CYP11A1 inhibitor and application thereof

Abstract

The invention discloses a compound shown as a formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of the compound and the stereoisomer or the pharmaceutically acceptable salt, and application of the compound and the pharmaceutical composition in preparation of drugs for treating / preventing CYP11A1-mediated diseases, and all groups in the formula (I) are defined as in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with CYP11A1 selective inhibitory activity, a stereoisomer or a pharmaceutically acceptable salt thereof, and use thereof in preparing medicines for treating related diseases. Background Art

[0002] Cytochrome p450 monooxygenase 11a1 (cyp11a1), also known as cholesterol side chain cleavage enzyme, is mainly involved in drug metabolism-related catalytic reactions and the synthesis of cholesterol, steroids and other lipids. CYP11A1 protein is located in the inner membrane of mitochondria and catalyzes the conversion of cholesterol to pregnenolone, which is the first and rate-limiting step in steroidogenesis. The reaction is carried out in the mitochondria of the adrenal cortex and is catalyzed by cytochrome CYP11A1 (also called P450scc). Together with CYP11A1, Adx and AdR also work together. CYP11A1, Adx and AdR belong to the cholesterol hydroxylase / lyase system (CH / L), which catalyzes the initial step of steroid synthesis in mammals, that is, the process of generating pregnenolone from cholesterol. Pregnenolone is an important precursor of steroid hormones. The reaction process includes three consecutive monooxygenation reactions, namely the formation of 22R-hydroxycholesterol (22HC), the formation of 20R, 22R-dihydroxycholesterol, and the cleavage of the C20-C22 bond. Each monooxygenation reaction requires the participation of two electrons and one molecular oxygen. The electrons are provided by NADPH and transferred to P450scc through NADPH-AdR and Adx. Adx forms a complex with P450scc and can act as a mobile electron transporter.

[0003] CYP11A1 is mainly expressed in the placenta, responding to the synthesis of placental hormones such as progesterone and testosterone, and is also highly expressed in the adrenal glands and testes, but is hardly expressed in other tissues. By inhibiting cyp11a1, which is a key enzyme in the steroid biosynthesis upstream of cyp17a1, complete blocking of the entire steroid biosynthesis can be achieved. Therefore, cyp11a1 inhibitors may have great potential for treating steroid hormone-dependent cancers such as prostate cancer, even in the late stages of the disease, especially in those patients who show hormone refractory. It has recently been demonstrated that compounds with cyp11a1 inhibition significantly inhibit tumor growth in vivo in a mouse crpc xenograft model.

[0004] CYP11A1 inhibitors with good activity, high safety and few side effects have been discovered, which have good clinical development prospects and can be used to treat cancer or other proliferative diseases or disorders. Summary of the invention

[0005] The present invention provides a small molecule compound having CYP11A1 inhibitory activity, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (I),

[0006]

[0007] Ring A is selected from

[0008] Ring B is selected from The left side of the B ring is connected to L1;

[0009] The C ring is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclic group, 6-12 membered bicyclic heterocyclic group, 8-14 membered tricyclic heterocyclic group, wherein the phenyl, heteroaryl, bicyclic carbocyclic group, bicyclic heterocyclic group, tricyclic heterocyclic group is optionally replaced by 1-4 R C In some embodiments, the C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocyclyl and phenyl, 5-6-membered carbocyclyl and phenyl, 5-6-membered heterocyclyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C In some embodiments, the C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocycloalkyl phenyl, 5-6-membered carbocyclyl phenyl, 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C In some embodiments, the C ring is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl, wherein the phenyl, heteroaryl, bicyclic carbocyclyl, bicyclic heterocycloalkyl, tricyclic heterocycloalkyl is optionally replaced by 1-4 R C In some embodiments, the C ring is selected from phenyl, 5-6 membered heteroaryl, 6-10 membered partially unsaturated bicyclic cycloalkyl, 6-12 membered partially unsaturated bicyclic heterocycloalkyl, 6-12 membered saturated bicyclic heterocycloalkyl, 8-12 membered tricyclic heterocycloalkyl, wherein the phenyl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally replaced by 1-4 R CIn some embodiments, the C ring is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered partially unsaturated bicyclic cycloalkyl, 8-12 membered partially unsaturated bicyclic heterocycloalkyl, 6-10 membered saturated bicyclic heterocycloalkyl, 8-12 membered tricyclic heterocycloalkyl, wherein the phenyl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally replaced by 1-4 R C In some embodiments, the C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocycloalkyl phenyl, 5-6-membered carbocyclyl phenyl, 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C In some embodiments, ring C is selected from optionally 1-4 R C One of the groups formed by the following structures:

[0010]

[0011] In some embodiments, Ring C is selected from C One of the groups formed by the following structures: In some embodiments, Ring C is selected from one of the following structures: In some embodiments, Ring C is selected from one of the following structures:

[0012] R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-4Alkyl, halogenated C 1-4 alkyl, CN, OH and NH2; in some embodiments, R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group; in some embodiments, R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C Each independently selected from F, Cl, Br, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group; in some embodiments, R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1- Alkyl, halogenated C 1-4 alkyl, CN, OH and NH2; in some embodiments, R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C Each independently selected from F, Cl, Br, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C each independently selected from F, Cl, Br, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CHFCH3, -CF2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHClCH3, -CCl2CH3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCHFCH3, -OCF2CH3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHClCH3, -OCCl2CH3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, ethynyl, =O, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -SCF3, -SF5, -P(O)(CH3)2, -P(O)(CH2CH3)2, -NH-P(O)(CH3)2, -NH-P(O)(CH2CH3)2, -OCH3, -OCH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3,

[0013] Or any two R C and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0014] L1 is selected from -CH2O-, and the left side of L1 is connected to A;

[0015] L2 is selected from W1-R L -W2, the left side of L2 is connected to B;

[0016] R L Select from key, C 1-4 Alkylene, C 2-4 alkenylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the alkylene, alkenylene, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 R L1 Substitution; in some embodiments, R L Select from key, C 1-2 Alkylene, 4-6 membered heterocycloalkyl or C 2-4 Alkenylene, wherein the alkylene, heterocycloalkylene, and alkenylene are optionally further substituted with 1 to 3 R L1 Substitution; in some embodiments, R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, 3-6 membered cycloalkyl, the alkylene, alkenylene, cycloalkyl optionally further substituted by 1-4 R L1 Substitution; in some embodiments, R L Select from key, C 1-2 Alkylene or C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-3 R L1 Substitution; in some embodiments, R L is selected from a bond, -CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, wherein the CH3, CH2, CH are optionally further substituted by 1-4 R L1 Replacement; R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or any two R L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2; in some embodiments, R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 alkenyl or 3-6 membered cycloalkyl, or any two R L1and its connecting atoms together form a 3-6 membered cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl is optionally further substituted by 1-3 substituents selected from halogen, CN, OH and NH2; in some embodiments, R L1 Each independently selected from F, Cl, Br, =O, C 1-2 Alkyl, vinyl, propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or any two R L1 and its connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the alkyl, vinyl, propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further substituted with 1-3 substituents selected from F, Cl, Br, CN, OH and NH2; in some embodiments, R L1 Each is independently selected from F, Cl, Br, =O, methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or any two R L1 and its connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally further substituted with 1, 2, or 3 substituents selected from F, Cl, Br, CN, OH, and NH2;

[0017] W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, wherein one or more -CH2- in the alkylene group is optionally replaced by 1 to 4 groups selected from -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, the alkylene group is optionally further substituted by 1 to 4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl, CN, OH and NH2; in some embodiments, W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -or-NR W1 CO-, one or more -CH2- in the alkylene group are optionally replaced by 1-4 selected from -NR W1 -、-CONR W1 -or-NR W1 CO-, the alkylene group is optionally further substituted by 1-4 groups selected from halogen, C 1-2 Alkyl or halogenated C1-2 In some embodiments, W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-; in some embodiments, W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-; In some embodiments, W1, W2 are each independently selected from a bond, -O-, -NH-, -N(CH3)-, -CON(CH3)-, -N(CH3)CO-, -C(=O)O- or -OC(=O)-;

[0018] R W1 Selected from H, C 1-4 alkyl, halogen; in some embodiments, R W1 Selected from H, C 1-2 alkyl, halogen; in some embodiments, R W1 is selected from H, -CH3, -CH2CH3, F, Cl, Br;

[0019] q is selected from 0 or 1; in some embodiments, q is selected from 0; in some embodiments, q is selected from 1;

[0020] p is each independently selected from 0, 1, 2, 3, or 4; in some embodiments, p is each independently selected from 0, 1, 2, or 3; in some embodiments, p is each independently selected from 0, 1, or 2; in some embodiments, p is each independently selected from 0 or 1; in some embodiments, p is each independently selected from 0;

[0021] L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, 3-6 membered cycloalkyl, -NH-, -O-, -(C 1-2 Alkylene)-NR W1 -、-(C 1-2 Alkylene)-NR W1 -(C 1-2 Alkylene)-, -(C 1-2 Alkylene)-NR W1 CH(CF3)-、-(C 1-2 Alkylene)-NR W1 CH(CH3)-、-(C 1-2 alkylene)-(4-membered heterocycloalkyl) or -(C 1-2 Alkylene)NR W1CO-, the alkylene, alkenylene, cycloalkyl group may be further substituted by 1-3 R L1 Replacement; R L1 are independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, 3-6 membered cycloalkyl; in some embodiments, L2 is selected from a bond, cyclopropyl, -CF2-, -CH2-NH-CH(CH3)-, -C(=O)-, -CH2-CH2-, -CH2-, -CH(3-6 membered cycloalkyl)-, -O-, -CH2-N(CH3)-CH2-, -CH2-NH-C(=O)-, -CH2-NH-, -CH2-(4 membered heterocycloalkyl)-, -CH2- NH-CH(CF3)-; in some embodiments, L2 is selected from cyclopropyl, -CF2-, -CH2-NH-CH(CH3)-, -C(=O)-, -CH2-, -CH(cyclopropyl)-, -O-, -CH2-N(CH3)-CH2-, -CH2-NH-C(=O)-, -CH2-NH-, -CH2-(4-membered heterocycloalkyl)-, -CH2-NH-CH(CF3)-; with the condition that,

[0022] 1) When ring C is selected from unsubstituted When L2 is

[0023] 2) When ring C is selected from substituted When R C Not -CH3, -CF3, -OCF3 and halogen;

[0024] 3) Ring C is not optionally substituted

[0025] As a more specific first technical solution of the present invention, a compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts, wherein:

[0026]

[0027] Ring A is selected from

[0028] Ring B is selected from The left side of the B ring is connected to L1;

[0029] The C ring is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclic group, 6-12 membered bicyclic heterocyclic group, 8-14 membered tricyclic heterocyclic group, wherein the phenyl, heteroaryl, bicyclic carbocyclic group, bicyclic heterocyclic group, tricyclic heterocyclic group is optionally replaced by 1-4 RC replace;

[0030] L1 is selected from -CH2O-, and the left side of L1 is connected to A;

[0031] L2 is selected from W1-R L -W2, the left side of L2 is connected to B;

[0032] R L Select from key, C 1-4 Alkylene, C 2-4 alkenylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the alkylene, alkenylene, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 R L1 replace;

[0033] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or two adjacent R L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the alkyl, alkoxy or cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0034] W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, wherein one or more -CH2- in the alkylene group is optionally replaced by 1 to 4 groups selected from -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, the alkylene group is optionally further substituted by 1 to 4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl, CN, OH and NH2;

[0035] R W1 Selected from H, C 1-4 Alkyl, halogen;

[0036] R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN, OH and NH2 substituents; in some embodiments,

[0037] R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group;

[0038] q is selected from 0 or 1;

[0039] p is each independently selected from 0, 1, 2, 3 or 4;

[0040] The condition is,

[0041] 1) When ring C is selected from unsubstituted When L2 is

[0042] 2) When ring C is selected from substituted When R C Not -CH3, -CF3, -OCF3 and halogen;

[0043] 3) Ring C is not optionally substituted

[0044] Further, a compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts, wherein:

[0045]

[0046] Ring A is selected from

[0047] Ring B is selected from

[0048] The C ring is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclic group, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl, wherein the phenyl, heteroaryl, bicyclic carbocyclic group, bicyclic heterocycloalkyl, tricyclic heterocycloalkyl is optionally replaced by 1-4 R C replace;

[0049] L1 is selected from -CH2O-, and the left side of L1 is connected to A;

[0050] L2 is selected from W1-R L -W2, the left side of L2 is connected to B;

[0051] R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, 3-6 membered cycloalkyl, the alkylene, alkenylene, cycloalkyl optionally further substituted by 1-4 R L1 replace;

[0052] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or two adjacent R L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the alkyl, alkoxy or cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0053] W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-;

[0054] R W1 Selected from H, C 1-4 Alkyl, halogen;

[0055] R C Each independently selected from halogen, OH, C1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group;

[0056] q is selected from 0 or 1;

[0057] p is each independently selected from 0, 1, 2, 3 or 4;

[0058] The condition is,

[0059] 1) When ring C is selected from unsubstituted When L2 is

[0060] 2) When ring C is selected from substituted When R C Not -CH3, -CF3, -OCF3 and halogen;

[0061] 3) Ring C is not optionally substituted

[0062] As a more specific second technical solution of the present invention, a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0063] The C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocyclyl and phenyl, 5-6-membered carbocyclyl and phenyl, 5-6-membered heterocyclyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C replace;

[0064] R L Select from key, C 1-2 Alkylene, 4-6 membered heterocycloalkyl or C 2-4 Alkenylene, wherein the alkylene, heterocycloalkylene, and alkenylene are optionally further substituted by 1 to 3 R L1 replace;

[0065] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 alkenyl or 3-6 membered cycloalkyl, or any two R L1 and its connecting atoms together form a 3-6 membered cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl is optionally further substituted by 1-3 substituents selected from halogen, CN, OH and NH2;

[0066] W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -or-NR W1 CO-, one or more -CH2- in the alkylene group are optionally replaced by 1-4 selected from -NR W1 -、-CONR W1 -or-NR W1 CO-, the alkylene group is optionally further substituted by 1-4 groups selected from halogen, C 1-2 Alkyl or halogenated C 1-2 Substitution of alkyl groups;

[0067] R W1 Selected from H, C 1-2 Alkyl, halogen;

[0068] R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, CN, OH and NH2 substituents; in some embodiments,

[0069] R C Each independently selected from halogen, OH, C1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group;

[0070] q is selected from 0 or 1;

[0071] p is each independently selected from 0, 1, 2 or 3;

[0072] The remaining groups are as described in the first technical solution above.

[0073] Further, a compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts, wherein:

[0074] The C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocycloalkyl phenyl, 5-6-membered carbocyclyl phenyl, 5-6-membered heterocycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C replace;

[0075] R L Select from key, C 1-2 Alkylene or C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-3 R L1 replace;

[0076] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 alkenyl or 3-6 membered cycloalkyl, or any two R L1 and its connecting atoms together form a 3-6 membered cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl is optionally further substituted by 1-3 substituents selected from halogen, CN, OH and NH2;

[0077] W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -、-CONR W1 -or-NR W1 CO-;

[0078] R W1 Selected from H, C 1-2 Alkyl, halogen;

[0079] R C Each independently selected from halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group;

[0080] q is selected from 0 or 1;

[0081] p is each independently selected from 0, 1, 2 or 3;

[0082] The remaining groups are as described in the first technical solution above.

[0083] As a more specific third technical solution of the present invention, a compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts, wherein,

[0084] Ring C is selected from optionally 1-4 R C One of the groups formed by the following structures:

[0085] L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, 3-6 membered cycloalkyl, -NH-, -O-, -(C 1-2 Alkylene)-NR W1 -、-(C 1-2 Alkylene)-NR W1 -(C 1-2 Alkylene)-, -(C 1-2 Alkylene)-NR W1CH(CF3)-、-(C 1-2 Alkylene)-NR W1 CH(CH3)-、-(C 1-2 alkylene)-(4-membered heterocycloalkyl) or -(C 1-2 Alkylene)NR W1 CO-, the alkylene, alkenylene, cycloalkyl group may be further substituted by 1-3 R L1 Replacement; R L1 are independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, 3-6 membered cycloalkyl;

[0086] R C Each independently selected from F, Cl, Br, OH, N3, C 1-2 Alkyl, halogenated C 1-2 Alkyl, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-2 Alkyl, halogenated C 1-2 alkyl, CN, OH and NH2; in some embodiments, R C Each independently selected from F, Cl, Br, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group;

[0087] q is selected from 0 or 1;

[0088] p is each independently selected from 0, 1 or 2;

[0089] The remaining groups are as described in the second technical solution above.

[0090] Further, a compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts, wherein:

[0091] Ring C is selected from optionally 1-4 R C One of the groups formed by the following structures:

[0092] L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, 3-6 membered cycloalkyl, -NH-, -O-, -(C 1-2 Alkylene)-NR W1 -(C 1-2 Alkylene)-or-(C 1-2 Alkylene)NR W1 CO-, the alkylene, alkenylene, cycloalkyl group may be further substituted by 1-3 R L1 Replacement; R L1 are independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, 3-6 membered cycloalkyl;

[0093] R C Each independently selected from F, Cl, Br, OH, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 Alkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group;

[0094] q is selected from 0 or 1;

[0095] p is each independently selected from 0, 1 or 2;

[0096] The remaining groups are as described in the second technical solution above.

[0097] As a more specific fourth technical solution of the present invention, a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0098] Ring C is selected from one of the following structures:

[0099] Or ring C is selected from one of the following structures: Or ring C is selected from one of the following structures:

[0101] The remaining groups are as described in the third technical solution above.

[0102] As a specific technical solution of the present invention, the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt, the compound is selected from one of the structures in the following Table A. The present invention also provides a pharmaceutical composition or pharmaceutical preparation, which contains the compound of any one of the above schemes, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0103] Furthermore, the composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the aforementioned schemes, its stereoisomer or pharmaceutically acceptable salt and a carrier and / or excipient.

[0104] The present invention also provides the use of the compound described in any of the aforementioned schemes, its stereoisomers or pharmaceutically acceptable salts, or the composition described in any of the aforementioned schemes in the preparation of a medicament for treating / preventing a disease mediated by CYP11A1. Furthermore, the disease mediated by CYP11A1 is a steroid hormone-dependent cancer, and the more preferred cancer is prostate cancer.

[0105] The present invention also provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound or a stereoisomer or a pharmaceutically acceptable salt thereof as described in any of the foregoing schemes, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably prostate cancer. In some embodiments, the mammal in the present invention does not include a human.

[0106] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-

[0107] 40mg, 1-25mg, 1-20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5 -400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-

[0108] 60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800m g, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10- 150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-3 0mg, 10-20mg; 20-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg,

[0109] 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg , 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg; 50-1500mg, 50-1000mg, 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,

[0110] 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg.

[0111] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof is the same as that in the above-mentioned pharmaceutical composition.

[0112] The amount of the compound according to the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0113] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0114] Synthetic route

[0115] Patent documents such as WO2018115591A1 introduce the preparation method of CYP11A1 inhibitors. Those skilled in the art can combine the document and known organic synthesis techniques to prepare the compounds of the present invention, and the starting materials are commercially available chemicals and (or) compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0116] Specific and similar reactants can be selectively identified through indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services.

[0117] the term

[0118] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0119] "Halogen" herein refers to F, Cl, Br, I or isotopes thereof.

[0120] "Halo" or "halogen substituted" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I or isotopes thereof, and the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be substituted by the same or different halogens.

[0121] "Deuterated" or "deuterated substance" refers to the situation where hydrogen atoms on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. are replaced by at least one isotope deuterium, and the upper limit of the number of deuterations is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms are replaced, more preferably 1-10 deuterium atoms are replaced, more preferably 1-6 deuterium atoms are replaced, and further preferably 1-3 deuterium atoms are replaced.

[0122] "Alkyl" refers to a monovalent straight or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms, and further preferably an alkyl group of 1-2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof.

[0123] "Alkylene" refers to a divalent straight chain or branched chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

[0124] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, usually has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and further preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Or cycloheptyl, etc.

[0125] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", and non-limiting examples include cyclopropylene, cyclobutylene, and the like.

[0126] "Heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which contains 1 to 3 heteroatoms selected from N, O or S when not specifically defined, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles, etc., and is 3 to 12-membered heterocycles, more preferably 4-12-membered heterocycles, more preferably 4-10-membered heterocycles, and further preferably 4-7-membered heterocycles when not specifically defined. Its definition includes heterocycloalkyl and heteroaryl. N and S in the heterocyclic ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... ]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, wait.

[0127] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0128] "Carbocycle" or "carbocyclic group" refers to substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic groups, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., and unless otherwise specified, has 3 to 12 carbon atoms, preferably 3-10 carbon atoms, and more preferably 3-6 carbon atoms. Its definition includes cycloalkyl and aryl. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., the bicyclic bridge ring includes etc., double ring and ring include etc., bicyclic spiro ring includes wait.

[0129] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0130] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0131] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples are ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0132] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, -OC 1-8 Alkyl, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl, more preferably -OC 1-2 Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0133] "Haloalkoxy" refers to -O-haloalkyl, and unless otherwise specified, is -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4 Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0134] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0135] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, propanesulfonyl.

[0136] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furanyl, pyrone, pyridone, and the like.

[0137] "Heterocycloalkyl" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and further preferably 5 or 6 ring members. In addition to carbon atoms, heterocycloalkyl also contains 1-3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, etc.

[0138] "Alkyl NH2" or "alkane NH2" refers to NH2 substituted with a single or double alkyl group, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkyl NH2. Non-limiting examples include dimethyl NH2, monomethyl NH2, diethyl NH2, monoethyl NH2, etc.

[0139] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0140] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0141] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0142] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0143] "Excipient" refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0144] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0145] "Solvate" refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0146] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates. DETAILED DESCRIPTION

[0147] The content of the present invention will be described in detail below through examples. If no specific conditions are specified in the examples, the experimental method according to conventional conditions is carried out. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Those skilled in the art can make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still belongs to the protection scope of the present invention.

[0148] Dess-Martin reagent; 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3-(1H)-one

[0149] DIPEA: N,N-diisopropylethylamine

[0150] NMP: N-methylpyrrolidone

[0151] TBDMSCl: tert-butyldimethylsilyl chloride

[0152] DMAP: 4-dimethyl NH2pyridine

[0153] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0154] T3P: Propylphosphonic acid tricyclic anhydride

[0155] DAST: Diethylaminosulfur trifluoride

[0156] MTBE: Methyl tert-butyl ether

[0157] Intermediate 1: 2-(Chloromethyl)-5-hydroxy-(4H)-pyran-4-one (Intermediate 1)

[0158] 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one(intermediate 1)

[0159]

[0160] Kojic acid (20.0 g, 140.7 mmol) was dissolved in 40 ml of thionyl chloride and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, the filter cake was slurried with 100 mL of petroleum ether, filtered, and the filter cake was dried to obtain intermediate 1 (29.8 g, 90%).

[0161] LCMS (ESI): m / z = 161.2 [M+H]

[0162] 1 H NMR (400MHz, DMSO) δ8.12(s,1H),6.57(s,1H),4.66(s,2H).

[0163] Intermediate 2: Methyl 1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (Intermediate 2)

[0164] (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate(intermediate 2)

[0165]

[0166] 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 h. After the reaction, the reaction solution was filtered, the filtrate was concentrated, and then slurried with 100 mL of a mixed solvent of ethyl acetate: petroleum ether = 1:1, filtered, and the filter cake was washed with water and dried to obtain intermediate 2 (47 g, 40%).

[0167] LCMS (ESI): m / z = 272.3 [M+H]

[0168] 1 H NMR (400MHz, CDCl3) δ4.10(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).

[0169] Intermediate 3: 5-Hydroxy-2-(isoindol-2-ylmethyl)-4H-pyran-4-one (Intermediate 3)

[0170] 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(intermediate 3)

[0171]

[0172] 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 and reacted at room temperature with mechanical stirring for 16 h. After the reaction was completed, the reaction solution was filtered, and the filter cake was slurried with 100 mL of water and 50 mL of ethyl acetate in turn, filtered, and the filter cake was dried to obtain Intermediate 3 (47 g, 40%).

[0173] LCMS (ESI): m / z = 244.1 [M+H]

[0174] 1 H NMR (400MHz, DMSO) δ9.06(s,1H),8.06(s,1H),7.39–7.04(m,4H),6.41(s,1H),3.95(s,4H),3.78(s,2H).

[0175] Intermediate 4: 6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate

[0176] 6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yltrifluoromethanesulfonate

[0177]

[0178] Step 1: Dissolve the raw substrate intermediate 3 (1.0 g, 4.12 mmol) and triethylamine (1.26 g, 12.36 mmol) in ultra-dry DCM (10 mL) at room temperature, cool to 0°C under nitrogen protection, then dropwise add a solution of trifluoromethanesulfonic anhydride (1.75 g, 6.18 mmol) in ultra-dry DCM (10 mL), and naturally warm to room temperature to react for 1 h after the dropwise addition. Add 30 mL of saturated sodium bicarbonate to quench the reaction, extract with DCM (50 mL × 3), combine the organic phases, wash with water (50 mL × 3), wash with saturated sodium chloride (50 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain intermediate 4 (1.0 g, 65%).

[0179] LC-MS (ESI): m / z = 376.1 [M+H] + .

[0180] Embodiment 1:

[0181]

[0182] Step 1: Weigh compound intermediate 1 (0.60 g, 3.76 mmol) and compound 1A (0.45 g, 3.76 mmol) in a 100 mL single-necked bottle, dissolve in dichloromethane (10 mL), add N,N-diisopropylethylamine (1.46 g, 11.28 mmol, stir at 20 degrees for 16 h after the addition is complete, monitor the reaction completion with TLC plate (petroleum ether: ethyl acetate = 1:1), add water (20 mL), stir for 5 min, extract with dichloromethane (10 mL), separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the target compound 1B (0.3 g, yield: 32.6%).

[0183] LCMS m / z=245.2[M+1] +

[0184] Step 2: Add compound 1B (300 mg, 1.23 mmol) to a 100 mL single-mouth bottle, dissolve in DMF (10 mL), and then add intermediate 2 (333 mg, 1.23 mmol) and potassium carbonate (0.51 g, 3.68 mmol). After the addition is completed, the system is protected by nitrogen and stirred at 20°C for 16 hours. The reaction solution is concentrated under reduced pressure to obtain the crude target compound, and the title compound 1 (20 mg, 4%) is separated by preparative HPLC.

[0185] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm; The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonia water); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate 15mL / min. d. Elution time 20min; Retention time: 12.60min.

[0186] LCMS m / z=420.2[M+1] +

[0187] 1 H NMR(400MHZ,DMSO)δ8.47(s,1H),8.41(d,1H),8.15(s,1H),7.31(d,1H),6.40(s,1H),3.99(d,4H) ,3.81(s,2H),3.72(d,2H),3.58(d,2H),2.86(s,3H),2.73(t,2H),1.84(d,3H),1.24-1.33(m,2H).

[0188] Embodiment 2:

[0189]

[0190] Step 1: Weigh compound intermediate 1 (0.50 g, 3.11 mmol) and compound 2A (0.38 g, 3.11 mmol) in a 100 mL single-mouth bottle, dissolve in dichloromethane (10 mL), add N,N-diisopropylethylamine (1.21 g, 9.34 mmol), stir at 20 degrees for 16 h after the addition is complete, monitor the reaction completion by TLC spot plate (petroleum ether: ethyl acetate = 1:1), add water (20 mL), stir for 5 min, extract with dichloromethane (10 mL), separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the target compound 2B (0.28 g, yield: 36.7%).

[0191] LCMS m / z=246.2[M+1] +

[0192] Step 2: Add compound 2B (280 mg, 1.14 mmol) to a 100 mL single-mouth bottle, dissolve in DMF (10 mL), and then add intermediate 2 (340 mg, 1.25 mmol) and potassium carbonate (0.47 g, 3.42 mmol). After the addition is completed, the system is protected by nitrogen and stirred at 20°C for 16 hours. The reaction solution is concentrated under reduced pressure to obtain the crude target compound, and the title compound 2 (20 mg, 4.2%) is separated by preparative HPLC.

[0193] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm; The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonia water); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate 15mL / min. d. Elution time 20min; Retention time: 10.40min.

[0194] LCMS m / z=421.1[M+1] +

[0195] 1 H NMR(400MHZ,DMSO)δ9.00(s,1H),8.67(s,1H),8.15(s,1H),6.41(s,1H),4.07(s,2H),4.02(s,2H) ,3.84(s,2H),3.72(d,2H),3.58(d,2H),2.85(s,3H),2.72(t,2H),1.84(d,3H),1.24-1.34(m,2H).

[0196] Embodiment 3:

[0197]

[0198] Step 1: Dissolve 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.15 g, 6 mmol) and intermediate 1 (1.05 g, 6.6 mmol) in acetonitrile (20 mL), add DIPEA (2 mL), and react at room temperature for 3 h. LCMS detected that the reaction of the raw materials was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain the target compound 3A (758 mg, 63.3%).

[0199] LC-MS (ESI): m / z = 245.5 [M+H] + .

[0200] Step 2: 3A (244 mg, 1 mmol) and intermediate 2 (325 mg, 1.2 mmol) were dissolved in DMF (10 mL), K2CO3 (276 mg, 2 mmol) was added, and the reaction was carried out at 80°C overnight. LCMS detected that the reaction of the raw materials was complete, ethyl acetate (40 mL) was added, and the mixture was washed with saturated brine (40 mL×3). The organic phase was dried, concentrated, and separated by column chromatography (DCM:MeOH=1:0~0:1) to obtain compound 3 (110 mg, 26.1%).

[0201] 1 H NMR (400MHz, DMSO-d6) δ8.37–8.33(m,1H),8.16(s,1H),7.68–7.63(m,1H),7.25–7.18(m,1H),6.41(s,1H),4.03–3.96(m,4H ),3.82(s,2H),3.75–3.70(m,2H),3.61–3.54(m,2H),2.86(s,3H),2.77–2.68(m,2H),1.87–1.80(m,3H),1.36–1.22(m,2H).

[0202] LC-MS (ESI): m / z = 420.2 [M+H] + .

[0203] Embodiment 4:

[0204]

[0205] Step 1: 3,6-dichloro-4,5-dimethylpyridazine (17.7 g, 100 mmol) was dissolved in acetonitrile (500 mL), and NBS (71.2 g, 400 mmol) and AIBN (0.82 g, 5 mmol) were added under stirring. The reaction mixture was refluxed for 2 d. LCMS detected that the raw material had been completely converted. The system was concentrated, ethyl acetate (500 mL) was added, and the mixture was filtered after sufficient shaking. The filter cake was washed with ethyl acetate (100 mL×5). The organic phase was concentrated and separated by column chromatography (PE:EA=0:1-1:3) to obtain compound 4A (10.2 g, 30.5%).

[0206] LC-MS (ESI): m / z = 332.2 [M+H] + .

[0207] Step 2: 4A (10.2 g, 30.5 mmol) was dissolved in DMF (25 mL), and 75 mL of a mixed solution of dissolved triphenylmethylamine (9.49 g, 36.6 mmol) and DIEPA (15.2 mL) was slowly added dropwise at 60°C. After the addition was complete, the reaction was continued at this temperature for 2 h. After the reaction was completed, 400 mL of ethyl acetate was added, and the mixture was washed with saturated brine (200 mL×4). The organic phase was dried and concentrated to obtain a crude product. 50 mL of ethyl acetate was added, and the mixture was filtered after sufficient shaking. The filter cake was dried to obtain compound 4B (3.3 g, 25.0%).

[0208] LC-MS (ESI): m / z = 243.2

[0209] Step 3: Weigh 4B (3.3 g, 7.63 mmol) in a sealed tube, add acetic acid hydrogen bromide solution (4.36 mL), react at 60°C for 2 h, cool to room temperature, and concentrate to obtain compound 4C (3.6 g, 90.5%), which can be used in the next step without further purification.

[0210] LC-MS (ESI): m / z = 243.2

[0211] Step 4: Disperse 4C (3.6 g, 6.91 mmol) in 40 mL of DCM, add trifluoroacetic acid (2.57 mL), react at room temperature overnight, and after the reaction is completed, concentrate to remove the solvent, add 40 mL of ethyl acetate to slurry, filter, and dry the filter cake to obtain compound 4D (1.6 g, 83.1%).

[0212] LC-MS (ESI): m / z = 280.1 [M+H] + .

[0213] Step 5: Disperse 4D (0.5 g, 1.79 mmol) in 100 mL of acetic acid, add Pd / C (0.38 g), and react at 70°C for 2 d. After the reaction is completed, filter and wash the filter cake with water (20 ml×3). Concentrate the filtrate to obtain compound 4E (0.16 g, 73.1%).

[0214] LC-MS (ESI): m / z = 122.2 [M + H] + .

[0215] Step 6: 4E (160 mg, 1.31 mmol) and intermediate 1 (230 mg, 1.44 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (1 mL) was added. The mixture was reacted at room temperature for 3 h. LCMS detected that the reaction of the raw material was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether).

[0216] =0:1~1:1) to give the target compound 4F (130 mg, 63.8%).

[0217] LC-MS (ESI): m / z = 246.5 [M+H] + .

[0218] Step 7: 4F (130 mg, 0.53 mmol) and intermediate 2 (172 mg, 0.64 mmol) were dissolved in DMF (5 mL), K2CO3 (176 mg, 1.28 mmol) was added, and the reaction was carried out at 80°C overnight. LCMS detected that the reaction of the raw materials was complete, ethyl acetate (20 mL) was added, and the mixture was washed with saturated brine (20 mL×3). The organic phase was dried, concentrated, and separated by column chromatography (DCM:MeOH=1:0~0:1) to obtain compound 4 (26 mg, 11.7%).

[0219] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,2H),8.13(s,1H),6.34(s,1H),4.01(s,2H),3.98(s,2H),3.78(s,2H),3. 72–3.68(m,2H),3.58–3.50(m,2H),2.84(s,3H),2.78–2.70(m,2H),1.86–1.82(m,3H),1.37–1.24(m,2H).

[0220] LC-MS (ESI): m / z = 421.2 [M+H] +

[0221] Embodiment 5:

[0222]

[0223] Step 1: Dissolve compound 5A (4.0 g, 13.4 mmol) and trimethylsilyl acetylene (13.2 g, 134 mmol) in 50 mL of tetrahydrofuran, add bis(triphenylphosphine)palladium dichloride (941 mg, 1.34 mmol) and triethylamine (5.5 g, 53.6 mmol) and react at 50°C in a sealed tube for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was dropped into 100 mL of ice water, extracted with dichloromethane (200 mL x 3), the organic phases were combined and concentrated, and purified by silica gel column chromatography (PE:EA=15:1) to obtain the target compound 5B (3.6 g, 85%).

[0224] LCMS (ESI): m / z=260.1[M+H-tBu]

[0225] Step 2: Compound 5B (3.60 g, 11.4 mmol) was dissolved in 10 mL of anhydrous dioxane solution, and 10 mL of 4 M hydrochloric acid dioxane was added, and the mixture was reacted at room temperature for 8 h. LCMS monitoring indicated that the reaction was complete and no hydrochloric acid addition product appeared. The excess solvent was removed by vortexing, and the residue 5C (partial TMS protection group had been removed in this step) was directly used in the next step (2.38 g).

[0226] LCMS (ESI): m / z = 216.2 [M+H]

[0227] Step 3: The crude product 5C (2.38 g) and potassium carbonate (2.38 g, 17.2 mmol) were suspended in 20 mL of methanol and reacted at room temperature for 2 h. After the reaction was completed, the product was filtered, the filtrate was concentrated, and the target compound 5D (1.39 g, total yield of two steps 83%) was obtained by silica gel column chromatography (PE:EA=1:1).

[0228] LCMS (ESI): m / z = 144.2 [M+H]

[0229] Step 4: Compound 5D (1.39 g, 9.71 mmol) and intermediate 1 (1.56 g, 9.71 mmol) were dissolved in 15 mL of acetonitrile, and DIPEA (3.76 g, 29.1 mmol) was added to react at room temperature for 16 h. After the reaction was completed, the reaction solution was dropped into 20 mL of ice water and extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated, and the target compound 5E (DCM: MeOH = 15: 1) (620 mg, 24%) was obtained by silica gel column chromatography.

[0230] LCMS (ESI): m / z = 268.3 [M+H]

[0231] Step 5: Compound 5E (280 mg, 1.05 mmol) and intermediate 2 (312 mg, 1.15 mmol) were dissolved in 2 mL of DMF, and cesium carbonate (681 mg, 2.10 mmol) was added to react at 70°C for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was dropped into ice water, filtered, and the filter cake was purified by HPLC to obtain the target compound 5 (107 mg, 23%).

[0232] LCMS (ESI): m / z = 443.2 [M+H]

[0233] 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.36(s,1H),7.33-7.31(m,1H),7.28-7.22(m,1H),6.38(s,1H),4.10(s,1H),3.95(d, 4H),3.78(s,2H),3.72(d,2H),3.64–3.53(m,2H),2.85(s,3H),2.75-2.70(m,2H),1.91–1.77(m,3H),1.36–1.20(m,2H).

[0234] Embodiment 6:

[0235]

[0236] Step 1: Add raw material 6A (5.8 g, 25.93 mmol), tetrahydropyrrole (2.59 g, 36.33 mmol), p-toluenesulfonic acid monohydrate (150 mg, 0.87 mmol) into 45 ml of anhydrous toluene, heat to reflux, remove the water generated by the reaction through a water separator. After 4 hours of reaction, the system is cooled to room temperature, and the reaction solution is directly used for the next step.

[0237] Step 2: To the reaction solution obtained in the previous step, p-toluenesulfonic acid monohydrate (150 mg, 0.87 mmol) and 6 mL of ethyl glyoxylate (50% toluene solution) were added, and the mixture was heated to reflux. The reaction was stopped after 2 hours, and the mixture was cooled to room temperature and concentrated. The target compound 6C (2.4 g, yield 29%) was purified and separated by silica gel column chromatography (PE:EA (v / v) = 1:0 to 5:1).

[0238] Step 3: Dissolve the raw material 6C (2.4 g, 7.44 mmol) in 9 ml of anhydrous ethanol, then add 80% hydrazine hydrate (0.7 g) and acetic acid (0.5 ml) to the system, and heat under reflux for 3.5 hours. Subsequently, the reaction mixture was concentrated and cooled at 0°C, and a solid precipitated, which was filtered to obtain the target compound 6D (0.75 g, yield 42%).

[0239] LCMS m / z=238.1[M+1]

[0240] Step 4: Add raw material 6D (1.1 g, 4.64 mmol), triethylamine (0.94 g, 9.28 mmol) and DMAP (57 mg, 0.46 mmol) successively into 50 ml THF solution, slowly add N-phenylbis(trifluoromethanesulfonyl)imide (3.32 g, 9.26 mmol) under ice bath, stir at room temperature for 10 hours after addition, add saturated citric acid solution for washing, extract with EA, dry with anhydrous sodium sulfate and filter, concentrate the filtrate and separate by silica gel column chromatography (PE:EA (v / v) = 1:0-5:1) to obtain the target compound 6E (1.1 g, yield 64%).

[0241] LCMS m / z=370.1[M+1]

[0242] Step 5: The raw material 6E (1.1 g, 2.98 mmol), triethylamine (7.54 g, 74.5 mmol), palladium acetate (0.27 g, 1.19 mmol) and DPPF (1.65 g, 2.95 mmol) were added to 60 mL of DMF solvent, and then formic acid (2.74 g, 59.6 mmol) reagent was added under ice bath, nitrogen protection, heated to 65 ° C and stirred for 1.5 hours, cooled, diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE: EA (v / v) = 1:0 to 1:5) to obtain the target compound 6F (0.3 g, yield 45%).

[0243] LCMS m / z=222.1[M+1]

[0244] Step 6: Add the raw material 6F (0.3 g, 1.36 mmol) to 0.5 mL of anhydrous methanol solution, then add 1 mL (4 M) of dioxane hydrochloride solution, stir at room temperature for 1 hour, concentrate the reaction solution to dryness, slurry with a small amount of ethyl acetate and filter, and dry the solid to obtain the target compound 6G (0.15 g, yield 91%).

[0245] LCMS m / z=122.1[M+1]

[0246] Step 7: Add raw material 6G (0.15 g, 1.24 mmol), 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.20 g, 1.24 mmol) and DIPEA (0.48 g, 3.72 mmol) successively into acetonitrile (10 mL) solvent, heat to 65 ° C for 16 hours, cool, concentrate the reaction solution, and purify by silica gel column chromatography (DCM: MeOH (v / v) = 1: 0 ~ 10: 1) to separate and obtain the target compound 6H (0.15 g, yield 49%).

[0247] LCMS m / z=246.1[M+1]

[0248] Step 8: Add raw material 6H (180 mg, 0.73 mmol), intermediate 2 (240 mg, 0.88 mmol), and cesium carbonate (480 mg, 1.46 mmol) into DMF (5 ml) successively, heat to 100 °C for 3 hours, filter, concentrate the filtrate and purify and separate the target compound 6 by TLC (DCM: MeOH = 10:1).

[0249] LCMS m / z=421.1[M+1]

[0250] 1 H NMR(400MHz,CD3OD)δ9.02(d,1H),8.09(s,1H),7.63-7.66(m,1H),6.59(s,1H),4.29-4.31(m,2H),4.19-4.21 (m,2H),3.96(s,2H),3.73-3.82(m,4H),2.85(s,3H),2.77-2.84(m,2H),1.99-2.04(m,3H),1.39-1.49(m,2H).

[0251] Embodiment 7:

[0252]

[0253] Step 1: 4,5,6,7-Tetrahydrothieno[3.2-c]pyridine (0.15 g, 1.1 mmol) and intermediate 1 (0.2 g, 1.25 mmol) were dissolved in acetonitrile (20 mL), and DIPEA (1 mL) was added. The reaction was carried out at room temperature for 3 h. LCMS detected that the reaction of the raw materials was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain the target compound 7A (0.3 g, 91%).

[0254] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0255] Step 2: 7A (100 mg, 0.38 mmol) and intermediate 2 (125 mg, 0.46 mmol) were dissolved in DMSO (5 mL), K2CO3 (157 mg, 1.14 mmol) was added, and the reaction was carried out at 80°C overnight. LCMS detected that the reaction of the raw materials was complete, ethyl acetate (40 mL) was added, and the mixture was washed with saturated brine (40 mL×3). The organic phase was dried, concentrated, and separated by column chromatography (DCM:MeOH=1:0~20:1) to obtain compound 7 (30 mg, 18%).

[0256] LC-MS (ESI): m / z = 439.1 [M+H] + .

[0257] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.10–7.09(m,1H),6.71–6.70(m,1H),6.48(s,1H),3.87–3.85(m,2H),3.75–3.75(m, 2H),3.65(s,2H),3.58(s,2H),2.94–2.87(m,4H),2.79(s,3H),2.73–2.66(m,2H),2.04–1.96(m,3H),1.48–1.37(m,2H).

[0258] Embodiment 8:

[0259]

[0260] Step 1: 4,5,6,7-Tetrahydrothieno[2.3-c]pyridine (0.15 g, 1.1 mmol) and intermediate 1 (0.2 g, 1.25 mmol) were dissolved in acetonitrile (20 mL), and DIPEA (1 mL) was added. The reaction was carried out at room temperature for 3 h. LCMS detected that the reaction of the raw materials was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain the target compound 8A (0.3 g, 91%).

[0261] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0262] Step 2: 8A (100 mg, 0.38 mmol) and intermediate 2 (125 mg, 0.46 mmol) were dissolved in DMSO (5 mL), K2CO3 (157 mg, 1.14 mmol) was added, and the reaction was carried out at 80°C overnight. LCMS detected that the reaction of the raw materials was complete, ethyl acetate (40 mL) was added, and the mixture was washed with saturated brine (40 mL×3). The organic phase was dried, concentrated, and separated by column chromatography (DCM:MeOH=1:0~20:1) to obtain compound 8 (30 mg, 18%).

[0263] LC-MS (ESI): m / z = 439.1 [M+H] + .

[0264] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.12–7.11(m,1H),6.80–6.78(m,1H),6.49(s,1H),3.87–3.83(m,2H),3.80(s,2H),3.75–3.74 (m,2H),3.60(s,2H),2.91–2.86(m,2H),2.79(s,3H),2.78–2.76(m,2H),2.73–2.66(m,2H),2.02–1.98(m,3H),1.48–1.38(m,2H).

[0265] Embodiment 9:

[0266]

[0267] Step 1: (R)-1-(2,4-dichlorophenyl)ethane-1-amine (0.32 g, 1.7 mmol) and intermediate 1 (0.33 g, 1.85 mmol) were dissolved in acetonitrile (20 mL), and DIPEA (1 mL) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-8% MeOH / DCM) to obtain compound 9B (450 mg, yield 85.08%).

[0268] LC-MS (ESI): m / z = 314.1 [M+H] +.

[0269] Step 2: Compound 9B (0.45 g, 1.43 mmol), triethylamine (0.2 g, 2.0 mmol), 4-dimethylaminopyridine (0.12 g, 0.46 mmol) were dissolved in DCM (10 mL), and Boc anhydride (0.44 g, 2.0 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-4% MeOH / DCM) to obtain compound 9C (0.46 g, yield 77.52%).

[0270] LC-MS (ESI): m / z = 414.0 [M+H] + .

[0271] Step 3: Compound 9C (0.2 g, 0.48 mmol) and intermediate 2 (157 mg, 0.58 mmol) were dissolved in DMF (10 mL), potassium carbonate (157 mg, 1.14 mmol) was added, and the mixture was reacted at 80°C overnight. LCMS detected that the reaction of the raw materials was complete and the reaction solution was poured into ice water for quenching. The mixture was extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by medium-pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 9 (18 mg, yield 8.46%).

[0272] LC-MS (ESI): m / z = 489.5 [M+H] + .

[0273] 1H NMR (400MHz, CDCl3) δ7.53–7.52(m,2H),7.37(s,1H),7.29(s,1H),6.41(s,1H),4.32(s,1H),3.86–3.84(m, 2H),3.73–3.71(m,2H),3.51(s,2H),2.79(s,3H),2.72–2.66(m,2H),2.03–1.97(m,3H),1.47–1.26(m,6H).

[0274] Embodiment 10:

[0275]

[0276] Step 1: Dissolve 10A (1 g, 3.36 mmol), cyclopropylboronic acid (576 mg, 6.72 mmol), ditriphenylphosphine palladium dichloride (236 mg, 0.34 mmol) and potassium phosphate (2.14 g, 10.08 mmol) in a mixed solvent of toluene (20 mL) and water (2 mL), react overnight at 100 ° C under a nitrogen atmosphere. After the reaction is complete, cool to room temperature, add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic layers, wash with saturated sodium bicarbonate solution (40 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 20:1) to obtain 10B (570 mg, 66%).

[0277] LC-MS(ESI):m / z=204.1[M+H-55] + .

[0278] Step 2: 10B (570 g, 2.20 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane solution (8 mL) and reacted at room temperature overnight. After 16 h, the solvent was removed by rotary evaporation under reduced pressure, 25 mL of saturated sodium bicarbonate solution was added to the residue, and extracted with ethyl acetate (20 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the residue was concentrated and separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 20:1) to obtain 10C (335 mg, 96%).

[0279] LC-MS (ESI): m / z = 160.1 [M+H] + .

[0280] Step 3 and 4: Using 10C as raw material, refer to the synthesis steps of Example 1 to synthesize compound 10.

[0281] 1 H NMR(400MHz,CD3Cl)δ7.53(s,1H),7.02-6.99(m,1H),6.89-6.86(m,1H),6.84(s,1H),6.41(s,1H),3.92(s,4H),3.82-3.74(m,2H),3.69-3 .66(m,4H),2.72(s,3H),2.66-2.59(m,2H),1.98-1.89(m,3H),1.85- 1.78(m,1H),1.42-1.30(m,2H),0.90-0.83(m,2H),0.61-0.56(m,2H).

[0282] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0283] Embodiment 11:

[0284]

[0285] Step 1: Add compound 11A (1.8 g, 7.6 mmol) to a 100 mL single-mouth bottle, dissolve in nitrogen methyl pyrrolidone (10 mL), then add cesium carbonate (5.4 g, 16.7 mmol), heat to 130°C and react overnight. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry, concentrate, and column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 11B (0.89 g, 40%).

[0286] LC-MS(ESI):m / z=220.1[M+H-56] + .

[0287] Step 2: Add compound 11B (0.89 g, 3.2 mmol) to a 100 mL single-necked bottle, dissolve in dichloromethane (15 mL), then add trifluoroacetic acid (3.0 mL), react at room temperature for 2 h, and concentrate to obtain compound 11C (1.0 g, 100%).

[0288] LC-MS (ESI): m / z = 176.1 [M+H] + .

[0289] Step 3: Add compound intermediate 2 (2.7 g, 10.0 mmol) to a 100 mL single-mouth bottle, dissolve in DMF (20 mL), then add kojic acid (1.4 g, 10.0 mmol) and potassium carbonate (2.8 g, 20.0 mmol), heat to 80°C and react overnight. Add saturated ammonium chloride solution to quench, extract with ethyl acetate, dry, concentrate, and column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 11D (2.1 g, 66%).

[0290] LC-MS (ESI): m / z = 318.1 [M+H] + .

[0291] Step 4: Compound 11D (2.1 g, 6.6 mmol) was dissolved in 10 ml of thionyl chloride and reacted at room temperature for 2 h. After the reaction, the mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain compound 11E (1.5 g, 67%).

[0292] LC-MS (ESI): m / z = 336.1 [M+H] + .

[0293] Step 5: Compound 11E (335.0 mg, 1.0 mmol) and compound 11C (175.0 mg, 1.0 mmol) were dissolved in 20 ml of acetonitrile, and DIPEA (390.0 mg, 3.0 mmol) was added and reacted with mechanical stirring at room temperature for 16 h. After the reaction was completed, the mixture was concentrated and column chromatography (petroleum ether / ethyl acetate = 10 / 1) was performed to obtain compound 11 (250.0 mg, 52%).

[0294] LC-MS (ESI): m / z = 475.1 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.13(d,1H),6.94(s,1H),6.90–6.81(m,1H),6.38(s,1H),3.90(d,4H),3.83–3. 66(m,5H),3.58(d,2H),2.85(s,3H),2.71(m,2H),1.84(d,3H),1.29(m,2H),0.78–0.73(m,2H),0.70–0.56(m,2H).

[0296] Embodiment 12:

[0297]

[0298] Step 1: Dissolve 2,3,4,5-tetrahydro-1H-benzo[D]azepine (hydrochloride) (1.14 g, 6.21 mmol) and intermediate 1 (1.0 g, 6.21 mmol) in acetonitrile (20 mL), add DIPEA (8 mL), and react at room temperature for 5 h. LCMS detected that the reaction of the raw materials was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain the target compound 12B (0.55 g, 33%).

[0299] LC-MS (ESI): m / z = 272.1 [M+H] + .

[0300] Step 2: Compound 12B (550 mg, 2.03 mmol) and intermediate 2 (550 mg, 2.03 mmol) were dissolved in DMF (20 mL), and K2CO3 (420 mg, 3.04 mmol) was added. The reaction solution was heated to 80°C and stirred overnight. LCMS detected that the raw material reaction was complete. Ethyl acetate (50 mL) was added, and the mixture was washed with saturated brine (50 mL×3). The organic phase was dried and concentrated, and the crude product was purified by HPLC to obtain compound 12 (280 mg, 31%).

[0301] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm). The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 1% ammonium acetate), gradient elution, mobile phase A content from 10%-55%, flow rate 12mL / min. Elution time 15min.

[0302] LC-MS (ESI): m / z = 447.2 [M+H] + .

[0303] 1 H NMR(400MHz,CD3OD)δ8.13(s,1H),7.23(s,4H),6.69(s,1H),4.41(s,2H),3.82-3.75(m,4H),3.55-3 .35(m,4H),3.22-3.19(m,4H),2.83(s,3H),2.82-2.75(m,2H),2.02-1.96(m,3H),1.45-1.36(m,2H).

[0304] Embodiment 13:

[0305]

[0306] Step 1: Dissolve intermediate 1 (3 g, 18.75 mmol) and imidazole (2.55 g, 37.50 mmol) in DMF (30 mL), add tert-butyldimethylsilyl chloride (3.11 g, 20.63 mmol) dropwise under ice bath, and react at room temperature for 1 h. After the reaction is complete, add 60 mL of water to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic layers, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 20:1) to obtain 13A (3.2 g, 62%).

[0307] LC-MS (ESI): m / z = 275.1 [M+H] + .

[0308] Step 2: 13A (3.2 g, 11.64 mmol) was dissolved in DMF (15 mL), followed by the addition of sodium azide (908 mg, 13.97 mmol), and the reaction was allowed to proceed overnight at room temperature. After 16 h, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 20:1) to obtain 13B (3.14 g, 96%).

[0309] LC-MS (ESI): m / z = 282.3 [M + H] + .

[0310] Step 3: 13B (1.5 g, 5.33 mmol) was dissolved in tetrahydrofuran (15 mL), triphenylphosphine (2.10 g, 8.01 mmol) was added in batches under ice bath, stirred for 10 min, 0.5 mL of pure water was slowly added dropwise, and the reaction was allowed to proceed overnight at 50°C. After the reaction was complete, the mixture was cooled to room temperature, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 20:1) to obtain 13C (887 mg, 65%).

[0311] LC-MS (ESI): m / z = 256.3 [M + H] + .

[0312] Step 4: 13C (400 mg, 1.57 mmol), 2,3-di(chloromethyl)thiophene (284 mg, 1.57 mmol), potassium iodide (52 mg, 0.31 mmol) and potassium carbonate (651 mg, 4.71 mmol) were dissolved in acetonitrile (20 mL) and reacted at 80 °C for 30 min under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, 40 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 40:1) to obtain 13D (234 mg, 41%).

[0313] LC-MS (ESI): m / z = 364.2 [M+H] + .

[0314] Step 5: 13D (234 mg, 0.64 mmol) was dissolved in tetrahydrofuran (10 mL), and a 1M tetrabutylammonium fluoride solution in tetrahydrofuran (0.77 mL) was added, and the mixture was reacted at room temperature overnight. After the reaction was complete, 25 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 25:1) to obtain 13E (133 mg, 83%).

[0315] LC-MS (ESI): m / z = 250.2 [M+H] + .

[0316] Step 6: Using 13E as raw material, refer to the synthesis procedure of the second step of Example 1 to synthesize compound 13.

[0317] 1 H NMR(400MHz, CDCl3)δ7.53(s,1H),7.18-7.16(m,1H),6.75-6.73(m,1H),6.41(s,1H),4.06-4.03(m,2H),3.93-3.90 (m,2H),3.81-3.75(m,4H),3.69-3.67(m,2H),2.72(s,3H),2.66-2.59(m,2H),1.98-1.89(m,3H),1.42-1.30(m,2H).

[0318] LC-MS (ESI): m / z = 425.1 [M+H] + .

[0319] Embodiment 14:

[0320]

[0321] Step 1: Using 13C and 3,4-bis(chloromethyl)thiophene as raw materials, refer to the synthesis procedure of the fourth step of Example 13 to synthesize compound 14A.

[0322] LC-MS (ESI): m / z = 364.1 [M+H] + .

[0323] Step 2: Using 14A as raw material, refer to the synthesis procedure of step 5 of Example 13 to synthesize compound 14B.

[0324] LC-MS (ESI): m / z = 250.1 [M+H] + .

[0325] Step 3: Using 14B as raw material, refer to the synthesis procedure of the second step of Example 1 to synthesize compound 14.

[0326] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),6.88(s,2H),6.48(s,1H),3.88-3.83(m,6H),3.81-3.78(m,2H),3.75 -3.74(m,2H),2.79(s,3H),2.73-2.66(m,2H),2.09-1.97(m,3H),1.48-1.40(m,2H).

[0327] LC-MS (ESI): m / z = 425.2 [M + H] + .

[0328] Embodiment 15:

[0329]

[0330] Step 1: Dissolve kojic acid (5.67 g, 40.54 mmol) and intermediate 2 (11.0 g, 40.54 mmol) in DMF (200 mL), add K2CO3 (8.40 g, 60.81 mmol), and heat the reaction solution to 80°C and stir overnight. After the reaction, add ethyl acetate (400 mL), wash with saturated brine (200 mL × 3), dry the organic phase, and concentrate to obtain compound 15B (12 g, 93%).

[0331] LC-MS (ESI): m / z = 318.1 [M+H] + .

[0332] Step 2: Compound 15B (12.0 g, 37.81 mmol) and TEA (11.67 g, 115.43 mmol) were dissolved in DCM (200 mL), and methylsulfonyl chloride (8.88 g, 77.52 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction, the mixture was concentrated, and the residue was purified by column chromatography (DCM: MeOH = 10: 1) to obtain compound 15C (5 g, 34%).

[0333] LC-MS (ESI): m / z = 396.1 [M+H] + .

[0334] Step 3: Compound 15C (300 mg, 0.76 mmol) and compound 15D (150 mg, 0.91 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (290 mg, 2.28 mmol) was added, and the mixture was reacted at room temperature for 12 h. After the reaction, the mixture was concentrated, and the crude product was purified by column chromatography (DCM: MeOH = 10: 1) to obtain compound 15 (135 mg, 42%).

[0335] LC-MS (ESI): m / z = 425.5 [M + H] + .

[0336] 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),6.28(s,1H),3.71(d,2H),3.62-3.52(m,4H),2.85(s,3H),2.78-2.62(m,4 H),2.60-2.52(m,2H),2.17-2.00(m,2H),1.90(s,2H),1.86-1.80(m,2H),1.54-1.38(m,5H),1.36-1.20(m,4H).

[0337] Embodiment 16:

[0338]

[0339] Step 1: Dissolve intermediate 1 (161 mg, 1 mmol) and compound 16A (182 mg, 1 mmol) in 10 mL of acetonitrile, add potassium carbonate (414 mg, 3 mmol), and heat the system to 70 °C for 10 h. Cool the system to room temperature, add water to dissolve the solid in the system, add 30 mL of a mixed solvent of ethyl acetate: methanol = 10:1 to extract, extract twice, combine the organic phases, and concentrate and dry to obtain compound 16B (110 mg, 41%)

[0340] LCMS (ESI): m / z = 270.1 [M+H]

[0341] Step 2: Compound 16B (110 mg, 0.41 mmol) and intermediate 2 (110 mg, 0.41 mmol) were dissolved in 8 mL DMF, cesium carbonate (200 mg, 0.61 mmol) was added, the system was heated to 80 °C for 1 h, the organic solvent in the system was concentrated and dried, and compound 16 (35 mg, 19%) was obtained by thin layer chromatography.

[0342] LCMS (ESI): m / z = 445.1 [M+H]

[0343] 1H NMR(400MHz, CDCl3)δ7.54(s,1H),7.26–7.21(m,2H),7.20–7.15(m,2H),6.35(s,1H),4.21(s,2H),3.88–3.81(m,2H),3.76–3.70 (m,2H),3.12(s,2H),2.78(s,3H),2.74–2.64(m,2H),2.19–2.11(m,2H),2.02–1.95(m,3H),1.48–1.35(m,2H),1.29–1.21(m,2H).

[0344] Embodiment 17:

[0345]

[0346] Step 1: Weigh the compound intermediate 2 (7.65 g, 28.18 mmol) and kojic acid (4.0 g, 28.18 mmol) in a 100 mL single-mouth bottle and dissolve them in DMF (50 mL). Add potassium carbonate (11.68 g, 84.54 mmol). After the addition is completed, stir at 85 degrees for 16 hours. TLC spot plate (dichloromethane: methanol = 10:1) detects that the reaction is complete. Add water (50 mL), stir for 5 minutes, extract with dichloromethane (50 mL), separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain the target compound 17A (3.5 g, yield: 39.1%).

[0347] LCMS m / z=318.1[M+1] +

[0348] Step 2: Compound 17A (3.5 g, 11.03 mmol) was added to a 100 mL single-mouth bottle and dissolved in dichloromethane (50 mL). Triphenylphosphine (8.69 g, 33.09 mmol), carbon tetrabromide (5.49 g, 16.54 mmol) and 2,6-lutidine (1.77 g, 16.54 mmol) were then added. After the addition was completed, the system was protected with nitrogen and stirred at 20°C for 16 h. The reaction was complete as detected by TLC spot plate (dichloromethane: methanol = 10:1). Water (50 mL) was added and stirred for 5 min. The mixture was extracted with dichloromethane (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain the target compound 17B (3.0 g, yield: 71.5%).

[0349] LCMS m / z=382.1[M+1] +

[0350] Step 3: Add compound 17B (3.0 g, 7.89 mmol) to a 100 mL single-mouth bottle, dissolve it in acetonitrile (30 mL), and then add sodium trifluoromethanesulfinate (3.69 g, 23.67 mmol). After the addition is complete, the system is protected by nitrogen and stirred at 85 ° C for 16 h. TLC plate (dichloromethane: methanol) is used.

[0351] =10:1) to detect the completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain the target compound 17C (2.0 g, yield: 58.5%).

[0352] LCMS m / z=434.1[M+1] +

[0353] Step 4: Add compound 17C (2.0 g, 4.61 mmol) to a 100 mL single-mouth bottle, dissolve in DMF (30 mL), and then add N-fluorobisbenzenesulfonamide (3.63 g, 11.53 mmol) and potassium phosphate (2.45 g, 11.53 mmol). After the addition is complete, the system is protected by nitrogen and stirred at 15°C for 16 hours. The reaction is complete as detected by TLC spot plate (dichloromethane: methanol = 10:1). Water (50 mL) is added and stirred for 5 minutes to precipitate a white solid. After filtration, the filter cake is concentrated under reduced pressure to obtain the target compound 17D (0.8 g, yield: 36.9%).

[0354] LCMS m / z=470.1[M+1] +

[0355] Step 5: Add compound 17D (0.4 g, 0.85 mmol) to a 100 mL single-mouth bottle, dissolve in DMF (10 mL), and then add isoindoline (0.15 g, 1.26 mmol) and N,N-diisopropylethylamine (0.33 g, 2.55 mmol). After the addition is complete, the system is protected by nitrogen and stirred at 90 ° C for 4 hours. TLC spot plate (dichloromethane: methanol = 10: 1) detects that the reaction is complete, and water (50 mL) is added and stirred for 5 minutes. A brown solid is precipitated. After filtration, the filter cake is concentrated under reduced pressure. The crude product is separated by preparative HPLC to obtain the title compound 17 (70 mg, 18%).

[0356] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm; The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonia water); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate 15mL / min. d. Elution time 20min; Retention time: 10.60min.

[0357] LCMS m / z=455.1[M+1] +

[0358] 1 H NMR(400MHZ,DMSO)δ7.74(s,1H),7.31-7.44(m,4H),5.35(s,1H),5.11(d,4H),3. 61-3.68(m,4H),2.87(s,3H),2.74(t,2H),1.89-1.98(m,3H),1.34-1.45(m,2H).

[0359] Embodiment 18:

[0360]

[0361] Step 1: Weigh compound intermediate 1 (1.0 g, 6.21 mmol) and compound 18A (0.99 g, 7.43 mmol) in a 100 mL single-necked bottle, dissolve in acetonitrile (10 mL), add N,N-diisopropylethylamine (2.41 g, 18.65 mmol), stir at 20 degrees for 16 h after the addition is complete, detect the reaction completion by TLC spot plate (dichloromethane: methanol = 10:1), add water (20 mL), stir for 5 min, extract with dichloromethane (20 mL), separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain the target compound 18B (0.2 g, yield: 12.5%).

[0362] LCMS m / z=258.1[M+1] +

[0363] Step 2: Add compound 18B (200 mg, 0.78 mmol) and DMF (10 mL) to a 100 mL single-mouth bottle to dissolve, then add intermediate 2 (230 mg, 0.85 mmol) and potassium carbonate (0.32 g, 2.32 mmol). After the addition is completed, the system is protected by nitrogen and stirred at 80°C for 4 h. The reaction is complete as detected by TLC spot plate (dichloromethane: methanol = 10:1). Water (20 mL) is added, stirred for 5 min, extracted with dichloromethane (20 mL), and the organic phase is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude target compound is subjected to preparative HPLC to obtain the title compound 18 (36 mg, 10.6%).

[0364] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm; The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonia water); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate 15mL / min. d. Elution time 20min; Retention time: 11.00min.

[0365] LCMS m / z=433.2[M+1] +

[0366] 1 H NMR(400MHZ,DMSO)δ8.11(s,1H),7.15-7.18(m,2H),7.08-7.12(m,2H),6.37(s,1H),3.71(d,2H),3.62(s,2H),3.54-3. 59(m,3H),3.47-3.52(m,1H),3.02-3.07(m,2H),2.85(s,3H),2.65-2.75(m,4H),1.78-1.84(d,3H),1.22-1.34(m,2H).

[0367] Embodiment 19:

[0368]

[0369] Step 1: Dissolve 19A (1 g, 5.63 mmol), di-tert-butyl dicarbonate (1.60 g, 7.32 mmol), triethylamine (1.14 g, 11.26 mmol) and 4-DMAP (69 mg, 0.56 mmol) in dichloromethane (10 mL) and react at room temperature for 2 h. After the reaction is complete, add 30 mL of water to the reaction solution, extract with ethyl acetate (15 mL × 3), combine the organic layers, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 19B (1.32 g, 85%).

[0370] LC-MS(ESI):m / z=222.2[M+H-56] + .

[0371] Step 2: 19B (1.32 g, 4.76 mmol) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), and a 1 M sodium hydroxide aqueous solution (5 mL) was slowly added dropwise to the reaction solution, and the reaction was carried out at room temperature for 30 min. After the reaction was complete, the pH was adjusted to about 3 with a 1 M dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product of 19C (1.08 g, 86%), which was used directly in the next step without further purification.

[0372] LC-MS(ESI):m / z=208.1[M+H-56] + .

[0373] Step 3: 19C (230 mg, 0.87 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (337 mg, 2.61 mmol) and HATU (364 mg, 0.96 mmol) were added, and the mixture was stirred at room temperature for 10 min, followed by the addition of morpholine (152 mg, 1.74 mmol) and the mixture was reacted at room temperature for 30 min. After the reaction was complete, 25 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 25:1) to obtain 19D (227 mg, 79%).

[0374] LC-MS (ESI): m / z = 333.2 [M+H] + .

[0375] Step 4: 19D (227 mg, 0.62 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane solution (5 mL) and reacted at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to obtain 19E (149 mg, 94%).

[0376] LC-MS (ESI): m / z = 233.2 [M+H] + .

[0377] Step 5: 19E (149 mg, 0.74 mmol), intermediate 1 (143 mg, 0.89 mmol) and N,N-diisopropylethylamine (287 mg, 2.22 mmol) were dissolved in acetonitrile (10 mL) and reacted at room temperature overnight. After the reaction was complete, the reaction solution was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 40:1) to obtain 19F (170 mg, 64%).

[0378] LC-MS (ESI): m / z = 357.4 [M+H] +.

[0379] Step 6: 19F (170 mg, 0.48 mmol), intermediate 2 (143 mg, 0.53 mmol) and potassium carbonate (199 mg, 1.44 mmol) were dissolved in DMF (10 mL) and reacted at 70 ° C for 3 h under nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, 25 mL of water was added, and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), 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 19 (35 mg, 14%).

[0380] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),7.26-7.24(m,3H),6.49(s,1H),4.06(s,4H),3.87-3.83(m,2H),3.81-3. 59(m,10H),2.80-2.76(m,4H),2.73-2.66(m,2H),2.08-2.06(m,1H),2.03-1.96(m,3H),1.49-1.37(m,2H).

[0381] LC-MS (ESI): m / z = 532.5 [M+H] + .

[0382] Embodiment 20:

[0383]

[0384] Step 1: Weigh 20A (5.0 g, 22.81 mmol) in a single-necked flask, add 150 ml of anhydrous dichloromethane, then add dibromohydantoin (6.52 g, 22.81 mmol) in batches under an ice-water bath, then warm to room temperature and stir overnight. After the reaction is complete, filter, concentrate the filtrate and purify it by column chromatography to obtain 20B (5.5 g, 80.89%).

[0385] LC-MS (ESI): m / z = 297.9 [M+H] + .

[0386] Step 2: The raw material substrate 20B (5.1 g, 17.11 mmol), methylboronic acid (5.12 g, 85.55 mmol), cesium carbonate (22.3 g, 68.44 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.25 g, 1.71 mmol) were dissolved in 1,4-dioxane (100 mL) at room temperature, and heated to 105°C under nitrogen protection for 5 h. After the reaction, 100 mL of water was added to quench the reaction, EA was extracted (100 mL × 3), the organic phases were combined and washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate: petroleum ether = 0:1 to 10:1) to obtain compound 20C (3.0 g, 75.19%).

[0387] LC-MS (ESI): m / z = 234.0 [M+H] + .

[0388] Step 3: Dissolve the raw material substrate tert-butyl nitrite (2.65 g, 25.72 mmol) and copper bromide (3.45 g, 15.38 mmol) in acetonitrile (50 mL) at room temperature, add 20C (3.0 g, 12.86 mmol, dissolved in 25 mL methyl tert-butyl ether) dropwise under an ice-water bath, and after the addition is complete, warm to room temperature and react for 2 hours. After the reaction is completed, add 50 mL of ice water and stir for ten minutes, then add ammonia water (10 mL) and methyl tert-butyl ether (50 mL) and continue stirring for 1 hour, separate the liquids, extract the aqueous phase with methyl tert-butyl ether (30 mL × 2), combine the organic phases and wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (pure petroleum ether) to obtain compound 20D (2.5 g, 65.44%).

[0389] 1 H NMR (400MHz, CDCl3) δ7.66–7.59(m,2H),7.43(dd,1H),2.47(s,3H).

[0390] Step 4: The raw material substrate 20D (2.5 g, 8.42 mmol), methylboronic acid (2.52 g, 42.1 mmol), cesium carbonate (10.97 g, 33.68 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.62 g, 0.84 mmol) were dissolved in 1,4-dioxane (60 mL) at room temperature, and heated to 105°C under nitrogen protection for 5 h. After the reaction, 150 mL of water was added to quench the reaction, EA was extracted (150 mL × 3), the organic phases were combined and washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain 20E (1.8 g, 92.06%).

[0391] 1 H NMR (400MHz, CDCl3) δ7.51(s,1H),7.47(d,1H),7.19(d,1H),2.32(s,3H),2.30(s,3H).

[0392] Step 5: Dissolve the raw material substrate 20E (1.8 g, 7.75 mmol) and azobisisobutyronitrile (0.13 g, 0.78 mmol) in acetonitrile (40 mL) at room temperature, then add NBS (4.14 g, 23.25 mmol), and heat to 85°C for 5 hours. After the reaction, concentrate under reduced pressure, and the residue is directly purified by column chromatography (pure petroleum ether) to obtain 20F (1.3 g, 43.01%).

[0393] 1 H NMR (400MHz, CDCl3) δ7.76(d,1H),7.69(dd,1H),7.48(d,1H),4.64(s,2H),4.63(s,2H).

[0394] Step 6: 20F (0.20 g, 0.51 mmol) was dissolved in DMF (5 mL), and a mixed solution of triphenylmethylamine (0.13 g, 0.59 mmol) and DIEPA (0.26 g, 2.05 mmol) dissolved in 5 mL DMF was slowly added dropwise at 60°C. After the addition was complete, the reaction was continued at this temperature for 5 h. After the reaction was completed, 40 mL of ethyl acetate was added, and the mixture was washed with saturated brine (20 mL×4). The organic phase was dried and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1) to obtain compound 20G (0.06 g, 24.13%).

[0395] Step 7: Disperse 20G (0.06 g, 0.12 mmol) in 10 mL DCM, add trifluoroacetic acid (2.57 mL), and react overnight at room temperature. After the reaction is completed, concentrate and remove the solvent to obtain compound 20H, which is used directly in the next step without purification.

[0396] LC-MS (ESI): m / z = 246.1 [M+H] + .

[0397] Step 8: Compound 20H (30 mg, 0.12 mmol) and 11E (60.3 mg, 0.18 mmol) were dissolved in dichloromethane (5 mL), and triethylamine (36 mg, 0.36 mmol) was added, and the mixture was reacted at 25° C. for 16 h. After the reaction, the mixture was concentrated, and the crude product was purified by column chromatography (DCM:MeOH=10:1) to give compound 20 (8 mg, 12.24%).

[0398] LC-MS (ESI): m / z = 545.5 [M+H] + .

[0399] 1 H NMR (400MHz, CDCl3) δ7.67–7.61(m,1H),7.60(s,2H),7.28(d,1H),6.49(s,1H),4.08(d,4H),3.8 6(d,2H),3.79(s,2H),3.74(d,2H),2.79(s,3H),2.70(dt,2H),2.05–1.96(m,3H),1.43(qd,2H).

[0400] Embodiment 21:

[0401]

[0402] Step 1: Add compound 21A (2 g, 11.26 mmol) and sodium bicarbonate (0.95 g, 11.26 mmol) to 1,2-dichloroethane (30 mL), stir at room temperature for 15 minutes, add p-anisaldehyde (1.69 g, 12.39 mmol), stir for 1 hour, and then add sodium cyanoborohydride (3.54 g, 56.3 mmol) in 3 batches. Stir overnight at room temperature, and the reaction is complete after TLC detection. Filter with diatomaceous earth pad, rinse the filter cake with dichloromethane (20 mL × 3), collect the filtrate, concentrate and dry under reduced pressure, and separate and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 21B (2.4 g, yield 71.68%).

[0403] LC-MS (ESI): m / z = 298.2 [M+H]+ .

[0404] Step 2: Compound 21B (2.4 g, 8.07 mmol) and tetraisopropyl titanate (3.21 g, 11.30 mmol) were added to anhydrous tetrahydrofuran (60 mL), nitrogen protection, ice-salt bath cooled to -10 ° C, ethyl magnesium bromide (8 mL, 32.28 mmol, 4 M in THF) was slowly added dropwise, stirred for 1 hour, and the ice-salt bath was removed. Stir at room temperature overnight, TLC detected that the reaction was complete, and the reaction system was poured into saturated ammonium chloride solution (60 mL) to quench, extracted with ethyl acetate (60 mL × 3), combined organic phases were washed once with saturated brine, concentrated and dried under reduced pressure, and the crude product was slurried with MTBE (30 mL) to obtain the target compound 21C (1.24 g, yield 52.19%).

[0405] LC-MS (ESI): m / z = 296.3 [M+H] + .

[0406] Step 3: Compound 21C (1.2 g, 4.06 mmol) was added to anhydrous dichloromethane (30 mL), protected by nitrogen, cooled to -78 °C, and DAST (0.78 g, 4.84 mmol) was slowly added dropwise. After stirring for 10 minutes, the temperature was slowly raised to 10 °C and stirred for 1 hour. The reaction was completed after TLC monitoring. The reaction system was poured into water (60 mL) for quenching, and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed once with saturated brine, concentrated and dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to obtain the target compound 21D (430 mg, yield 35.62%).

[0407] LC-MS (ESI): m / z = 298.2 [M+H] + .

[0408] Step 4: Compound 21D (430 mg, 1.45 mmol) was added to anhydrous dichloromethane (30 mL), and 1-chloroethyl chloroformate (1.23 g, 8.70 mmol) was added. The mixture was protected by nitrogen and refluxed at 50 °C for two hours. The raw material disappeared after monitoring by TLC. The reaction system was concentrated under reduced pressure. After removing the solvent, methanol (30 mL) was added and reacted at 60 °C for 2 hours. After monitoring by TLC, the reaction was completed, and the mixture was extracted with dichloromethane (60 mL×3). The organic phases were combined, washed once with saturated brine, concentrated and dried under reduced pressure, and the residue was slurried with MTBE (10 mL) to obtain the target compound 21E hydrochloride (290 mg).

[0409] Step 5: Compound 21E (290 mg) was added to acetonitrile (10 mL), and intermediate 1 (290 mg, 1.80 mmol) was added. The mixture was protected by nitrogen and stirred at 40 °C overnight. After the reaction was completed by TLC, the reaction system was concentrated under reduced pressure. The residue was slurried with MTBE (10 mL) to obtain the target compound 21F (254 mg, yield 51.40%).

[0410] LC-MS (ESI): m / z = 302.30 [M+H] + .

[0411] Step 6: Compound 21F (250 mg, 0.83 mmol) was added to anhydrous DMF (10 mL), and intermediate 2 (270 mg, 1.00 mmol) was added. The mixture was protected by nitrogen and stirred at 80 °C for 4 hours. After the reaction was completed by TLC, water (40 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (60 mL×3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to obtain the target compound 21 (50 mg, yield 12.64%).

[0412] LC-MS (ESI): m / z = 477.50 [M+H] + .

[0413] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.21–7.10(m,3H),6.49(s,1H),4.05(s,4H),3.89–3.82(m,2H),3.78(s,2H),3.75–3.71(m,2H ),2.79(s,3H),2.73–2.64(m,2H),2.08–2.02(m,1H),2.02–1.97(m,2H),1.52–1.45(m,2H),1.45–1.37(m,2H),1.05–0.99(m,2H).

[0414] Embodiment 22:

[0415]

[0416] Step 1: Using 22A as raw material, refer to the synthesis steps of the first step of Example 9 to synthesize compound 22B.

[0417] LC-MS (ESI): m / z = 314.1 [M+H] + .

[0418] Step 2: Using 22B as raw material, refer to the synthesis procedure of the second step of Example 9 to synthesize compound 22C.

[0419] LC-MS (ESI): m / z = 414.0 [M+H] + .

[0420] Step 3: Using 22C as raw material, refer to the synthesis procedure of the third step of Example 9 to synthesize compound 22.

[0421] LC-MS (ESI): m / z = 489.5 [M+H] + .

[0422] 1 H NMR (400MHz, CDCl3) δ7.53–7.47(m,2H),7.35(s,1H),7.27–7.26(m,1H),6.40(s,1H),4.31–4.26(m,1H),3.87–3.85 (m,2H),3.73–3.71(m,2H),3.49–3.47(m,2H),2.79(s,3H),2.72–2.66(m,2H),2.04–1.98(m,3H),1.47–1.26(m,6H).

[0423] Embodiment 23:

[0424]

[0425] Step 1: Using compound 23A as raw material, refer to step 4 of compound Example 5 to synthesize compound 23B.

[0426] LC-MS (ESI): m / z = 324.0 [M+H] + .

[0427] Step 2: Using compound 23B as raw material, refer to step 5 of compound Example 5 to synthesize compound 23C.

[0428] LC-MS (ESI): m / z = 497.1

[0429] Step 3: Compound 23C (0.4 g, 0.80 mmol) was dissolved in toluene (10 ml), and then tert-butyl carbamate (0.19 g, 1.62 mmol), Pd2(dba)3 (0.092 g, 0.16 mmol), cesium carbonate (1.04 g, 3.19 mmol), and DINAP (0.15 g, 0.24 mmol) were added in sequence. After the addition was completed, nitrogen was replaced, and then the temperature was raised to 80°C and reacted for 20 hours. After the reaction was completed, ethyl acetate (20 mL) was added to dilute, the insoluble matter was filtered out, and the crude compound 23C was concentrated to dryness to obtain the crude product, which was directly used in the next step.

[0430] LC-MS (ESI): m / z = 534.2

[0431] Step 4: Dissolve the crude compound 23C obtained in the previous step in tetrahydrofuran (5 mL), then add 15% hydrochloric acid (5 mL), stir overnight. Add saturated sodium bicarbonate to adjust the pH to 8-9, and then extract the reaction solution with ethyl acetate (20 mL*2). After the organic phases are combined, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by flash chromatography to obtain compound 23D (0.17 g, 26.14%).

[0432] LC-MS (ESI): m / z = 434.2 [M + H] + .

[0433] Step 5: Compound 23D (0.17 g, 0.39 mmol) was dissolved in dry acetonitrile, then cooled to 0°C under nitrogen protection, tert-butyl nitrite (0.080 g, 0.78 mmol) was added dropwise to the reaction solution, and stirred for 5 minutes. Azidotrimethylsilane (0.072 g, 0.62 mmol) was then added dropwise, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, most of the solvent was removed by concentration to obtain a crude product, which was purified by silica gel column to obtain compound 23 (50.0 mg, 27.90%).

[0434] LC-MS (ESI): m / z = 460.5 [M+H] + .

[0435] 1 H NMR(400MHz, CDCl3)δ7.69(s,1H),7.17(d,1H),6.90–6.87(m,2H),6.48(s,1H),4.02(d,4H),3.88–3 .77(m,2H),3.76–3.74(m,4H),2.79(s,3H),2.73–2.66(m,2H),2.04–1.97(m,3H),1.48–1.38(m,2H).

[0436] Example 24 and Example 25:

[0437]

[0438] Step 1: 24A (1.0 g, 4.78 mmol) and cesium carbonate (2.34 g, 7.18 mmol) were dissolved in DMF (15 mL) and stirred for 15 minutes, then iodomethane (0.82 g, 5.78 mmol) was added dropwise and reacted at room temperature for 18 hours. The reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate (20 mL×3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and purified by a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-30% EA / PE) to obtain a mixture 24B (1.0 g, 93.7%).

[0439] LC-MS (ESI): m / z = 224.3 [M+H] + .

[0440] Step 2: 24B (1.0 g, 4.48 mmol) was dissolved in DCM (10 mL) at room temperature, trifluoroacetic acid (3 mL, 40.26 mmol) was added to the solution, and the mixture was reacted at room temperature for 2 h. The mixture was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of 24C (1.04 g, 97.9%), which was used directly in the next step without further purification.

[0441] LC-MS (ESI): m / z = 124.2 [M + H] + .

[0442] Step 3: Compound 24C trifluoroacetate (0.14 g, 0.6 mmol) and 15C (0.2 g, 0.5 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.1 g, 0.75 mmol) was added, and the mixture was stirred at 70°C for 18 h. The reaction solution was poured into ice water, extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain 160 mg of the mixture. The mixture was prepared by SFC to obtain Isomer A (retention time: 1.174 min, 50.1 mg, 23.4%, compound 24); Isomer B (retention time: 2.258 min, 99.7 mg, 46.66%, compound 25).

[0443] SFC preparation method: Instrument: Waters 150Prep-SFC E preparative liquid phase; Chromatographic column: Chiralcel ADcolumn. The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A, B composition: Mobile phase A: CO2; Mobile phase B: 0.1% NH3·H2O in MeOH and ACN, gradient elution, mobile phase B: content 70%, flow rate: 100mL / min. Column pressure: 100bar, column temperature: 25℃, absorption wavelength: 220nm, cycle time: 4.3min.

[0444] Compound 24:

[0445] LC-MS (ESI): m / z = 423.2 [M+H] + .

[0446] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),7.18(s,1H),6.46(s,1H),3.94–3.92(m,4H),3.87–3.84(m,4H),3 .78(s,3H),3.76–3.74(m,1H),2.79(s,3H),2.73–2.66(m,2H),2.04–1.98(m,3H),1.48–1.26(m,2H).

[0447] Compound 25:

[0448] LC-MS (ESI): m / z = 423.3 [M + H] + .

[0449] 1 H NMR (400MHz,CDCl3)δ7.60(s,1H),7.03(s,1H),6.47(s,1H),3.91–3.90(m,2H),3.87–3.84(m,5H),3.82(s,3H),3.76–3.74(m,2H),2.79(s,3H),2.73–2.66(m,2H),2.04–1.97(m,3H),1.48–1.38(m,2H).Biological tests:

[0450] 1. The purpose of this study is to use the enzyme linked immunosorbent assay (ELISA) method to detect the testosterone level in NCI-H295R cells, so as to evaluate the inhibitory effect of the compound on the levels of pregnenolone and testosterone in NCI-H295R cells.

[0451] H295R cells were purchased from ATCC, and the complete cell culture medium was DMEM:F12+10% FBS+0.00625mg / ml insulin+0.00625mg / ml transferrin+6.25ng / ml selenium+1.25mg / ml BSA+0.00535mg / ml linoleic acid, and cultured in a 37°C, 5% CO2 incubator. Cells in the exponential growth phase were collected and cultured with hormone deprivation medium (phenol red-free 1640+1% PS+10% css FBS+1.25mg / ml BSA

[0452] +0.00625mg / ml insulin +0.00625mg / ml transferrin +6.25ng / ml selenium +0.00535mg / ml linoleic acid) culture cells for 3 days. On the third day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration plate with hormone deprivation medium, so that the cells were 60,000 / well, and the volume was 90μL per well, and then 10μL of compounds of different concentrations were added, and the cells were placed in a CO2 incubator for 3 days. After the culture was completed, according to the testosterone detection Elisa kit (Biyuntian, PT872) operating instructions, 50μL of cell culture supernatant was taken from each well, centrifuged at 500g, 5min room temperature, and then the supernatant was collected. The samples were added to the corresponding wells according to 25μl / well, and then the prepared horseradish peroxidase-labeled testosterone was added according to 75μl / well, fully mixed for 10 seconds, and the reaction wells were sealed with a sealing film (white), and incubated at room temperature in the dark for 120min. Then wash the plate 3 times with 300 μl per well, and after the last wash, place it on thick absorbent paper and pat it dry, add 100 μl / well of the colorimetric reagent TMB solution, seal the reaction wells with a sealing film (white), incubate at room temperature in the dark for 15-20 minutes, then add 50 μl / well of the stop solution, mix well and measure the OD immediately. 450 Absorbance value. The absorbance readings were used with Graphpad Prim 8.0 software to draw a S-shaped concentration curve using a four-parameter nonlinear regression model and calculate the IC 50 The results were processed according to formula (1) to calculate the inhibition rate of each concentration of the compound, and the concentration IC of the compound when the inhibition rate was 50% was calculated using Graphpad Prim 8.0 software. 50 Value. Among them, RLU compoundThe readings for the drug treatment groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0453] Inhibition rate % = 100-RLU compound / RLU control ×100 type (1)

[0454] Table 1

[0455]

[0456] NA: Not detected

[0457] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the testosterone level in NCI-H295R cells.

[0458] 2. Pharmacokinetics test in rats

[0459] 2.1 Experimental animals: Male SD rats, about 220 g, 6-8 weeks old, 3 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0460] 2.2 Experimental design: On the day of the experiment, three SD rats were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

[0461] Table 2 Dosage information

[0462]

[0463] Dosing vehicle: 0.5% MC

[0464] Before and after drug administration, 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The time points for blood collection in the venous group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; the time points for blood collection in the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and testing.

[0465] Table 3 Pharmacokinetic parameters of test compounds in rat plasma

[0466]

[0467] Conclusion: The compounds of the present invention have good bioavailability and pharmacokinetic characteristics.

Claims

1. A compound represented by formula (I), its stereoisomer or pharmaceutically acceptable salt, Ring A is selected from Ring B is selected from The left side of the B ring is connected to L1; The C ring is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclic group, 6-12 membered bicyclic heterocyclic group, 8-14 membered tricyclic heterocyclic group, wherein the phenyl, heteroaryl, bicyclic carbocyclic group, bicyclic heterocyclic group, tricyclic heterocyclic group is optionally replaced by 1-4 R C replace; L1 is selected from -CH2O-, and the left side of L1 is connected to A; L2 is selected from W1-R L -W2, the left side of L2 is connected to B; R L Select from key, C 1-4 Alkylene, C 2-4 alkenylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the alkylene, alkenylene, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 R L1 replace; R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or any two R L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the alkyl, alkoxy or cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2; W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, wherein one or more -CH2- in the alkylene group is optionally replaced by 1 to 4 groups selected from -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O- or -OC(=O)-, the alkylene group is optionally further substituted by 1 to 4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl, CN, OH and NH2; R W1 Selected from H, C 1-4 Alkyl, halogen; R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl, CN, OH and NH2; q is selected from 0 or 1; p is each independently selected from 0, 1, 2, 3 or 4; The condition is, 1) When ring C is selected from unsubstituted When L2 is 2) When ring C is selected from substituted When R C Not -CH3, -CF3, -OCF3 and halogen; 3) Ring C is not optionally substituted 2. The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein: The C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocycloalkyl phenyl, 5-6-membered carbocyclyl phenyl, 5-6-membered heterocycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl 3-6-membered cycloalkyl or 9-12-membered tricyclic heterocyclyl, wherein the heterocyclyl, heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, O and S, and the phenyl, heteroaryl, heterocycloalkyl, carbocyclyl and cycloalkyl are optionally replaced by 1-4 R C replace; R L Select from key, C 1-2 Alkylene, 4-6 membered heterocycloalkyl or C 2-4 Alkenylene, wherein the alkylene, heterocycloalkylene, and alkenylene are optionally further substituted by 1 to 3 R L1 replace; R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 alkenyl or 3-6 membered cycloalkyl, or any two R L1 and its connecting atoms together form a 3-6 membered cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl is optionally further substituted by 1-3 substituents selected from halogen, CN, OH and NH2; W1 and W2 are each independently selected from a bond, C 1-4 Alkylene, -O-, -S-, -NR W1 -、-CONR W1 -or-NR W1 CO-, one or more -CH2- in the alkylene group are optionally replaced by 1-4 selected from -NR W1 -、-CONR W1 -or-NR W1 CO-, the alkylene group is optionally further substituted by 1-4 groups selected from halogen, C 1-2 Alkyl or halogenated C 1-2 Substitution of alkyl groups; R W1 Selected from H, C 1-2 Alkyl, halogen; R C Each independently selected from halogen, OH, N3, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2, -(CH2) p -OC 1-4 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl, CN, OH and NH2; q is selected from 0 or 1; p is independently selected from 0, 1, 2 or 3.

3. The compound of formula (I) according to claim 2, its stereoisomer or pharmaceutically acceptable salt, wherein: Ring C is selected from optionally 1-4 R C One of the groups formed by the following structures: L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, 3-6 membered cycloalkyl, -NH-, -O-, -(C 1-2 Alkylene)-NR W1 -、-(C 1-2 Alkylene)-NR W1 -(C 1-2 Alkylene)-, -(C 1-2 Alkylene)-NR W1 CH(CF3)-、-(C 1-2 Alkylene)-NR W1 CH(CH3)-、-(C 1-2 alkylene)-(4-membered heterocycloalkyl) or -(C 1-2 Alkylene)NR W1 CO-, the alkylene, alkenylene, cycloalkyl group may be further substituted by 1-3 R L1 Replacement; R L1 are independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, 3-6 membered cycloalkyl; R C Each independently selected from F, Cl, Br, OH, N3, C 1-2 Alkyl, halogenated C 1-2 Alkyl, -O-halogenated C 1-2 Alkyl, C 2-4 Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-2 Alkyl)2, -(CH2) p -OC 1-2 alkyl, -C(=O)-(4-6 membered heterocycloalkyl) or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group, the cycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, C 1-2 Alkyl, halogenated C 1-2 Substitution of alkyl, CN, OH and NH2; q is selected from 0 or 1; p is each independently selected from 0, 1 or 2.

4. The compound of formula (I) according to claim 2, its stereoisomer or pharmaceutically acceptable salt, wherein ring C is selected from one of the following structures:

5. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table A below: Table A 6. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition or pharmaceutical preparation according to claim 1, comprising 1-1500 mg of the compound according to any one of claims 1-5 or its stereoisomer or pharmaceutically acceptable salt and a carrier and / or excipient.

8. Use of the compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt, or the composition according to claims 6 to 7 in the preparation of a medicament for treating / preventing a disease mediated by CYP11A1.

9. The use according to claim 8, wherein the CYP11A1-mediated disease is selected from the group consisting of treating steroid hormone-dependent cancers.

10. A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 5 or a stereoisomer or a pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1 to 1500 mg, and the disease preferably being prostate cancer.

Images