H). Example 45: [ka]

[0280] Step 1: 3,4-Dihydroxybenzoate ethyl 45A (1.1 g, 6.02 mmol), dodecacarbonyltrilthenium (0.19 g, 0.30 mmol), and triphenylphosphine (0.16 g, 0.60 mmol) were dissolved in toluene (30 mL), protected with nitrogen gas, heated to 90°C, stirred for 30 minutes, and then a toluene solution of 1-Boc-4-ethynylpiperidine (2.14 g, 10.23 mmol) was added dropwise. After the dropwise addition was complete, the temperature was raised to 120°C and the reaction was continued with stirring for 24 hours. The reaction mixture was cooled to room temperature, filtered over diatomaceous earth, washed with ethyl acetate (20 mL x 2), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a medium-pressure preparative apparatus, Biotage Isolera One (20 g silica gel column, eluent: 0-40% EA / PE), to obtain mixture 45B (2.1 g, 89.11%). LC-MS (ESI): m / z=292.2[M+H-100] + .

[0281] Step 2: 45B (0.95 g, 2.43 mmol) was dissolved in THF (20 mL), lithium borohydride (0.064 g, 2.92 mmol) was added to the solution, the mixture was protected with nitrogen gas, the temperature was raised to 70°C, and the reaction was continued with stirring for 18 hours. The reaction mixture was injected into 30 mL of dilute hydrochloric acid, extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a medium-pressure preparative apparatus, Biotage Isolera One (12 g silica gel column, eluent: 0-30% EA / PE), to obtain 45C (0.45 g, 53%). LC-MS (ESI): m / z = 332.1 [M-OH] + .

[0282] Step 3: At room temperature, 45C (0.3g, 0.86 mmol) and carbon tetrabromide (0.29g, 0.86 mmol) were dissolved in DCM (15 mL), stirred for 5 minutes, and triphenylphosphine (0.25g, 0.95 mmol) was slowly added to the solution. The mixture was protected with nitrogen gas and stirred for 18 hours to allow the reaction to continue. The reaction mixture was poured into water and extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-30% EA / PE) to obtain 45D (0.22 g, 62.04%). LC-MS (ESI): m / z=357.0[M-55] + .

[0283] Step 4: Compound 45D (0.22 g, 0.53 mmol) and 5-trifluoromethylisoindoline hydrochloride (0.12 g, 0.53 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.088 g, 0.64 mmol) was added, and the mixture was stirred and reacted at 70°C for 18 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-60% EA / PE) to obtain 45E (0.215 g, 78.23%). LC-MS (ESI): m / z = 519.3 [M + H] + .

[0284] Step 5: Compound 45E (0.215 g, 0.41 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 1 hour. Complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated to obtain the trifluoroacetate salt of 45F (0.20 g, 91%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 419.2[M+H] + .

[0285] Step 6: Cyclopropanol (0.021 g, 0.36 mmol) and carbonyldiimidazole (0.058 g, 0.36 mmol) were dissolved in THF (10 mL), stirred at room temperature for 30 minutes, and then triethylamine (0.073 g, 0.72 mmol) and trifluoroacetate of compound 45F (0.1 g, 0.19 mmol) were added. The mixture was protected with nitrogen gas, heated to 70°C, and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 45 (0.04 g, 33.17%).

[0286] LC-MS (ESI): m / z = 503.3 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.46 - 7.42 (m,2H),7.28 - 7.26 (m,1H),6.81 - 6.76 (m,2H),6.76 - 6.66 (m,1H),4.27 - 4.26 (m,1H),4.08 - 4.05 (m,1H),4.04 (s,4H),3.80 (s,2H),2.72 - 3.66 (m,2H),2.00 - 1.95 (m,1H),1.85 - 1.82 (m,2H),1.62 - 1.50 (m,4H),1.43 - 1.37 (m,2H),0.69 - 0.63 (m,4H). Example 46: [ka]

[0287] Step 1: Compound 46A (1.00 g, 6.31 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (0.25 g, 6.31 mmol) was added, and the mixture was stirred at 25°C for 30 minutes. Methyl iodide (1.34 g, 9.48 mmol) was then added, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was concentrated, and water (20 mL) was added and beaten. The mixture was filtered, washed twice with water, and the filter cake was collected and dried to obtain compound 46B (0.9 g, 82.35%). LCMS (ESI): m / z = 174.2[M+H] +

[0288] Step 2: Compound 46B (1 g, 5.78 mmol) and N-bromosuccinimide (1.13 g, 6.36 mmol) were dissolved in tetrahydrofuran (25 mL), water (5 mL) was added, and then sulfuric acid (0.05 mL) was added. The mixture was stirred at room temperature for 2 hours, 20 mL of water was added, and the pH was adjusted to 10 with saturated sodium bicarbonate. The mixture was concentrated, the organic phase was removed, a large amount of solid precipitated, filtered, the filter cake was collected and dried to obtain compound 46C (1.2 g, 82.35%). LCMS (ESI): m / z = 252.2[M+H] + .

[0289] Step 3: Compound 46C (0.12 g, 0.49 mmol) was added to dichloromethane (5 mL), and then boron tribromide (0.62 g, 2.49 mmol) was added. The mixture was reacted overnight at room temperature, water was added, and the mixture was extracted. The organic phase was washed with saturated sodium bicarbonate, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 5%~50%) to obtain compound 46D (0.1 g, 85.72%). LCMS (ESI): m / z = 238.0 [M+H] + .

[0290] Step 4: Compound 46D (0.1 g, 0.42 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.12 g, 0.42 mmol), and cesium carbonate (0.27 g, 0.84 mmol) were dissolved in N,N dimethylformamide (5 mL), stirred at 100 °C for 3 hours, cooled to room temperature, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 5%~70%) to obtain compound 46E (0.12 g, 65.63%). LCMS (ESI): m / z = 435.6[M+H] + .

[0291] Step 5: Compound 46E (0.1 g, 0.23 mmol), (tributyltin)methanol (0.089 g, 0.28 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.018 g, 0.023 mmol) were dissolved in 1,4-dioxane (10 mL), protected with nitrogen gas, heated to 90 °C, stirred for 3 hours, cooled to room temperature, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 5%~50%) to obtain compound 46F (0.08 g, 90.00%). LCMS (ESI): m / z = 387.2[M+H] + .

[0292] Step 6: Compound 46F (0.1 g, 0.26 mmol) and triethylamine (0.13 g, 1.3 mmol) were dissolved in dichloromethane (5 mL), and methanesulfonyl chloride (0.033 g, 0.29 mmol) was slowly added. The mixture was stirred at room temperature for half an hour, and then 5-(trifluoromethyl)isoindoline hydrochloride (0.070 g, 0.31 mmol) was added. The mixture was stirred at room temperature for 3 hours, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 5%~50%) to obtain compound 46G (0.11 g, 76.14%). LCMS (ESI): m / z = 556.3[M+H] + .

[0293] Step 7: Compound 46G (0.3g, 0.54 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. After concentration, crude product 46H was obtained and used directly in the next step. LCMS (ESI): m / z = 456.3[M+H] + .

[0294] Step 8: Cyclopropanol (0.029 g, 0.50 mmol), N,N'-carbonyldiimidazole (0.080 g, 0.49 mmol), and triethylamine (0.20 g, 1.98 mmol) were dissolved in tetrahydrofuran (5 mL), stirred at room temperature for half an hour, then compound 46H (0.15 g, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse-phase column chromatography (acetonitrile:water = 3%~70%) to obtain compound 46 (0.12 g, 67.39%).

[0295] 1 H NMR (400MHz,DMSO-d6) δ 8.54 (d,1H),7.57 (s,1H),7.53 (d,1H),7.43-7.29 (m,3H),7.10 (d,1H),4.18 (s,2H),4.13 - 3.90 (m,5H),3.88 (s,4H),2.86-2.82 (m,2H),2.63 (s,3H),2.12-2.07(m,1H),1.88 (d,2H),1.26-1.22 (m,2H),0.69 - 0.56 (m,4H). LCMS (ESI): m / z = 540.3[M+H] + . Example 47: [ka]

[0296] Step 1: 47A (8g, 54.78 mmol) was dissolved in tetrahydrofuran (80 mL), and sodium hydride (3.29 g, 136.95 mmol) was slowly added little by little under ice water bath. After half an hour, methyl iodide (11.66 g, 82.17 mmol) was added, and the reaction was carried out at 60°C for 6 hours. After the reaction was complete, the product was diluted with water, extracted with ethyl acetate, the organic phases were combined, and the mixture was spin-dried. The product was then purified by normal phase (petroleum ether:ethyl acetate = 4:1) to obtain product 47B (6.4 g, 73%). LC-MS (ESI): m / z = 161.10[M+H] +

[0297] Step 2: 47B (3g, 18.73 mmol) and N-bromosuccinimide (5.00g, 28.09 mmol) were dissolved in acetonitrile (40 mL), and then reacted at 50°C for 4 hours. After the reaction was complete, the mixture was spin-dried and purified by normal-phase chromatography (petroleum ether:ethyl acetate = 4:1) to obtain product 47C (4.5g, 100%). LC-MS (ESI): m / z = 239.1[M+H] + .

[0298] Step 3: 47C (5g, 20.91 mmol) was dissolved in dichloromethane (70 mL), and boron tribromide (78.58 g, 313.64 mmol) was slowly added little by little, followed by a reaction at 40°C overnight. After the reaction was complete, the mixture was carefully poured into water, the reaction was quenched with saturated sodium bicarbonate, and then extracted with dichloromethane. The organic phases were combined and spin-dried to obtain crude product 47D (4g, 85%). LC-MS (ESI): m / z = 224.9 [M+H] + .

[0299] Step 4: 47D (2g, 8.89 mmol), 4-[(methylsulfonyloxy)methyl]piperidine-1-carboxylate tert-butyl (3.91g, 13.34 mmol), and potassium carbonate (3.07g, 22.23 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was then reacted at 80°C for 3 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, and the mixture was spin-dried. Purification by normal phase (petroleum ether:ethyl acetate = 3:1) was obtained to obtain product 47E (2.3g, 61%). LC-MS (ESI): m / z = 422.2[M+H] +

[0300] Step 5: 47E (2g, 4.74 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.37g, 0.47 mmol), and (tributylstannyl)methanol (2.28g, 7.11 mmol) were dissolved in 1,4-dioxane (25 mL), purged three times with nitrogen gas, and then reacted at 90°C for 6 hours. After the reaction was complete, the mixture was directly spin-dried, adsorbed onto silica gel, and purified by normal-phase (petroleum ether:ethyl acetate = 1:2) to obtain product 47F (0.6g, 34%). LC-MS (ESI): m / z = 374.3 [M+H] +

[0301] Step 6: 47F (0.32 g, 0.86 mmol) was dissolved in dichloromethane (8 mL), N,N-dimethylformamide (0.05 mL) was added, and oxalyl chloride (0.13 g, 1.02 mmol) was slowly added little by little under ice water bath, and the reaction was continued for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, and then extracted three times with dichloromethane. The organic phases were combined and spin-dried to obtain 47G (0.3 g, 89%). LC-MS (ESI): m / z = 392.1[M+H] +

[0302] Step 7: 47G (0.3g, 0.77 mmol), 5-(trifluoromethyl)-2,3-dihydro-1H-isoindole (0.19g, 1.00 mmol), and potassium carbonate (0.21g, 1.54 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 80°C for 3 hours. After the reaction was complete, water was added to dilute the mixture, and it was extracted with ethyl acetate. The organic phases were combined, spin-dried, and purified by normal phase (petroleum ether:ethyl acetate = 1:1) to obtain product 47H (0.1g, 24%). LC-MS (ESI): m / z = 543.3 [M + H] +

[0303] Step 8: 47H (0.090 g, 0.17 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.53 g, 13.42 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was directly spin-dried to obtain crude product 47I (70 mg, 93%). LC-MS (ESI): m / z = 443.3 [M + H] + .

[0304] Step 9: Cyclopropanol (0.019 g, 0.32 mmol) and N,N-carbonyldiimidazole (0.052 g, 0.32 mmol) were dissolved in tetrahydrofuran (4 mL) and reacted at room temperature for 0.5 hours. Then triethylamine (0.065 g, 0.64 mmol) and 47I (0.070 g, 0.16 mmol) were added, and the mixture was refluxed at 70°C overnight. After the reaction was complete, the mixture was directly spin-dried and sent to preparative HPLC. Separation method by preparative HPLC: 1. Instrument: waters2767 preparative liquid, chromatography column: SunFire@ PrepC18 (19 mm × 250 mm) 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.5% ammonium acetate). b. Gradient elution was performed, and the content of mobile phase A was 20% to 60%. c. Flow rate was 15 mL / min. Compound 47 (8 mg, 9.5%) was obtained by lyophilization.

[0305] 1 H NMR (400MHz,DMSO-d6) δ 8.97 (d,1H),8.92 (d,1H),7.84 (d,1H),7.59 (s,1H),7.54 (d,1H),7.43 (d,1H),7.30 (d,1H),4.44 (s,2H),4.08 (d,2H),3.99 (s,4H),3.27(s,5H),2.82 (d,1H),1.27 (d,4H),0.66-0.59 (m,4H). LC-MS (ESI): m / z = 527.2[M+H] + . Example 48: [ka]

[0306] Step 1 Cyclopropanol (87 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), and CDI (243 mg, 1.5 mmol) was added. The mixture was stirred at room temperature for 0.5 hours to allow the reaction to proceed. Then, a solution of 35B (418 mg, 1.0 mmol) in tetrahydrofuran (10 mL) and triethylamine (303 mg, 3.0 mmol) were added, the mixture was heated to 60°C, and the reaction was allowed to proceed overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 48 (130 mg, 26%).

[0307] LC-MS (ESI): m / z = 502.2[M+H] + . 1 H NMR (400MHz,CDCl3) δ 8.09 (d,1H),7.07 (d,1H),6.95 - 6.91 (m,1H),6.91 - 6.85 (m,2H),6.78 (s,1H),4.33 (t,2H),4.26 - 3.76 (m,9H),3.74 - 3.66 (m,1H),2.78 - 2.66 (m,2H),1.80 - 1.60 (m,5H),1.27 - 1.05 (m,2H),0.77 - 0.72 (m,4H),0.72 - 0.64 (m,4H). 19 F NMR (376MHz,CDCl3) δ -60.04 (s). Example 49: [ka]

[0308] Step 1 1-Methylsulfonylazetidine-3-ol (226.5 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), and CDI (240.0 mg, 1.5 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of 26D (0.4 g, 1.0 mmol) in tetrahydrofuran (10 mL) and triethylamine (300.0 mg, 3.0 mmol) were added. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 49 (250.0 mg, 57%).

[0309] LC-MS (ESI): m / z = 583.2 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 8.10 (d,1H),7.51 - 7.40 (m,2H),7.29 (d,1H),6.93 - 6.92 (m,1H),6.78 (s,1H),5.20 - 5.04 (m,1H),4.35 (t,2H),4.21 - 3.94 (m,10H),3.88 (s,2H),2.94 - 2.66 (m,5H),1.83 - 1.66 (m,5H),1.26 - 1.16 (m,2H). 19 F NMR (377MHz,CDCl3) δ -60.02 (s). Example 50: [ka]

[0310] Step 1: Compound 10B (0.65 g, 1.93 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (0.37 g, 3.65 mmol) and methanesulfonyl chloride (0.28 g, 2.45 mmol) were added sequentially under an ice bath. The reaction mixture was heated to room temperature and stirred for 1 hour. Then, triethylamine (0.37 g, 3.65 mmol) and compound 50B (0.38 g, 1.93 mmol) were added sequentially, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 50C (0.55 g, 60%). LC-MS (ESI): m / z = 478.70 [M+H] + .

[0311] Step 2: Compound 50C (0.55 g, 1.15 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature for 2 hours. Complete reaction of the starting materials was detected by LC-MS, and after concentrating the reaction solution, compound 50D (450 mg, crude product) was obtained and used directly in the next step without purification. LC-MS (ESI): m / z = 378.50 [M+H] + .

[0312] Step 3: Compound 50D (0.2 g, 0.53 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.16 g, 1.59 mmol) and methanesulfonyl chloride (0.1 g, 0.87 mmol) were added sequentially under ice water bath. The reaction mixture was heated to room temperature and stirred for 3 hours. Complete reaction of the starting materials was detected by LC-MS, and the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 50 (75 mg, 31%).

[0313] LC-MS (ESI): m / z = 456.50 [M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.08 (d,1H),7.08 (d,1H),6.97 (d,1H),6.93-6.89 (m,2H),6.76 (s,1H),4.30 (t,2H),3.84-3.77 (m,6H),3.56-3.48 (m,2H),2.82 (s,3H),2.72-2.62 (m,2H),1.92-1.84 (m,1H),1.83-1.76 (m,2H),1.71-1.64 (m,2H),1.60-1.52 (m,1H),1.28-1.17 (m,2H),0.93-0.87 (m,2H),0.63-0.57 (m,2H). Example 51: [ka]

[0314] Step 1: Trans-1-(BOC-amino)-4-(2-hydroxyethyl)cyclohexane (1.5 g, 6 mmol) was dissolved in THF (20 mL), NaH (0.3 g, 7 mmol) was added under ice water bath, and the mixture was transferred to room temperature and reacted for 1 hour. Then 26B (0.9 g, 3 mmol) was added and the mixture was reacted at room temperature for 24 hours until completely reacted. After quenching with water (10 mL), the mixture was extracted with EA (20 mL x 2), the organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 51A (1.1 g, 70%). LC-MS (ESI): m / z=420.6[M+H-100] + .

[0315] Step 2: Compound 51A (1.1 g, 1.9 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (8.0 mL) was added. The mixture was reacted at room temperature for 10 minutes, then concentrated to obtain compound 51B (900 mg, 92%), which was used directly in the next step. LC-MS (ESI): m / z = 420.6 [M + H] +.

[0316] Step 3: Compound 51B (900 mg, 1.7 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (0.8 g, 6.0 mmol) and 27B (0.7 g, 3 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 51 (200 mg, 14%).

[0317] LC-MS (ESI): m / z = 504.6 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 8.10 (d,1H),7.47 (d,1H),7.44 (s,1H),7.29 (d,1H),6.92 (d,1H),6.77 (s,1H),4.41 (s,1H),4.31 (t,2H),4.07 - 4.03 (m,1H),4.02 (s,4H),3.87 (s,2H),3.44 (s,1H),2.01 (s,2H),1.85 (d,2H),1.68 (q,2H),1.45 (s,1H),1.21 - 1.01 (m,4H),0.65 (s,4H). 19 F NMR (400MHz,CDCl3) δ -59.81 (s). Example 52: [ka]

[0318] Step 1: Compound 12A (3.0 g, 13.57 mmol), compound 52A (3.33 g, 14.93 mmol), bis(triphenylphosphine)palladium dichloride (0.95 g, 1.36 mmol), and cuprous iodide (0.52 g, 2.71 mmol) were dissolved in tetrahydrofuran (100 mL) at room temperature. Under a nitrogen gas atmosphere, triethylamine (4.38 g, 43.28 mmol) was added, and the reaction mixture was heated to 40°C and stirred for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:ethyl acetate = 1:3 (v / v)) to obtain compound 52B (1.1 g, 23%). LC-MS (ESI): m / z = 364.30 [M+H] + .

[0319] Step 2: Compound 52B (0.5 g, 1.38 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (0.31 g, 3.10 mmol) and methanesulfonyl chloride (0.36 g, 2.06 mmol) were added sequentially under ice water bath. The reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to obtain compound 52C (0.25 g, 41%). LC-MS (ESI): m / z = 442.80 [M+H] + .

[0320] Step 3: Compound 52C (200 mg, 0.45 mmol) and 5-trifluoromethylisoindoline hydrochloride (130 mg, 0.58 mmol) were dissolved in DCM (10 mL), and triethylamine (0.14 g, 1.38 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 50D (0.15 g, 62%). LC-MS (ESI): m / z = 533.20 [M+H] + .

[0321] Step 4: Compound 50D (0.15 g, 0.28 mmol) was dissolved in dichloromethane (10 mL), and then dioxane hydrochloride solution (3 mL) was added. The reaction was allowed to proceed at room temperature for 2 hours, and the complete reaction of the starting materials was detected by LC-MS. After concentrating the reaction mixture, compound 50E (120 mg, crude product) was obtained and used directly in the next step without purification. LC-MS (ESI): m / z = 433.20 [M+H] + .

[0322] Step 5: Compound 50E (0.12 g, 0.28 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.085 g, 0.84 mmol) and cyclopropane carbonyl chloride (0.044 g, 0.42 mmol) were added sequentially under an ice bath. After the addition was complete, the reaction was continued under an ice bath for 4 hours, and the complete reaction of the starting materials was detected by LC-MS. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 52 (20 mg, 14%).

[0323] LC-MS (ESI): m / z = 501.50 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 7.98 (d,1H),7.62 (s,1H),7.57 (d,1H),7.47 (d,1H),6.79 (s,1H),6.43 (s,1H),4.05 (s,4H),3.90 (s,2H),3.63-3.52 (m,1H),2.08-2.00 (m,2H),1.94-1.86 (m,2H),1.55-1.43 (m,4H),0.92-0.80 (m,1H),0.68-0.58 (m,4H). Example 53: [ka]

[0324] Step 1 Compound 53A (400 mg, 0.99 mmol), 4-ethynylpiperidine-1-carboxylate tert-butyl (248 mg, 1.19 mmol), and cuprous oxide (71 mg, 0.50 mmol) were added to pyridine (10 mL) at room temperature, the mixture was purged three times with nitrogen gas, and the reaction mixture was heated to 120 °C and stirred for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain the target compound 53B (450 mg, 94%). LC-MS (ESI): m / z=430.1[M- t [AD+H] + .

[0325] Step 2: 53B (450 mg, 0.92 mmol), tetrakis(triphenylphosphine)palladium (106 mg, 0.092 mmol), and zinc cyanide (162 mg, 1.38 mmol) were added to super-dehydrated DMF (20 mL), purged three times with nitrogen gas, and the reaction mixture was heated to 100°C and stirred for 6 hours. After the reaction was complete, the mixture was filtered, the filtrate was diluted with EA, and washed twice with water. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotated to obtain the target compound 53C (240 mg, 68%) by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v / v)). LC-MS (ESI): m / z=329.2[M- t [AD+H] +

[0326] Step 3: 53C (240 mg, 0.63 mmol) was dissolved in ether (10 mL), and lithium borohydride (69 mg, 3.15 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, the aqueous phase was extracted with EA, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain the target compound 53D (220 mg, 98%) by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v / v)). LC-MS (ESI): m / z=301.2[M- t [AD+H] + .

[0327] Step 4: 53D (220 mg, 0.62 mmol) was dissolved in DCM (10 mL), and Dess-Martin oxidizing agent (393 mg, 0.93 mmol) was gradually added at room temperature. After the addition was complete, the mixture was reacted at room temperature for two hours. The mixture was quenched with saturated sodium thiosulfate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain the target compound 53E (204 mg, 93%) by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v / v)). LC-MS (ESI): m / z=299.2[M- t [AD+H] + .

[0328] Step 5: 53E (184 mg, 0.52 mmol) was dissolved in methanol (10 mL), and 5-trifluoromethyl group-2,3-dihydro-1H-isoindole hydrochloride (139 mg, 0.62 mmol) was added. The mixture was stirred at room temperature for 1 hour, then sodium borohydride cyanohydride (49 mg, 0.78 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain the target compound 53F (204 mg, 75%) by silica gel column chromatography (eluent: dichloromethane: methanol (v / v) = 10:1). LC-MS (ESI): m / z=470.2[M- t [AD+H] + .

[0329] Step 6: 53F (204 mg, 0.39 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 1 hour. After complete reaction, the reaction mixture was concentrated, and the crude product 53G was used directly in the next step without purification.

[0330] Step 7: Cyclopropanol (34 mg, 0.59 mmol) was dissolved in tetrahydrofuran (5.0 mL), and CDI (96 mg, 0.59 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of product 53G obtained in the previous step in tetrahydrofuran (5.0 mL) and triethylamine (191.0 mg, 1.9 mmol) were added, the mixture was heated to 60°C, and the reaction was allowed to proceed overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (v / v) = 1:3) to obtain compound 53 (90 mg, 46%).

[0331] LC-MS (ESI): m / z = 510.2[M+H] + . 1 H NMR (400MHz,Chloroform-d) δ 7.79 (s,1H),7.58 (d,1H),7.53 - 7.39 (m,2H),7.29 (d,1H),6.44 (s,1H),4.46 - 3.78 (m,9H),3.07 - 2.82 (m,3H),2.12 (d,2H),1.70 (d,2H),0.80 - 0.62 (m,4H). Example 54: [ka]

[0332] Step 1 Compound 54A (2.78 g, 10.0 mmol) was dissolved in pyridine (10 mL), and then 1-Boc-4-ethynylpiperidine (2.52 g, 12.0 mmol) and cuprous oxide (0.72 g, 5.0 mmol) were added. The mixture was heated to 120 °C and stirred for 4 hours to allow the reaction to proceed. After concentration and removal of the solvent, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain compound 54B (2.0 g, 55%). LC-MS (ESI): m / z = 360.1 [M + H] + .

[0333] Step 2: 54B (2.0 g, 5.56 mmol) was dissolved in 1,2-dichloroethane (20 mL), and then 5-trifluoromethyl group-2,3-dihydro-1H-isoindole hydrochloride (1.24 g, 5.56 mmol) and sodium borohydride acetate (2.36 g, 11.16 mmol) were added. Finally, acetic acid (0.27 g, 4.45 mmol) was added, and the mixture was reacted overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain the target compound 54C (2.2 g, 74%). LC-MS (ESI): m / z = 531.2[M+H] + .

[0334] Step 3: 54C (2.0 g, 3.77 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (4.0 mL) was added. The mixture was reacted at room temperature for 1 hour. After complete reaction, the reaction solution was concentrated to obtain compound 54D, and the next step in the reaction was carried out directly.

[0335] Step 4: Cyclopropanol (170.0 mg, 3.0 mmol) was dissolved in tetrahydrofuran (10.0 mL), and CDI (490.0 mg, 3.0 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, triethylamine (601.0 mg, 6.0 mmol) and a solution of 54D (860.0 mg, 2.0 mmol) in tetrahydrofuran (5.0 mL) were added in sequence. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain compound 54 (500.0 mg, 48%).

[0336] LC-MS (ESI): m / z = 515.2[M+H] + . 1 H NMR (400MHz,DMSO) δ 7.59 (s,1H),7.55 (d,1H),7.44 (d,1H),7.11 (s,1H),6.88 (s,1H),6.56 (s,1H),4.03 - 3.98 (m,2H),3.91 (d,9H),3.27 (s,2H),3.07 - 2.87 (m,3H),2.07 - 1.94 (m,2H),1.61 - 1.42 (m,2H),0.65 - 0.62 (m,4H). 19 F NMR (377MHz,CDCl3) δ -58.30 (s). Example 55: [ka]

[0337] Step 1: 55A (11.4 g, 50 mmol) was dissolved in methanol (40 mL), Pd / C (1.1 g, 10% wt) was added, and the mixture was replaced three times by inserting a hydrogen gas balloon. The reaction was then allowed to proceed at room temperature for 18 hours. After complete reaction, the reaction mixture was filtered and concentrated to obtain 55B (9.2 g, 94%). LC-MS (ESI): m / z = 198 [M + H] + .

[0338] Step 2: N-BOC-4-piperidinecarboxylic acid (3.9 g, 20 mmol) was dissolved in DMF (40 mL), 55B (4.6 g, 20 mmol) and N-methylimidazole (6.6 g, 80 mmol) were added, and TCFH (8.4 g, 30 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 min. After complete reaction, 40 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 55C (5.3 g, 65%). LC-MS (ESI): m / z = 409[M+H] + .

[0339] Step 3: Triphenylphosphine (7.9 g, 30 mmol) was dissolved in toluene (50 mL), DDQ (6.8 g, 30 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Then 55C (4.1 g, 10 mmol) was added, and the mixture was reacted at 110 °C for 12 hours until the reaction was complete. Ethyl acetate (50 mL) was added to the reaction mixture, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 1:1) to obtain 55D (3.5 g, 90%). LC-MS (ESI): m / z=335[M+H-56] + .

[0340] Step 4: Compound 55D (3.1 g, 8 mmol) was dissolved in THF (30 mL), DABAL-H (24 mL, 1 M) was added at 0°C, and the mixture was transferred to room temperature and reacted for 1 hour. After complete reaction, dilute hydrochloric acid (30 mL) was added to quench the reaction, ethyl acetate (20 mL x 2) was added for extraction, the organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 2:1) to obtain 55E (2.2 g, 75%). LC-MS (ESI): m / z=307[M+H-56] + .

[0341] Step 5: 55E (2.2g, 6 mmol) was dissolved in ethyl acetate (20 mL), IBX (3.4g, 12 mmol) was added, and the mixture was reacted at 80°C for 12 hours. After complete reaction, the mixture was filtered and concentrated to obtain 55F (2.1g, 97%).

[0342] Step 6: 55F (1.8g, 5 mmol) was dissolved in DCE (20 mL), and 5-trifluoromethylisoindoline hydrochloride (1.1g, 5.0 mmol), sodium borohydride acetate (1.4g, 6.8 mmol), and 5 drops of glacial acetic acid were added in sequence. The mixture was allowed to react at room temperature for 1 hour until completely reacted. After complete reaction, 10 mL of water was added to the reaction mixture, and the mixture was extracted using DCM (20 mL x 2). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain 55G (2.1g, 80%).

[0343] Step 7: Compound 55G (2.1g, 4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (8.0 mL) was added. The mixture was reacted at room temperature for 10 minutes, then concentrated to obtain compound 55H (2.0g, 90%), which was used directly in the next step.

[0344] Step 8: 55H (862 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (516 mg, 4.0 mmol) and 27B (669 mg, 3 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 25C (300 mg, 30%).

[0345] LC-MS (ESI): m / z = 516.6 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.46 (d,1H),7.42 (s,1H),7.28 (s,2H),6.98 (s,1H),4.36 - 4.03 (m,3H),4.01 (s,3H),3.96 (d,6H),3.22 - 3.09 (m,1H),3.10 - 2.93 (m,2H),2.15 (d,2H),2.04 - 1.84 (m,2H),0.69 (s,4H). 19 F NMR (400MHz,CDCl3) δ -59.98 (s). Example 56: [ka]

[0346] Step 1: 56A (4.4g, 14.3 mmol), 4-fluoro-3-hydroxybenzonitrile (1.9g, 14.3 mmol), and potassium carbonate (4.96g, 35.9 mmol) were dissolved in acetonitrile (50 mL) and reacted at room temperature for 12 hours. After the reaction was complete, water (30 mL) was added to the reaction system to quench the reaction, the mixture was extracted with ethyl acetate (30 mL x 2), washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 56B (5.1g, 98%). LC-MS (ESI): m / z = 363.4 [M + H] + .

[0347] Step 2: Compound 56B (5.1 g, 14.0 mmol) was dissolved in methanol (50 mL), and sodium borohydride (1.6 g, 42.0 mmol) was added under ice bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction system was added to water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 56C (5.1 g, 100%). LC-MS (ESI): m / z = 365.1[M+1] +

[0348] Step 3: Compound 56C (5.1g, 14.0 mmol) and potassium carbonate (4.83g, 35.0 mmol) were dissolved in DMF (50 mL), heated to 85°C, and reacted for 12 hours. After the reaction was cooled to room temperature, water (100 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain a mixture of 56D-1 and 56D-2 (2.1g, 44%). LC-MS (ESI): m / z = 345.2[M+1] +

[0349] Step 4: A mixture of compounds 56D-1 and 56D-2 (816 mg, 2.37 mmol) and potassium hydroxide (1.99 g, 35.5 mmol) were dissolved in ethanol (10 mL) and water (5 mL). The mixture was reacted at 100°C for 24 hours, and after monitoring the cessation of the reaction by LC-MS, the reaction was cooled to room temperature. The pH was adjusted to 6-7 with dilute hydrochloric acid, washed with ethyl acetate (30 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude mixture of compounds 56E-1 and 56E-2 (608 mg, 70%). LC-MS (ESI): m / z = 364.1[M+H] +

[0350] Step 5: A mixture of compounds 56E-1 and 56E-2 (608 mg, 1.67 mmol), HATU (954 mg, 2.51 mmol), and DIPEA (433 mg, 3.34 mmol) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 15 minutes. 5-(trifluoromethyl)isoindoline hydrochloride (412 mg, 1.84 mmol) was added to the reaction system and stirred at room temperature for 3 hours. After monitoring the reaction termination by LC-MS, water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 2). The mixture was washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain a mixture of 56F-1 and 56F-2 (455 mg, 51%). LC-MS (ESI): m / z = 533.2[M+H] +

[0351] Step 6: A mixture of compounds 56F-1 and 56F-2 (455 mg, 0.85 mmol) was dissolved in anhydrous toluene (10 ml), 1 M DABAL-H (1.1 ml) was added at 0°C, the temperature was maintained, and the reaction was allowed to proceed for 6 hours. Completion of the reaction was detected by TLC, water (1.1 ml), 15% NaOH (1.1 ml), and then another (2.2 ml) of water were added and the mixture was stirred. The mixture was dried over anhydrous sodium sulfate, the solid was filtered, washed with dichloromethane (10 ml), the organic phase was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain a mixture of 56G-1 and 56G-2 (133 mg, 30%). LC-MS (ESI): m / z = 519.2[M+H] +

[0352] Step 7: A mixture of compounds 56G-1 and 56G-2 (133 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. After monitoring the complete reaction by LC-MS, the mixture was directly concentrated to obtain a crude mixture of 56H-1 and 56H-2 (107 mg), which was added directly to the next step in the reaction without purification. LC-MS (ESI): m / z = 419.1[M+H] + .

[0353] Step 8: A mixture of compounds 56H-1 and 56H-2 (107 mg, 0.25 mmol) was dissolved in anhydrous dichloromethane (2 mL), triethylamine (126 mg, 1.25 mmol) was added, and the mixture was stirred for 15 minutes. Methanesulfonyl chloride (34 mg, 0.30 mmol) was added, and the mixture was reacted at room temperature for 3 hours. After concentrating the reaction solution, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 56 (59 mg, 38%). The mixture of compound 56 was separated by SFC to obtain four isomers: compound 56-1 (12 mg, retention time 4.224 min, 8%), 56-2 (13 mg, retention time 4.748 min, 7%), 56-3 (6 mg, retention time 5.571 min, 1%), and 56-4 (5 mg, retention time 6.168 min, 2%). Preparative chromatography separation conditions: 1. Instrument: SHIMADZU LC-30AD sf, 2. Chromatography column: Chiral AD column, 3. Mobile phase system: A for n-hexane, B for 0.05% DEA in ethanol and acetonitrile, 4. Gradient: B 40%, 5. Flow rate: 3 mL / min Compound 56-1: LC-MS (ESI): m / z = 497.2[M+H] + . 1H NMR (400MHz, CD3OD) δ 7.54 - 7.48 (m,2H),7.42 - 7.36 (m,1H),6.94 - 6.89 (m,1H),6.89 - 6.79 (m,2H),4.36 - 4.28 (m,1H),4.07 - 3.99 (m,1H),3.95 (s,4H),3.80 (s,2H),3.78 - 3.74 (m,1H),3.31 - 3.29 (m,2H),2.82 (s,3H),2.79 - 2.69 (m,2H),2.15 - 2.02 (m,1H),1.90 - 1.77 (m,2H),1.63 - 1.50 (m,2H). Compound 56-2: LC-MS (ESI): m / z=497.2[M+H] + . 1 H NMR (400MHz, CD3OD) δ 7.54 - 7.48 (m,2H),7.42 - 7.36 (m,1H),6.94 - 6.89 (m,1H),6.89 - 6.79 (m,2H),4.36 - 4.28 (m,1H),4.07 - 3.99 (m,1H),3.95 (s,4H),3.80 (s,2H),3.78 - 3.74 (m,1H),3.31 - 3.29 (m,2H),2.82 (s,3H),2.79 - 2.69 (m,2H),2.15 - 2.02 (m,1H),1.90 - 1.77 (m,2H),1.63 - 1.50 (m,2H). Compound 56-3: LC-MS (ESI): m / z=497.2[M+H] + . 1H NMR (400MHz, CD3OD) δ 7.54 - 7.48 (m,2H),7.42 - 7.36 (m,1H),6.94 - 6.89 (m,1H),6.89 - 6.79 (m,2H),4.36 - 4.28 (m,1H),4.07 - 3.99 (m,1H),3.95 (s,4H),3.80 (s,2H),3.78 - 3.74 (m,1H),3.31 - 3.29 (m,2H),2.82 (s,3H),2.79 - 2.69 (m,2H),2.15 - 2.02 (m,1H),1.90 - 1.77 (m,2H),1.63 - 1.50 (m,2H). Compound 56-4: LC-MS (ESI): m / z=497.2[M+H] + . 1 H NMR (400MHz, CD3OD) δ 7.54 - 7.48 (m,2H),7.42 - 7.36 (m,1H),6.94 - 6.89 (m,1H),6.89 - 6.79 (m,2H),4.36 - 4.28 (m,1H),4.07 - 3.99 (m,1H),3.95 (s,4H),3.80 (s,2H),3.78 - 3.74 (m,1H),3.31 - 3.29 (m,2H),2.82 (s,3H),2.79 - 2.69 (m,2H),2.15 - 2.02 (m,1H),1.90 - 1.77 (m,2H),1.63 - 1.50 (m,2H). Example 57

change

[0354] ステップ1: At room temperature, compound 57A (4.0 g, 24.06 mmol) was dissolved in methanol (80 mL), cooled to 0°C, and liquid bromine (3.85 g, 24.06 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 2 hours. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate solution, the methanol was spin-dried, the remaining reaction mixture was extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain compound 57B (4.5 g, 76%). LC-MS (ESI): m / z=245.0&247.0[M+H] + .

[0355] Step 2: At room temperature, 57B (4.5 g, 18.36 mmol), 4-fluoro-3-hydroxybenzonitrile (2.52 g, 18.36 mmol), and potassium carbonate (6.34 g, 45.90 mmol) were dissolved in acetonitrile (50 mL) and reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain compound 57C (5.0 g, 90%). LC-MS (ESI): m / z = 302.0 [M+H] + .

[0356] Step 3: At room temperature, compound 57C (5.0 g, 16.59 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and sodium borohydride (1.26 g, 33.18 mmol) was slowly added at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 57D (4.0 g, 79%), which was then directly followed in the next step without purification. LC-MS (ESI): m / z = 304.1[M+H] + .

[0357] Step 4: At room temperature, compound 57D (4.0 g, 13.19 mmol) and potassium carbonate (3.64 g, 26.38 mmol) were dissolved in N,N-dimethylformamide (40 mL), ...

Claims

1. A compound represented by formula (I), its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, 【Chemistry 1】 A is selected from a 4-14 membered heterocyclic group, a 5-6 membered cycloalkyl group, and a phenyl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group, cycloalkyl group, and phenyl group optionally contain 1-4 R Ａ Replaced by, B is selected from a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocyclic group, and a 6-12 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms selected from N, O, and S, and the carbocyclic group, heterocyclic group, and heteroaryl group optionally contain 1-4 R Ｂ Replaced by, C is selected from a phenyl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered partially unsaturated bicyclic heterocyclic group, and an 8-14 membered tricyclic heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl group, heterocyclic group, and phenyl group optionally contain 1-4 R Ｃ Replaced by, L １ 、L ２ are each independently selected from W １ -R Ｌ -W ２ and the left side of L １ is connected to A, and the left side of L ２ is connected to B, and L １ and L ２ are not joined simultaneously R Ｌ C １－４ Alkylene group, C ２－４ Selected from an alkenylene group and a 3-6 membered cycloalkyl group, the alkylene group, alkenylene group, and cycloalkyl group may optionally have 1-4 R1s. Ｌ１ Further substitution occurs with R Ｌ１ These are, independently, halogen, =O, and C. １－４ alkyl group, C ２－４ Alkenyl group, C １－４ Selected from alkoxy groups and 3- to 6-membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group can optionally be halogen, CN, OH, and NH. ２ Further substituted with 1 to 4 substituents selected from, W １ , W ２ These are, independently, bonded, -O-, -S-, and -NR Ｗ１ -, -CONR Ｗ１ -, -NR Ｗ１ Selected from CO-, -C(=O)O-, and -OC(=O)-, R Ｗ１ H, C １－４ Selected from alkyl groups and halogens, The options are B and L. ２ C, together with the atoms linked to them, forms a tetracyclic heterocyclic group, and optionally, halogens, CN, OH, NO ２ ,=O,COOH,C １－４ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -OC １－４ Alkyl group, -O-halo C １－４ Substituted with 1 to 4 groups selected from alkyl groups, R Ａ These are H, halogen, CN, OH, COOH, and C, respectively, independently. １－４ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -OC １－４ Alkyl group, -NH-S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ - (CH ２ ) ｐ -R ａ , -P(O)-(C １－４ Alkyl) ２ , -C(O)-OR ａ ,-(CH ２ ) ｐ -C(O)-(CH ２ ) ｐ -R ａ , -NHC(O)-R ａ , -C(O)N(C １－４ Alkyl) ２ , -NHC(O)-C １－４ Alkyl alkyl groups or 3-6 member heterocycloalkyl groups, -NHR ａ Selected from the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group, halogen, OH, NH ２ ,CN,-O-HALOC １－４ Alkyl alkyl groups, deuterium, or C １－４ The heterocycloalkyl group is further substituted with 1 to 4 groups selected from alkyl groups, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S. R ａ C ２－４ Alkynyl group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, C １－４ Alkoxy group, -O-C ３－６ Cycloalkyl groups, deuterated C １－４ alkyl group, C １－４ Selected from alkyl groups, the alkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and alkoxy group may optionally be halogens, C １－４ Alkyl, Halo C １－４ Alkyl alkyl groups, deuterated C １－４ Alkyl group, 6-membered heterocycloalkyl group, 5-6 membered heteroaryl group, C ２－４ Alkynyl group, 3-5 membered cycloalkyl group, -O-halo C １－４ Alkyl alkyl group, OH, -S(O) ２ -CH ３ or = CH ２ , = CHF, = CF ２ The alkyl group is further substituted with 1 to 4 groups selected from, the alkyl group is further substituted with 1 to 3 groups selected from OH and CN, and the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. R Ｂ is, independently of each other, H, halogen, CN, =O, OH, NO ２ , -SF ５ , C １－４ alkyl group, -P(O)-(CH ３ ) ２ , -S(O) ２ -CH ３ , -S(O) ２ -CH ２ R ａ -, NH ２ , -C １－４ alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, 3- to 5-membered cycloalkyl group, halo C １－２ alkyl group, 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, S, 3- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, S, and the alkoxy group, cycloalkyl group, heteroaryl group, heterocycloalkyl group are optionally further substituted with a group of C １－２ alkyl group, R Ｃ is, independently of each other, H, halogen, CN, =O, OH, NO ２ , C １－４ alkyl group, halo C １－４ alkyl group, -O-C ３－５ cycloalkyl group, C ３－５ cycloalkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, -SCF ３ , -SF ５ , -(NH) ｐ -P(O)(C １－４ alkyl) ２ , -(CH ２ ) ｐ -O-C １－４ alkyl group, and is selected from p is selected from 0, 1, 2, 3, 4 and is a compound represented by formula (I), its stereoisomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt thereof.

2. A is selected from a 4-6 member monocyclic heterocyclic group, a 7-9 member bicyclic heterocyclic group, a 5-6 member cycloalkyl group, and a phenyl group, and the heterocyclic group, cycloalkyl group, and phenyl group optionally have 1-4 R Ａ Replaced by, R Ａ These are H, halogen, CN, OH, COOH, and C, respectively, independently. １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, -OC １－４ Alkyl group, -NH-S(O) ２ -C １－２ Alkyl alkyl group, -S(O) ２ -C １－２ Alkyl alkyl group, -S(O) ２ - (CH ２ ) ｐ -R ａ , -P(O)-(C １－２ Alkyl) ２ , -C(O)-OR ａ ,-(CH ２ ) ｐ -C(O)-(CH ２ ) ｐ -R ａ , -NHC(O)-R ａ , -C(O)N(C １－４ Alkyl) ２ , -NHC(O)-C １－４ Alkyl alkyl groups, 3-6 member heterocycloalkyl groups, or -NHR ａ Selected from the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group, halogen, OH, NH ２ ,CN,-O-HALOC １－２ Alkyl alkyl groups, deuterium, or C １－４ The heterocycloalkyl group is further substituted with 1 to 4 groups selected from alkyl groups, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S. R ａ C ２－４ Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C １－４ Alkoxy group, -O-C ３－６ Cycloalkyl groups, deuterated C １－２ alkyl group, C １－２ Selected from alkyl groups, the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group may optionally be halogens, C １－２ Alkyl, Halo C １－２ Alkyl alkyl groups, deuterated C １－２ Alkyl alkyl group, OH, -S(O) ２ -CH ３ ❖ = CH ２ , =CHF or =CF ２ The alkyl group is further substituted with the group, and the alkyl group is further substituted with 1 to 3 groups selected from OH and CN. p is selected from 0, 1, or 2. B is selected from a 6-membered heteroaryl group, a 5-6 membered heterocyclic group condensed with a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered carbocyclic group, a 5-6 membered heteroaryl group condensed with a 5-6 membered heteroaryl group, a benzo-5-6 membered heteroaryl group, a 5-6 membered aryl group condensed with a 5-6 membered aryl group, a 4-6 membered heterocyclic spiro-5-6 membered heteroaryl group, and a benzo-5-6 membered heterocyclic group, wherein the heterocyclic group, heteroaryl group, carbocyclic group, and aryl group are optionally composed of 1 to 4 R groups. Ｂ Replaced by, R Ｂ These are, independently, halogen, CN, and -P(=O)(C). １－２ Alkyl) ２ , = O, -SF ５ , C １－２ Alkyl alkyl group, -S(O) ２ -C １－２ Alkyl, NH ２ , C １－２ Alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, cyclopropyl group, halo C １－２ Selected from alkyl groups and 5-6 membered heteroaryl groups, the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group may be optionally C １－２ Further substituted with an alkyl group, C is selected from a phenyl group, a phenyl group formed by the condensation of a 5-7 member heterocyclic group, a phenyl group formed by the condensation of a 5-6 member carbocyclic group, and a 5-6 member heteroaryl group formed by the condensation of a 5-6 member heterocyclic group. The heterocyclic group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S. The phenyl group, heterocyclic group, carbocyclic group, and heteroaryl group optionally contain 1 to 4 R atoms. Ｃ Replaced by, R Ｃ These are, independently, CN, OH, and C. １－２ Alkyl, Halo C １－２ Alkyl group, -O-cyclopropyl group, cyclopropyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, -SCF ３ , -SF ５ , - (NH) ０－１ -P(O)(C １－２ Alkyl) ２ , C １－２ C substituted with an alkoxy group １－２ Selected from alkyl groups, L １ C １－２ Alkylene-O, C １－２ Alkylene group, N(C) １－２ Alkylene)-C １－２ Alkylene group, -O-, C ２－４ Selected from alkenylene groups, the alkylene group optionally comprises 1 to 3 R groups. Ｌ１ Further substitution occurs with R Ｌ１ These are, independently, halogen, =O, and C. １－２ Alkyl, Halo C １－２ alkyl group, C ２－４ Alkenyl group, C １－２ Alkoxy group, Halo C １－２ Selected from alkoxy groups and 3-6 membered cycloalkyl groups, L ２ C １－２ Alkylene group, -N(CH) ３ ) - Selected from, and the alkylene group optionally has 1 to 3 R Ｌ１ Further substitution occurs with R Ｌ１ These are, independently, halogen, =O, and C. １－２ Alkyl, Halo C １－２ alkyl group, C ２－４ Alkenyl group, C １－２ Alkoxy group, Halo C １－２ A compound of formula (I) according to claim 1, selected from an alkoxy group and a 3- to 6-membered cycloalkyl group, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

3. It has the structure of formulas (I-1), (I-2), (I-3), and (I-4), 【Chemistry 2】 X ａ It is selected from CH or N, A1 is, 【Transformation 3】 Selected from the basis, B2 is an optional selection of 1 to 4 R Ｂ Replaced with, 【Chemistry 4】 Selected from the basis, B6 can optionally contain 1 to 4 R Ｂ Replaced with, 【Transformation 5】 Selected from the basis, B1 is an optional selection of 1 to 4 R Ｂ Replaced with, 【Transformation 6】 Selected from the basis, As an option, 【Transformation 7】 teeth, 【Transformation 8】 Selected from, R Ａ is -S(O) ２ - (CH ２ ) ｐ -R ａ , -P(O)-(C １－２ Alkyl) ２ , -C(O)-OR ａ ,-(CH ２ ) ｐ -C(O)-(CH ２ ) ｐ -R ａ , -S(O) ２ -C １－２ Alkyl alkyl group, -NHC(O)-R ａ , -C(O)N(C １－４ Alkyl) ２ , -NHC(O)-C １－２ Alkyl alkyl groups, 3-6 member heterocycloalkyl groups, or -NHR ａ Selected from, the alkyl group and heterocycloalkyl group are optionally halogen, OH, and NH ２ ,CN,-O-HALOC １－２ Alkyl alkyl groups, deuterium, or C １－２ The heterocycloalkyl group is further substituted with 1 to 4 groups selected from alkyl groups, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S. R Ｂ These are, independently, halogen, CN, and -P(=O)(C). １－２ Alkyl) ２ , = O, -SF ５ , C １－２ Alkyl alkyl group, -S(O) ２ -C １－２ Alkyl, NH ２ , C １－２ Alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, cyclopropyl group, halo C １－２ Selected from alkyl groups and 5-6 membered heteroaryl groups, the alkyl group, alkoxy group, cyclopropyl group, and heteroaryl group may be optionally C １－２ Further substituted with an alkyl group, R Ｃ These are, independently, CN, OH, and C. １－２ Alkyl, Halo C １－２ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, -O-cyclopropyl group, cyclopropyl group, -SF ５ Selected from, R ａ C ２－４ Alkynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, C １－４ Alkoxy group, -O-cyclopropyl group, -CD ３ ien-CH ２ D, -CHD ２ The methyl group and ethyl group are selected from the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group, and the halogen and C are optionally selected from the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, and alkoxy group. １－２ Alkyl, Halo C １－２ Alkyl alkyl groups, deuterated C １－２ Alkyl alkyl group, OH, -S(O) ２ -CH ３ ❖ = CH ２ , =CHF or =CF ２ The methyl group and ethyl group are further substituted with 1 to 3 groups selected from OH and CN. n1 is selected from 1, 2, or 3. n3 is selected from 0, 1, 2, and 3, and is a compound of formula (I) according to claim 2, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

4. R Ａ is -S(O) ２ - (CH ２ ) ｐ -R ａ , -S(O) ２ -C １－２ Alkyl alkyl group, -C(O)-OR ａ ,-C(O)-CH ２ -R ａ , -NHC(O)-R ａ , -C(O)N(C １－４ Alkyl) ２ , -NHC(O)-C １－２ Alkyl alkyl groups, 3-6 member heterocycloalkyl groups, or -NHR ａ The alkyl group and heterocycloalkyl group are selected from F, Cl, Br, OH, and NH. ２ , CN, D, -CH ３ or -CH ２ CH ３ The heterocycloalkyl group is further substituted with 1 to 4 groups selected from, and the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S. R Ｂ These are independently F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, ethoxy group, vinyl group, propenyl group, butenyl group, ethynyl group, propynyl group, cyclopropyl group, -CF ３ ,-CHF ２ ien-CH ２ F is selected from a 5-membered heteroaryl group and a 6-membered heteroaryl group, and the methyl group, ethyl group, methoxy group, ethoxy group, cyclopropyl group, and heteroaryl group are optionally further substituted with a methyl group or an ethyl group. R Ｃ These are, independently, a methyl group, an ethyl group, and -CF ３ ,-CHF ２ ien-CH ２ CH ２ F, -CH ２ CF ３ ien-CH ２ CHF ２ ien-CH ２ CH ２ F, vinyl group, propenyl group, ethynyl group, propynyl group, -O-cyclopropyl group, cyclopropyl group, -SF ５ Selected from, R ａ These include ethynyl group, propynyl group, cyclopropyl group, cyclobutyl group, 4-6 member heterocycloalkyl group, pyrazolyl group, methoxy group, ethoxy group, -O-cyclopropyl group, -CD ３ The methyl group and ethyl group are selected from the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group, and the cyclopropyl group, cyclobutyl group, heterocycloalkyl group, pyrazolyl group, methoxy group, and ethoxy group are optionally F, Cl, Br, methyl group, ethyl group, and -CD. ３ ien-CH ２ D, -CHD ２ OH, -S(O) ２ -CH ３ ❖ = CH ２ , =CHF or =CF ２ The methyl group and ethyl group are further substituted with 1 to 3 groups selected from OH and CN. n1 is selected from 1 or 2. n3 is selected from 0, 1, or 2. L １ The bond is -CH ２ -O-, -CH ２ CH ２ -O-, -CH ２ -, -O-, -CH ２ CH ２ -, -N(CH ３ ) - CH ２ - Selected from ethylene, propylene, and the -CH ２ - is an optional selection of 1 to 3 R Ｌ１ Further substitution occurs with R Ｌ１ These are, independently, F, Cl, Br, =O, methyl group, ethyl group, and -CF. ３ ,-CHF ２ ien-CH ２ F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF ３ , -OCHF ２ , -OCH ２ Selected from F, cyclopropyl group, and cyclobutyl group, L ２ The bond is -CH ２ -, -CH(CH ３ )-,-N(CH ３ ) - Selected from the -CH ２ -, -CH(CH ３ ) - is an optional selection of 1 to 3 R Ｌ１ Further substitution occurs with R Ｌ１ These are, independently, F, Cl, Br, =O, methyl group, ethyl group, and -CF. ３ ,-CHF ２ ien-CH ２ F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF ３ , -OCHF ２ , -OCH ２ A compound of formula (I) according to claim 3, selected from F, a cyclopropyl group, and a cyclobutyl group, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

5. A1 is, 【Chemistry 9】 Selected from the basis, B2 is an optional selection of 1 to 4 R Ｂ Replaced with, 【Chemistry 10】 Selected from the basis, R Ａ is -NHC(O)-R ａ Selected from, R Ｂ Each of these is independently selected from F, Cl, Br, =O, CN, methyl group, ethyl group, methoxy group, and ethoxy group, and the methyl group, ethyl group, methoxy group, and ethoxy group are optionally further substituted with methyl or ethyl groups. R Ｃ Each of these is independently -CF ３ ,-CHF ２ ien-CH ２ CH ２ Selected from F and cyclopropyl groups, R ａ This includes a cyclopropyl group, a cyclobutyl group, a pyrazolyl group, and -CD. ３ Selected from the following, the cyclopropyl group, cyclobutyl group, and pyrazolyl group may optionally be F, Cl, Br, methyl group, ethyl group, or -CD. ３ ien-CH ２ D, -CHD ２ Further substituted under the basis of, n3 is selected from 1 or 2. L １ The bond is -CH ２ -O-, -CH ２ CH ２ -O-, ethylene, and propylene are selected, and the -CH ２ - is an optional selection of 1 to 3 R Ｌ１ Further substitution occurs with R Ｌ１ Each of these is independently selected from F, Cl, Br, methyl group, ethyl group, cyclopropyl group, and cyclobutyl group. L ２ is, -CH ２ - Selected from the above -CH ２ - is an optional selection of 1 to 3 R Ｌ１ Further substitution occurs with R Ｌ１ Each of these is independently selected from F, Cl, Br, a methyl group, an ethyl group, a cyclopropyl group, and a cyclobutyl group, and comprises a compound of formula (I) according to claim 3 or 4, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

6. It has the structure of formula (I-5), 【Chemistry 11】 Here, X ａ It is selected from CH or N, R Ａ These are, independently, halogen, CN, OH, COOH, and C. １－４ Alkyl alkyl group, -OC １－４ Alkyl group, -NH-S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -C(O)N(C １－４ Alkyl) ２ , -NHC(O)-C １－４ Alkyl alkyl group, -C(O)-OR ａ ,-(CH ２ ) ｐ -C(O)-(CH ２ ) ｐ -R ａ , -NHC(O)-R ａ , - NHR ａ , selected from 3- to 6-membered heterocycloalkyl groups, wherein the alkyl group and heterocycloalkyl group are optionally halogens, OH, and NH ２ ,CN,-O-HALOC １－４ Alkyl alkyl groups, deuterium, or C １－４ The heterocycloalkyl group is further substituted with 1 to 4 groups selected from alkyl groups, wherein the heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O, and S, preferably R Ａ These are, independently, halogen, CN, OH, COOH, and C. １－２ Alkyl alkyl group, -OC １－２ Alkyl group, -NH-S(O) ２ -C １－２ Alkyl alkyl group, -S(O) ２ -C １－２ Alkyl alkyl group, -C(O)N(C １－２ Alkyl) ２ , -NHC(O)-C １－２ Alkyl alkyl group, -C(O)-OR ａ ,-(CH ２ ) ｐ -C(O)-(CH ２ ) ｐ -R ａ , -NHC(O)-R ａ , - NHR ａ , selected from 3-4 member heterocycloalkyl groups, wherein the alkyl group and heterocycloalkyl group are optionally a halogen, OH, NH ２ ,CN,-O-HALOC １－２ Alkyl alkyl groups, deuterium, or C １－２ Further substitution with 1 to 4 groups selected from alkyl groups, R ａ C １－４ Alkyl alkyl groups, deuterated C １－４ alkyl group, C １－４ Alkoxy group, 3-5 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -O-C ３－６ Selected from cycloalkyl groups, the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can optionally be OH, -S(O) ２ -CH ３ , halogen, C １－４ Alkyl, Halo C １－４ Alkyl alkyl groups, deuterated C １－４ Alkyl group, -O-halo C １－４ The group is further substituted with 1 to 4 groups selected from alkyl groups, the alkyl group is further substituted with 1 to 3 groups selected from OH and CN, the heterocycloalkyl group and heteroaryl group contain 1 to 3 heteroatoms selected from N, O, and S, preferably R ａ C １－２ Alkyl alkyl groups, deuterated C １－２ alkyl group, C １－２ Alkoxy group, 3-4 membered cycloalkyl group, 3-4 membered heterocycloalkyl group, 5 membered heteroaryl group, -O-C ３－４ Selected from cycloalkyl groups, the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can optionally be OH, -S(O) ２ -CH ３ , halogen, C １－２ Alkyl, Halo C １－２ Alkyl alkyl groups, deuterated C １－２ Alkyl group, -O-halo C １－２ The alkyl group is further substituted with 1 to 4 groups selected from alkyl groups, and the alkyl group is further substituted with 1 to 3 groups selected from OH and CN. R Ｃ These are H, halogen, CN, OH, and C, respectively, independently. １－４ Alkyl, Halo C １－４ Alkyl alkyl group, -O-C ３－５ Cycloalkyl groups, C ３－５ Selected from cycloalkyl groups, preferably H or halo C １－２ It is an alkyl group, more preferably H or CF ３ And, B2 is an optional selection of 1 to 4 R Ｂ Replaced with, 【Chemistry 12】 Selected from the basis, R Ｂ These are, independently, halogen, CN, =O, and C. １－２ Alkyl, NH ２ , C １－２ Alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, Halo C １－２ Selected from alkyl groups, n3 is selected from 0, 1, or 2. p is selected from 0, 1, or 2, and is a compound of formula (I) according to claim 1, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

7. The compound is selected from one of the structures in Table 1, and is a compound according to claim 1, a stereoisomer thereof, a deuteride, a solvate, a cocrystal, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition or pharmaceutical preparation comprising a compound according to any one of claims 1 to 7, a stereoisomer thereof, a deuteride, a solvate, a cocrystal or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

9. A pharmaceutical composition or pharmaceutical preparation according to claim 8, comprising 1 to 1500 mg of a compound according to any one of claims 1 to 7, a stereoisomer thereof, a deuteride, a solvate, a cocrystal or a pharmaceutically acceptable salt thereof, and a carrier and / or excipient.

10. Uses of a compound according to any one of claims 1 to 7, its stereoisomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, or a composition according to claim 8 or 9, in the manufacture of a pharmaceutical product for treating / preventing a CYP11A1-mediated disease.

11. The use according to claim 10, wherein the CYP11A1-mediated disease is selected from the treatment of steroid hormone-dependent cancers.

12. A method for treating a disease of a mammal, comprising administering to a subject a therapeutically effective amount of a compound, stereoisomer thereof, deuteride, solvate, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably prostate cancer.

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