CYP11A1 inhibitor and application thereof

Abstract

A compound represented by formula (I), or a stereoisomer, a tautomer, a deuterated compound, a solvate, a co-crystal or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and uses thereof in preparation of drugs for treatment / prevention of CYP11A1 mediated diseases, each group in the formula (I) being as defined in the specification.

Description

CYP11A1 inhibitors and uses thereof

[0001] This application requires the following:

[0002] Priority to the prior application, patent application number 202310320916.4, filed with the State Intellectual Property Office of China on March 29, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0003] Priority to the prior application, patent application number 202310428094.1, filed with the State Intellectual Property Office of China on April 20, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0004] Priority to the prior application, patent application number 202310667272.6, filed with the State Intellectual Property Office of China on June 7, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0005] Priority to the prior application, patent application number 202310821299.6, filed with the State Intellectual Property Office of China on July 6, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0006] Priority to the prior application, patent application number 202310979027.9, filed with the State Intellectual Property Office of China on August 4, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0007] Priority to the prior application, patent application number 202311059482.3, filed with the State Intellectual Property Office of China on August 22, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0008] Priority to the prior application, patent application number 202311216619.1, filed with the State Intellectual Property Office of China on September 20, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0009] Priority to the prior application, patent application number 202311669033.0, filed with the State Intellectual Property Office of China on December 7, 2023, entitled “CYP11A1 inhibitors and uses thereof”;

[0010] The above priority content is incorporated herein by reference in its entirety. Technical Field

[0011] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with selective CYP11A1 inhibitory activity, its stereoisomers, tautomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, and its use in preparing medicines for treating related diseases. Background Art

[0012] Cytochrome P450 monooxygenase 11a1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is primarily involved in catalyzing reactions related to drug metabolism and the synthesis of cholesterol, steroids, and other lipids. CYP11A1 protein is located in the inner mitochondrial membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in steroid hormone synthesis. This reaction occurs in the mitochondria of the adrenal cortex and is catalyzed by cytochrome CYP11A1 (also known as P450scc), along with Adx and AdR. CYP11A1, Adx, and AdR belong to the cholesterol hydroxylase / lyase (CH / L) system, which catalyzes the initial step of steroid synthesis in mammals: the conversion of cholesterol to pregnenolone. Pregnenolone is an important precursor of steroid hormones. This reaction involves three sequential monooxygenation reactions: the formation of 22R-hydroxycholesterol (22HC), the formation of 20R,22R-dihydroxycholesterol, and the cleavage of the C20-C22 bond. Each monooxygenation reaction requires two electrons and one molecular oxygen. The electrons are provided by NADPH and transferred to P450scc via NADPH-AdR and Adx. Adx forms a complex with P450scc and acts as a mobile electron transporter.

[0013] CYP11A1 is mainly expressed in the placenta, responding to the synthesis of placental-derived hormones such as progesterone and testosterone, and is also highly expressed in the adrenal glands and testicles, but 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 refractoryness. It has recently been demonstrated that compounds with CYP11A1 inhibition significantly inhibit tumor growth in vivo in a mouse crpc xenograft model.

[0014] There is an urgent need to discover CYP11A1 inhibitors with good activity, high safety, and minimal side effects, which have good clinical development prospects and can be used to treat cancer or other proliferative diseases or conditions.

[0015] Summary of the Invention

[0016] The present invention provides a small molecule compound having CYP11A1 inhibitory activity, and its stereoisomers, tautomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound is represented by Formula (I), Formula (II), Formula (Ia), Formula (Ib), (Ic), (Id), or (I-d1).

[0017] Xa is selected from CH or N; in some embodiments, Xa is selected from CH; in some embodiments, Xa is selected from N;

[0018] X b is selected from CH or N; in some embodiments, X b is selected from CH; in some embodiments, X b Selected from N;

[0019] The C1 ring is selected from 5-6 membered heteroaryl, phenyl or benzo 5-6 membered cycloalkyl; in some embodiments, the C1 ring is selected from 5-6 membered heteroaryl, phenyl; in some embodiments, the C1 ring is selected from 5 membered heteroaryl, phenyl; in some embodiments, the C1 ring is selected from phenyl;

[0020] Ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl;

[0021] In some embodiments, Ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl;

[0022] In some embodiments, ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, 7-8 membered bicyclic bridged heterocyclyl;

[0023] In some embodiments, ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, 7-8 membered bicyclic bridged heterocyclyl;

[0024] In some embodiments, ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl;

[0025] In some embodiments, ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl;

[0026] In some embodiments, ring A is selected from 4-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered cycloalkyl, 6 membered heterocycloalkyl and 5 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl;

[0027] In some embodiments, ring A is selected from 5-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered cycloalkyl, 6 membered heterocycloalkyl and 5 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl;

[0028] In some embodiments, ring A is selected from 5-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered cycloalkyl, 6 membered heterocycloalkyl and 5 membered cycloalkyl;

[0029] In some embodiments, Ring A is selected from one of the following structures: Or selected from

[0030] In some embodiments, Ring A is selected from one of the following structures: Or selected from Or selected from Or selected from

[0031] Ring B is selected from The left side of the B ring is connected to L1;

[0032] Ring C is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl, and Ring C is not

[0033] In some embodiments, ring C is selected from phenyl, five-membered heteroaryl, six-membered heteroaryl, 5-7-membered heterocycloalkylphenyl, 5-6-membered carbocyclylphenyl, 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl, or 9-12-membered tricyclic heterocycloalkyl, and ring C is not

[0034] In some embodiments, the C ring is selected from 5-7 membered heterocycloalkylphenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 9-12 membered tricyclic heterocycloalkyl, and the ring C is not

[0035] In some embodiments, ring C is selected from 5-7 membered heterocycloalkylphenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, and ring C is not

[0036] In some embodiments, Ring C is selected from one of the following structures: Or selected from

[0037] In some embodiments, Ring C is selected from one of the following structures: Or selected from

[0038] L1 is selected from W1-R La -W2, L1 is connected to A on the left;

[0039] L2 is selected from W3-R Lb -W4, the left side of L2 is connected to B, and L1 and L2 are not bonds at the same time;

[0040] R La 、R Lb Each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0041] In some embodiments, R La 、R Lb Each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0042] In some embodiments, R La 、R Lb Each independently selected from a bond, C 1-2 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0043] In some embodiments, R La 、R Lb Each independently selected from a bond, C 1-2 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0044] In some embodiments, R La 、R Lb Each independently selected from a bond, -CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, or selected from -C(CH3)=CH-, -CH=C(CH3)-, wherein the CH3, CH2, CH are optionally further replaced by 1-4 R L1 replace;

[0045] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkenyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl;

[0046] In some embodiments, R L1 are each independently selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkenyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl;

[0047] In some embodiments, R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl;

[0048] In some embodiments, R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, 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;

[0049] In some embodiments, R L1 are independently selected from halogen, =O, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0050] In some embodiments, RL1 are each independently selected from halogen, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0051] In some embodiments, R L1 are independently selected from halogen, =O, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two adjacent R L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0052] In some embodiments, 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, or two R on the same carbon atom or two adjacent carbon atoms L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0053] In some embodiments, R L1 are each independently selected from halogen, 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, or two R on the same carbon atom or two adjacent carbon atoms L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0054] In some embodiments, 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, or two R on the same carbon atom or two adjacent carbon atoms L1and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0055] In some embodiments, 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, or two adjacent R L1 and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0056] In some embodiments, R L1 Each is independently selected from F, Cl, Br, =O, methyl, ethyl, -CF3, -CHF2, -CH2F, vinyl, propenyl, methoxy, ethoxy, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, or two adjacent R L1 and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0057] W1, W2, W3, and W4 are each independently selected from a bond, -O-, -S-, or -NR W1 -, -Se-, -C(O)-;

[0058] In some embodiments, W1, W2, W3, and W4 are each independently selected from a bond, -O-, -S-, -NR W1 -, -Se-;

[0059] In some embodiments, W1, W2, W3, and W4 are each independently selected from a bond, -O-, -S-, -NR W1 -;

[0060] In some embodiments, W1, W2, W3, and W4 are each independently selected from a bond, -O-, -NR W1 -;

[0061] In some embodiments, W1, W2, W3, and W4 are each independently selected from a bond, -O-;

[0062] R W1 Selected from H, halogen, C 1-4 alkyl;

[0063] In some embodiments, R W1 Selected from H, halogen, C 1-2 alkyl;

[0064] In some embodiments, R W1Selected from H, F, Cl, Br, methyl, ethyl;

[0065] In some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -C(=O)-N(C 1-2 Alkylene)-, -O-, -C(=O)-O-, C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-3 R L1 replace;

[0066] In some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -C(=O)-N(C 1-2 Alkylene)-, -O-, -C(=O)-O-, the alkylene and alkenylene groups are optionally further substituted with 1-3 R L1 replace;

[0067] In some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, -(C 1-2 Alkylene)-Se-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -O-, C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-3 R L1 replace;

[0068] In some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, -(C 1-2 Alkylene)-Se-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -O-, the alkylene and alkenylene groups are optionally further substituted with 1-3 R L1 replace;

[0069] In some embodiments, L1 is selected from a bond, -CH2O-, -CH2CH2O-, -CH2-, -CH2CH2-, -OCH2-, -OCH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, -C(=O)-N(CH3)-, -C(=O)-N(CH2CH3)-, -O-, -C(=O)-O-, or selected from -C(CH3)=CH-, -CH=C(CH3)-, wherein the CH3, CH2, CH are optionally further replaced by 1-3 R L1 replace;

[0070] In some embodiments, L1 is selected from a bond, -CH2-O-, -CH2-Se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, -O-, -C(CH3)=CH-, -CH=C(CH3)-,

[0071] In some embodiments, L1 is selected from a bond, -CH2-O-, -CH2-Se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, -O-;

[0072] In some embodiments, L1 is selected from a bond, -CH2-O-, -CH=CH-, -CH2-, -CH2CH2-, -O-;

[0073] In some embodiments, L1 is selected from a bond, -CH2-O-, -CH=CH-, -CH2-,

[0074] In some embodiments, L1 is selected from -CH2O-, -CH=CH-;

[0075] In some embodiments, L1 is selected from -CH=CH-;

[0076] L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, -NH-, -O-, wherein the alkylene is optionally further substituted with 1-3 R L1 replace;

[0077] In some embodiments, L2 is selected from a bond, C 1-2 Alkylene, -NH-, -O-, the alkylene is optionally further substituted with 1-3 R L1 replace;

[0078] In some embodiments, L2 is selected from a bond, -CH2-, -CH2CH2-, -C(=O)-, -NH-, -O-, wherein the CH3, CH2 are optionally further replaced by 1-3 R L1 replace;

[0079] In some embodiments, L2 is selected from -CH2-;

[0080] R A Each independently selected from halogen, =O, CN, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution;

[0081] In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-NH-R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3;

[0082] In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-R a 、-C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3;

[0083] In some embodiments, R A Each independently selected from =O, C 1-4 Alkyl, -S(O)2-C 1-4Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-2 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3;

[0084] In some embodiments, R A Selected from -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-NH-R a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally further 1-3 selected from halogen, OH, NH2, CN, -S (O) 2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution;

[0085] In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl or -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution;

[0086] In some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-6-8 membered bicyclic heterocycloalkyl, -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a , the alkyl group or heterocycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3;

[0087] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0088] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0089] In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、 -C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3;

[0090] In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally further substituted with 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3;

[0091] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a , the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0092] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0093] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0094] In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a , the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0095] In some embodiments, R AEach independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a , the alkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0096] In some embodiments, R A Each independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-R a 、-S(O)2-(CH2)2-R a 、-C(O)-OR a 、-C(O)-O-CH2-R a 、-CH2-C(O)-R a 、-(CH2)2-C(O)-R a 、-C(O)-CH2-R a 、-C(O)-(CH2)2-R a 、-C(O)-O-halogenated C 1-3 Alkyl, wherein the CH3 and CH2 are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0097] In some embodiments, R AEach independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-R a 、-S(O)2-(CH2)2-R a 、-C(O)-OR a 、-C(O)-O-CH2-R a 、 -CH2-C(O)-R a 、-(CH2)2-C(O)-R a 、-C(O)-CH2-R a 、-C(O)-(CH2)2-R a , the CH3 and CH2 are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0098] In some embodiments, R A Each independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-R a 、-S(O)2-(CH2)2-R a 、-C(O)-OR a 、-C(O)-O-CH2-R a 、-CH2-C(O)-R a 、-(CH2)2-C(O)-R a 、-C(O)-CH2-R a 、-C(O)-(CH2)2-R a 、-C(O)-O-halogenated C 1-3 alkyl;

[0099] In some embodiments, R A Each independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-R a 、-S(O)2-(CH2)2-R a 、-C(O)-OR a 、-C(O)-O-CH2-R a 、-CH2-C(O)-R a 、-(CH2)2-C(O)-R a 、-C(O)-CH2-R a 、-C(O)-(CH2)2-R a ;

[0100] In some embodiments, R A Each is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-3-5-membered cycloalkyl, -S(O)2-CH2-4-6-membered heterocycloalkyl, -S(O)2-CH2-5-6-membered heteroaryl, -S(O)2-(CH2)2 -3-5 membered cycloalkyl, -S(O)2-(CH2)2-4-6 membered heterocycloalkyl, -S(O)2-(CH2)2-5-6 membered heteroaryl, -C(O)-O-3-5 membered cycloalkyl, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-O-5-6 membered heteroaryl, -C(O)-O-CH2-3-5 membered cycloalkyl, -C(O)-O-CH2-4-6 -C(O)-O-CH2-5-6 membered heteroaryl, -CH2-C(O)-3-5 membered cycloalkyl, -CH2-C(O)-4-6 membered heterocycloalkyl, -CH2-C(O)-5-6 membered heteroaryl, -(CH2)2-C(O)-3-5 membered cycloalkyl, -(CH2)2-C(O)-4-6 membered heterocycloalkyl, -(CH2)2-C(O)- 5-6 membered heteroaryl, -C(O)-CH2-3-5 membered cycloalkyl, -C(O)-CH2-4-6 membered heterocycloalkyl, -C(O)-CH2-5-6 membered heteroaryl, -C(O)-(CH2)2-3-5 membered cycloalkyl, -C(O)-(CH2)2-4-6 membered heterocycloalkyl, -C(O)-(CH2)2-5-6 membered heteroaryl, -C(O)-O-halogenated C 1-3 Alkyl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with F, Cl, Br, OH, methyl, ethyl groups;

[0101] In some embodiments, R AEach is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-3-5 membered cycloalkyl, -S(O)2-CH2-4-6 membered heterocycloalkyl, -S(O)2-CH2-5-6 membered heteroaryl, -S(O)2-(CH2)2-3-5 membered cycloalkyl , -S(O)2-(CH2)2-4-6 membered heterocycloalkyl, -S(O)2-(CH2)2-5-6 membered heteroaryl, -C(O)-O-3-5 membered cycloalkyl, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-O-5-6 membered heteroaryl, -C(O)-O-CH2-3-5 membered cycloalkyl, -C(O)-O-CH2-4-6 membered heterocycloalkyl, -C(O)-O-CH 2-5-6 membered heteroaryl, -CH2-C(O)-3-5 membered cycloalkyl, -CH2-C(O)-4-6 membered heterocycloalkyl, -CH2-C(O)-5-6 membered heteroaryl, -(CH2)2-C(O)-3-5 membered cycloalkyl, -(CH2)2-C(O)-4-6 membered heterocycloalkyl, -(CH2)2-C(O)-5-6 membered heteroaryl, -C(O)-CH2-3-5 membered cycloalkyl -C(O)-CH2-4-6 membered heterocycloalkyl, -C(O)-CH2-5-6 membered heteroaryl, -C(O)-(CH2)2-3-5 membered cycloalkyl, -C(O)-(CH2)2-4-6 membered heterocycloalkyl, -C(O)-(CH2)2-5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl and heteroaryl groups are optionally further substituted with F, Cl, Br, OH, methyl and ethyl groups;

[0102] In some embodiments, R A Each independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-O-3-5 membered cycloalkyl, -C(O)-CH2-3-5 membered cycloalkyl, -S(O)2-CH2-3-5 membered cycloalkyl, -C(O)-O-halogenated C 1-3 Alkyl, the cycloalkyl, heterocycloalkyl may be further substituted with F, Cl, Br, OH, methyl, ethyl groups;

[0103] In some embodiments, R A Each is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-O-3-5 membered cycloalkyl, -C(O)-CH2-3-5 membered cycloalkyl, -S(O)2-CH2-3-5 membered cycloalkyl, wherein the cycloalkyl and heterocycloalkyl groups are optionally further substituted with F, Cl, Br, OH, methyl or ethyl groups;

[0104] In some embodiments, R A Each is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-oxetanyl, -C(O)-O-azetidinyl, -C(O)-O-cyclobutyl, -C(O)-O-piperidinyl, -C(O)-CH2-cyclopropyl, -S(O)2-CH2-cyclopropyl, -S(O)2-CH2-cyclobutyl, -S(O)2-CH2-cyclopentyl, -C(O)-O-halogenated C 1-3 Alkyl, the oxetanyl, azetidinyl, cyclobutyl, piperidinyl, cyclopropyl, cyclopentyl are optionally further substituted with F, Cl, Br, OH, methyl, ethyl groups;

[0105] In some embodiments, R A Each independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-oxetanyl, -C(O)-O-azetidinyl, -C(O)-O-cyclobutyl, -C(O)-O-piperidinyl, -C(O)-CH2-cyclopropyl, -S(O)2-CH2-cyclopropyl, -S(O)2-CH2-cyclobutyl, -S(O)2-CH2-cyclopentyl, the oxetanyl, azetidinyl, cyclobutyl, piperidinyl, cyclopropyl, cyclopentyl are optionally further substituted by F, Cl, Br, OH, methyl, ethyl groups;

[0106] In some embodiments, R A Selected from -C(O)-O-(CH2) p -R a 、-C(O)-(CH2) 1-2 -R a 、-NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a ;

[0107] In some embodiments, Select one of the following structures: Or selected from the following structures; Or selected from the following structures: Or selected from the following structures: Or choose

[0108] In some embodiments, Select one of the following structures: Or selected from Or selected from Or selected from

[0109] In some embodiments, Select one of the following structures:

[0110] In some embodiments, Select one of the following structures:

[0111] R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, =O, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 or =CH2 group substitution;

[0112] In some embodiments, R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 group substitution;

[0113] In some embodiments, R a Selected from C 2-4Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 group substitution;

[0114] In some embodiments, R a 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1, 2, 3 or 4 members selected from halogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, or -S(O)2-CH3 group substitution;

[0115] In some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 group substitution;

[0116] In some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, 6 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0117] In some embodiments, R a Selected from deuterated C 1-2 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, =O, -S(O)2-CH3, C 1-2 Alkoxy, deuterated C 1-2 Alkyl radical substitution;

[0118] In some embodiments, R a Selected from C 2-4Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 Alkoxy group substitution;

[0119] In some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0120] In some embodiments, R a Selected from deuterated C 1-2 Alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, OH, =O, C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 1-2 Alkoxy, -S(O)2-CH3 group substitution;

[0121] In some embodiments, R a Selected from deuterated C 1-2 Alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further substituted with halogen, methyl, deuterated methyl, methoxy, ethoxy, OH, =O, or -S(O)2-CH3 groups;

[0122] In some embodiments, R a Selected from ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, OH, C 1-2 Alkyl, C 1-2 Alkoxy, -S(O)2-CH3 group substitution;

[0123] In some embodiments, R a Selected from ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with halogen, methyl, methoxy, ethoxy, OH, -S(O)2-CH3;

[0124] In some embodiments, R a Selected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by halogen, OH, C1-2 Alkyl, -S(O)2-CH3 group substitution;

[0125] In some embodiments, R a Selected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by halogen, OH, C 1-2 In some embodiments, R a Selected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with F, Cl, Br, OH, methyl, ethyl, -S(O)2-CH3 groups;

[0126] In some embodiments, R a is selected from 3-5 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with F, Cl, Br, OH, methyl or ethyl groups;

[0127] In some embodiments, R a Selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl, oxolanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl, oxolanyl are optionally further substituted with F, Cl, Br, OH, methyl, ethyl, -S(O)2-CH3;

[0128] In some embodiments, R a is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl, and oxolanyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxolanyl, and oxolanyl are optionally further substituted with F, Cl, Br, OH, methyl, and ethyl groups;

[0129] R C Each independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se-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, -O-(CH2) p -C 3-6Cycloalkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group;

[0130] In some embodiments, R C are independently selected from H, 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, -O-(CH2) p -C 3-6 Cycloalkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group;

[0131] In some embodiments, R C are independently selected from H, 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;

[0132] In some embodiments, R C Each independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se-halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, =O, C 3-6 Cycloalkyl, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 alkyl)2, -(CH2) p -OC 1-4 Alkyl, -O-(CH2) p -C 3-6 Cycloalkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0133] In some embodiments, R C are independently selected from H, 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 their connecting atoms together form a 3-6 membered cycloalkyl group;

[0134] In some embodiments, R C Selected from F, Cl, halogenated C 1-2 Alkyl, C 2-4 Alkynyl, 3-4 membered cycloalkyl, -OC 3-4 Cycloalkyl;

[0135] In some embodiments, R C is selected from F, Cl, CHF2, CF3, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl;

[0136] In some embodiments, R C Selected from CF3;

[0137] In some embodiments, R CEach is independently selected from H, CN, F, Cl, Br, OH, -SF5, methyl, difluoromethyl, trifluoromethyl, ethyl, ethynyl, cyclopropyl, -O-cyclopropyl, -O-CH2-cyclopropyl, cyclobutyl, -O-cyclobutyl, -O-CH2-cyclobutyl, -Se-trifluoromethyl, or any two R C and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0138] 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, Or any two R C and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0139] In some embodiments, R C Each is independently selected from H, F, Cl, Br, OH, methyl, ethyl, cyclopropyl, cyclobutyl, trifluoromethyl, ethynyl, or any two R C and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0140] In some embodiments, R C Each independently selected from H, F, Cl, Br, OH, methyl, ethyl, cyclopropyl, cyclobutyl, or any two R C and their connecting atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0141] In some embodiments, Select one of the following structures: Or selected from Or selected from Or selected from

[0142] q is selected from 0 or 1;

[0143] In some embodiments, q is selected from 0;

[0144] In some embodiments, q is selected from 1;

[0145] p is each independently selected from 0, 1, 2, 3, or 4;

[0146] In some embodiments, p is each independently selected from 0, 1, 2, or 3;

[0147] In some embodiments, p is each independently selected from 0, 1, or 2;

[0148] m is selected from 1, 2, 3, or 4;

[0149] In some embodiments, m is selected from 1, 2, or 3;

[0150] In some embodiments, m is selected from 1, or 2;

[0151] In some embodiments, m is selected from 1;

[0152] n is selected from 1, 2, 3, or 4;

[0153] In some embodiments, n is selected from 1, 2, or 3;

[0154] In some embodiments, n is selected from 1, or 2;

[0155] In some embodiments, n is selected from 1;

[0156] The condition is,

[0157] (1) When ring A is selected from When R A Not -S(O)2-(CH2) 0-1 CH3, and Not for

[0158] (2) When R A Selected from -S(O)2-(CH2) 0-1 When CH3, the A ring is not and Not for

[0159] (3) When the C ring is selected from When R C is not H, and Not for

[0160] (4) When R C When only H is selected, the C ring is not and Not for

[0161] As a more specific first technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0162] Ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl; in some embodiments, Ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl;

[0163] Ring B is selected from The left side of the B ring is connected to L1;

[0164] Ring C is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl, and Ring C is not

[0165] L1 is selected from W1-R La -W2, L1 is connected to A on the left;

[0166] L2 is selected from W3-R Lb -W4, the left side of L2 is connected to B, and L1 and L2 are not bonds at the same time;

[0167] R La 、R Lb Each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0168] R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkenyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl; in some embodiments, R L1 are each independently selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkenyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl; in some embodiments, R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl; in some embodiments, R L1 are independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, 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;

[0169] W1, W2, W3, and W4 are each independently selected from a bond, -O-, -S-, or -NR W1 -, -Se- or -C(O)-; in some embodiments, W1, W2, W3, W4 are each independently selected from a bond, -O-, -S-, -NR W1 -;

[0170] R W1 Selected from H, halogen, C 1-4 alkyl;

[0171] R AEach independently selected from halogen, =O, CN, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3; In some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl or -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3; In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-6-8 membered bicyclic heterocycloalkyl, -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a The alkyl, alkenyl, alkynyl, and heterocycloalkyl groups are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2)1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0172] R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, =O, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 alkyl, -S(O)2-CH3 or =CH2; in some embodiments, R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 alkyl, -S(O)2-CH3; in some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 alkyl, -S(O)2-CH3; in some embodiments, R a Selected from C 2-4Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl The alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 group substitution;

[0173] R C Each independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se-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, -O-(CH2) p -C 3-6 Cycloalkyl 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 are independently selected from H, 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, -O-(CH2) p -C 3-6 Cycloalkyl 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 are independently selected from H, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C2-4 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;

[0174] q is selected from 0 or 1;

[0175] p is each independently selected from 0, 1, 2, 3, or 4;

[0176] m is selected from 1, 2, 3, or 4;

[0177] n is selected from 1, 2, 3, or 4;

[0178] The condition is,

[0179] (1) When ring A is selected from When R A Not -S(O)2-(CH2) 0-1 CH3, and Not for

[0180] (2) When R A Selected from -S(O)2-(CH2) 0-1 When CH3, the A ring is not and Not for

[0181] (3) When the C ring is selected from When R C is not H, and Not for

[0182] (4) When R C When only H is selected, the C ring is not and Not for

[0183] As a more specific second technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein:

[0184] Ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, 7-8 membered bicyclic bridged heterocyclyl; in some embodiments, Ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, cycloalkyl, 7-8 membered bicyclic bridged heterocyclyl; in some embodiments, ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl; in some embodiments, ring A is selected from 5-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl;

[0185] Ring C is selected from phenyl, five-membered heteroaryl, six-membered heteroaryl, 5-7-membered heterocycloalkylphenyl, 5-6-membered carbocyclylphenyl, 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl, or 9-12-membered tricyclic heterocycloalkyl;

[0186] R La 、R Lb Each independently selected from a bond, C 1-2 Alkylene, C 2-4 Alkenylene or C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-4 R L1 replace;

[0187] R L1 are independently selected from halogen, =O, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atomsL1 and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R L1 are each independently selected from halogen, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R L1 are independently selected from halogen, =O, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two adjacent R L1 and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0188] R W1 Selected from H, halogen, C 1-2 alkyl;

[0189] R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-NH-R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、 -C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p-(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl or -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-6-8 membered bicyclic heterocycloalkyl, -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a , the alkyl, alkenyl, alkynyl, heterocycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3; In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a , the alkyl, alkenyl, alkynyl are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN;

[0190] R a Selected from deuterated C 1-2 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, =O, -S(O)2-CH3, C 1-2 Alkoxy, deuterated C 1-2 alkyl or =CH2; in some embodiments, R a Selected from deuterated C 1-2 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 In some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 In some embodiments, R a Selected from C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0191] R C Each independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se-halogenated C 1-2 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, -O-(CH2) p -C 3-6 Cycloalkyl 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 are independently selected from H, 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, -O-(CH2) p -C3-6 Cycloalkyl 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 are independently selected from H, 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 their connecting atoms together form a 3-6 membered cycloalkyl group;

[0192] p is each independently selected from 0, 1, 2, or 3;

[0193] m is selected from 1, 2, or 3;

[0194] n is selected from 1, 2, or 3;

[0195] The remaining groups are as described in the first technical solution.

[0196] As a more specific third technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein,

[0197] Ring A is selected from 4-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 5 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered cycloalkyl, 6 membered heterocycloalkyl and 5 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl; in some embodiments, Ring A is selected from 5-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl 6-membered heterocycloalkyl, 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl, 5-membered heterocycloalkyl and 5-membered cycloalkyl, 6-membered heterocycloalkyl and 5-membered cycloalkyl, 4-membered cycloalkyl spiro 6-membered heterocycloalkyl, 5-membered cycloalkyl spiro 6-membered heterocycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl; in some embodiments, ring A is selected from 5-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-membered heterocycloalkyl and 5-membered heterocycloalkyl, 5-membered heterocycloalkyl and 6-membered heterocycloalkyl, 5-membered heterocycloalkyl spiro 5-membered heterocycloalkyl, 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl, 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl, 5-membered heterocycloalkyl and 5-membered cycloalkyl, 6-membered heterocycloalkyl and 5-membered cycloalkyl;

[0198] The C ring is selected from 5-7 membered heterocycloalkylphenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, and 9-12 membered tricyclic heterocycloalkyl; in some embodiments, the C ring is selected from 5-7 membered heterocycloalkylphenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl;

[0199] R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-R a、-C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4Alkyl or -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-6-8 membered bicyclic heterocycloalkyl, -N(CH3)-C(O)-(CH2) p -R a , the alkyl, alkenyl, alkynyl, heterocycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3; In some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a or selected from -C(O)-O-halogenated C 1-4Alkyl, wherein the alkyl, alkenyl, alkynyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R A Each independently selected from halogen, CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a , the alkyl, alkenyl, and alkynyl groups are optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0200] R a Selected from deuterated C 1-2 Alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, OH, =O, C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 1-2 alkoxy, -S(O)2-CH3 or =CH2; in some embodiments, R a Selected from deuterated C 1-2 Alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, OH, C 1-2 Alkyl, C 1-2 Alkoxy, -S(O)2-CH3; In some embodiments, R a Selected from ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by halogen, OH, C 1-2 Alkyl, C 1-2 Alkoxy, -S(O)2-CH3; In some embodiments, R a Selected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by halogen, OH, C 1-2 alkyl or -S(O)2-CH3; in some embodiments, R aSelected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by halogen, OH, C 1-2 Alkyl radical substitution;

[0201] p is each independently selected from 0, 1, or 2;

[0202] m is selected from 1, 2, or 3;

[0203] n is selected from 1, 2, or 3;

[0204] The remaining groups are as described in the second technical solution.

[0205] As a more specific fourth technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein,

[0206] Ring A is selected from one of the following structures: Or selected from Or selected from Or selected from Or selected from Or selected from

[0207] Ring C is selected from one of the following structures: Or selected from Or selected from Or selected from

[0208] L1 is selected from a bond, -(C 1-2 Alkylene)-O-, -(C 1-2 Alkylene)-Se-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -C(=O)-N(C 1-2 Alkylene)-, -O-, -C(=O)-O- or C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-3 R L1 In some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, -(C 1-2 Alkylene)-Se-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C2-4 Alkenylene, -O- or C 2-4 Alkyne, the alkylene, alkenylene optionally further 1-3 R L1 Substituted; in some embodiments, L1 is selected from a bond, -(C 1-2 Alkylene)-O-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -C(=O)-N(C 1-2 Alkylene)-, -O-, -C(=O)-O-, the alkylene and alkenylene groups are optionally further substituted with 1-3 R L1 replace;

[0209] L2 is selected from a bond, C 1-2 Alkylene, -C(=O)-, -NH-, -O-, wherein the alkylene is optionally further substituted with 1-3 R L1 In some embodiments, L2 is selected from a bond, C 1-2 Alkylene, -NH-, -O-, the alkylene is optionally further substituted with 1-3 R L1 replace;

[0210] 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, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R L1 are each independently selected from halogen, 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, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, 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;

[0211] R AEach independently selected from =O, C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、 -NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-2 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from =O, C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2)1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-2 Alkyl or -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; in some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-6-8 membered bicyclic heterocycloalkyl, -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a, the alkyl group or heterocycloalkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3; in some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -NH-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a , the alkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN; in some embodiments, R A Each independently selected from -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a , the alkyl group is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, and CN;

[0212] R a Selected from deuterated C1-2 alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted with halogen, methyl, deuterated methyl, methoxy, ethoxy, OH, =O, -S(O)2-CH3 or =CH2; in some embodiments, R a Selected from deuterated C 1-2 alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are optionally further substituted with halogen, methyl, methoxy, ethoxy, OH, or -S(O)2-CH3; in some embodiments, R a is selected from ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted by halogen, methyl, methoxy, ethoxy, OH, -S(O)2-CH3; in some embodiments, R a is selected from 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted by halogen, methyl, OH or -S(O)2-CH3; in some embodiments, R a Selected from 3-5 membered cycloalkyl and 4-6 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with halogen, methyl or OH groups;

[0213] R C Each is independently selected from H, CN, F, Cl, Br, OH, -SF5, methyl, difluoromethyl, trifluoromethyl, ethyl, ethynyl, cyclopropyl, -O-cyclopropyl, -O-CH2-cyclopropyl, cyclobutyl, -O-cyclobutyl, -O-CH2-cyclobutyl, -Se-trifluoromethyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C Each is independently selected from H, F, Cl, Br, OH, -SF5, methyl, difluoromethyl, trifluoromethyl, ethyl, ethynyl, cyclopropyl, -O-cyclopropyl, -O-CH2-cyclopropyl, cyclobutyl, -O-cyclobutyl, -O-CH2-cyclobutyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; in some embodiments, R C Each is independently selected from H, F, Cl, Br, OH, methyl, ethyl, cyclopropyl, cyclobutyl, trifluoromethyl, ethynyl, 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 H, F, Cl, Br, OH, methyl, ethyl, cyclopropyl, cyclobutyl, or any two RC and their connecting atoms together form a 3-6 membered cycloalkyl group;

[0214] p is each independently selected from 0, 1, or 2;

[0215] m is selected from 1, or 2;

[0216] n is selected from 1, or 2;

[0217] The remaining groups are as described in the third technical solution.

[0218] As a more specific fifth technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein,

[0219] Select one of the following structures: Or selected from Or selected from Or selected from Or selected from Or selected from Or selected from Or selected from Or selected from

[0220] Select one of the following structures: Or selected from Or selected from Or selected from Or selected from Or selected from

[0221] L1 is selected from a bond, -CH2-O-, -CH2-Se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, -O- or -C(CH3)=CH-, -CH=C(CH3)- or In some embodiments, L1 is selected from a bond, -CH2-O-, -CH=CH-, -CH2-, -CH2CH2-, -O-; In some embodiments, L1 is selected from -CH2-O-, -CH=CH-, a bond, -CH2-, In some embodiments, L1 is selected from -CH2-O-, -CH=CH-;

[0222] L2 is selected from -CH2-;

[0223] The remaining groups are as described in the fourth technical solution.

[0224] As a more specific sixth technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound has the structure of formula (Ia) or (Ic):

[0225] in,

[0226] Xa is selected from CH or N;

[0227] X b Selected from CH or N;

[0228] The C1 ring is selected from 5-6 membered heteroaryl, phenyl or benzo 5-6 membered cycloalkyl;

[0229] The remaining groups are as described in any of the above technical solutions.

[0230] As a more specific seventh technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound has the structure of formula (Ia):

[0231] in,

[0232] Xa is selected from CH or N;

[0233] The remaining groups are as described in any of the above technical solutions.

[0234] As a more specific eighth technical solution of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, wherein the compound has the structure of formula (Ic):

[0235] in,

[0236] Xa is selected from CH or N;

[0237] X b Selected from CH or N;

[0238] The C1 ring is selected from 5-6 membered heteroaryl, phenyl or benzo 5-6 membered cycloalkyl;

[0239] The remaining groups are as described in any of the above technical solutions.

[0240] As a more specific ninth technical solution of the present invention, a compound represented by formula (I), (Ia), or (Ic), its stereoisomer, tautomer, deuterated form, solvate, cocrystal, or pharmaceutically acceptable salt,

[0241] R A Selected from -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-NH-R a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 Alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2Alkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally further 1-3 selected from halogen, OH, NH2, CN, -S (O) 2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution;

[0242] R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, =O, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 or =CH2 group substitution;

[0243] R C Selected from F, Cl, halogenated C 1-2 Alkyl, C 2-4 Alkynyl, 3-4 membered cycloalkyl, -OC 3-4 Cycloalkyl;

[0244] L1 is selected from -(C 1-2 Alkylene)-O-, C 1-2 Alkylene, C 2-4 alkenylene, -C(O)-NH-;

[0245] n is selected from 1 or 2;

[0246] p is selected from 0, 1 or 2;

[0247] The remaining groups are as described in any of the above technical solutions.

[0248] As a more specific tenth technical solution of the present invention, a compound represented by formula (I), (Ia), or (Ic), its stereoisomers, tautomers, deuterated substances, solvates, cocrystals, or pharmaceutically acceptable salts,

[0249] R A Selected from -C(O)-O-(CH2) p -R a 、-C(O)-(CH2) 1-2 -R a 、-NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a、-NH-C(O)-OR a ;

[0250] R a 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-4 members selected from halogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, or -S(O)2-CH3 group substitution;

[0251] R C is selected from F, Cl, CHF2, CF3, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl;

[0252] The remaining groups are as described in any of the above technical solutions.

[0253] As a more specific eleventh technical solution of the present invention, a compound represented by formula (I) or (Ia), its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein

[0254] L1 is selected from -CH=CH-;

[0255] The remaining groups are as described in any of the above technical solutions.

[0256] As a specific technical solution of the present invention, the compound of the present invention, its stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, is selected from one of the following structures:

[0257] Table 1

[0258] The present invention also provides a pharmaceutical composition or pharmaceutical preparation comprising the compound described in any one of the aforementioned schemes, its stereoisomers, tautomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

[0259] 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 stereoisomers, tautomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts and a carrier and / or excipient.

[0260] The present invention also provides the use of a compound according to any of the foregoing schemes, a stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, or a composition according to any of the foregoing 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.

[0261] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any of the preceding embodiments, or a stereoisomer, tautomer, deuterated form, solvate, or pharmaceutically acceptable salt thereof, preferably 1-1500 mg. The disease is preferably prostate cancer. In some embodiments, the mammal of the present invention includes a human.

[0262] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses 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, 1-40 mg, 1-25 mg, 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, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 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, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0263] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, cocrystal, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 0 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof.

[0264] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably prostate cancer.

[0265] A method for treating a disease in a mammal, comprising administering a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-100 In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0266] 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, deuterated substance or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance or pharmaceutically acceptable salt is the same as its amount in the above-mentioned pharmaceutical composition.

[0267] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0268] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0269] Synthesis route

[0270] Patent documents such as WO2018115591A1 describe methods for preparing CYP11A1 inhibitors. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0271] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, 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 facilities, many of which standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0272] the term

[0273] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0274] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0275] "Halo" or "halogen substitution" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens.

[0276] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one isotope, deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, more preferably 1-10 deuterium atoms, more preferably 1-6 deuterium atoms, and even more preferably 1-3 deuterium atoms.

[0277] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, further preferably an alkyl group having 1 to 4 carbon atoms, and further preferably an alkyl group having 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 chain isomers thereof.

[0278] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0279] "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.

[0280] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", non-limiting examples of which include cyclopropylene, cyclobutylene, and the like.

[0281] "Heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, and includes monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles. Unless otherwise specified, it is a 3- to 14-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. This definition includes heterocycloalkyl and heteroaryl groups. The nitrogen and sulfur atoms in the heterocyclyl 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-dioxane, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, pyranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, wait.

[0282] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolylene, piperidinylene, aziridinylene, and the like.

[0283] "Carbocycle" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., unless otherwise specified, and 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.

[0284] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0285] "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.

[0286] "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 include ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0287] "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-hexoxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0288] "Haloalkoxy" refers to -O-haloalkyl, unless otherwise specified, -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0289] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0290] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

[0291] "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.

[0292] "Heterocycloalkyl" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, 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.

[0293] "AlkylNH2" or "alkaneNH2" 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 monoalkylNH2. Non-limiting examples include dimethylNH2, monomethylNH2, diethylNH2, monoethylNH2, etc.

[0294] The term "vinyl group" refers to a vinyl group (-CH=CH-), including a cis-form, a trans-form, or a mixture of cis- and trans-forms.

[0295] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0296] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0297] 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.

[0298] "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 target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0299] "Excipient" refers to a substance that is not itself a therapeutic agent and 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 provide various 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., sodium cross-linked carboxymethylcellulose); (4) tragacanth; (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.

[0300] "Isomers" include "stereoisomers" and "tautomers." "Stereoisomers" refer to isomers in which the atoms or groups of atoms in a molecule have the same order of attachment but different spatial arrangements. Stereoisomers include cis-trans isomers, optical isomers, and conformational isomers. "Tautomers" refer to compounds that can be converted into each other through a reversible chemical reaction called tautomerization, usually caused by the concomitant migration of hydrogen atoms and π bonds (double or triple bonds). Examples include the following pairs of compounds: aldehyde / ketone-enol, imine-enamine.

[0301] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0302] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0303] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0304] Dess-Martin reagent: 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxyl-3-(1H)-one

[0305] DIPEA: N,N-diisopropylethylamine

[0306] NMP: N-methylpyrrolidone

[0307] TBDMSCl: tert-butyldimethylsilyl chloride

[0308] DMAP: 4-dimethylaminopyridine

[0309] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0310] T3P: Propylphosphonic acid tricyclic anhydride

[0311] Intermediate 1:

[0312] 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, the reaction solution was filtered, and the filter cake was slurried with 100 mL of petroleum ether, filtered, and dried to obtain Intermediate 1 (29.8 g, yield: 90%).

[0313] LCMS (ESI): m / z = 161.2 [M+H]

[0314] 1 H NMR (400MHz, DMSO) δ8.12(s,1H),6.57(s,1H),4.66(s,2H).

[0315] Intermediate 2:

[0316] first step:

[0317] Compound 2a (2 g, 9.30 mmol) and triethylamine (2.82 g, 27.9 mmol) were dissolved in dichloromethane (8 mL). Methanesulfonyl chloride (1.28 g, 11.16 mmol) was slowly added dropwise under an ice bath. The mixture was allowed to warm to room temperature after completion of the addition. After 3 h, TLC confirmed the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the target compound, Intermediate 2 (2.74 g).

[0318] LC-MS (ESI): m / z = 294.1 [M+H] + .

[0319] Example 1:

[0320] first step:

[0321] 1A (1 g, 7.29 mmol), intermediate 1 (1.29 g, 8.02 mmol), and DIPEA (2.83 g, 21.87 mmol) were dissolved in acetonitrile (15 mL) and allowed to react overnight at room temperature. After completion, the reaction solution was concentrated, and 25 mL of water was added to the residue. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 1B (1.08 g, 58% yield).

[0322] LC-MS (ESI): m / z = 262.2 [M+H] + .

[0323] Step 2:

[0324] 1B (1.08 g, 4.13 mmol), intermediate 2 (1.33 g, 4.54 mmol), and potassium carbonate (1.71 g, 12.39 mmol) were dissolved in DMF (25 mL) and reacted at 70°C under a nitrogen atmosphere for 3 h. After the reaction was complete, the mixture was cooled to room temperature, and 40 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were 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 1C (1.47 g, 78% yield).

[0325] LC-MS (ESI): m / z = 459.6 [M+H] + .

[0326] Step 3:

[0327] 1C (1.47 g, 3.21 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (10 mL) and allowed to react at room temperature for 3 h. After completion, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 1D (1.01 g, 88% yield).

[0328] LC-MS (ESI): m / z = 359.4 [M+H] + .

[0329] Step 4:

[0330] 1D (200 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (227 mg, 2.24 mmol) was added. Cyclopropylmethanesulfonyl chloride (130 mg, 0.84 mmol) was then added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react overnight at room temperature. 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 x 3). The combined organic layers were 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) = 20:1) to afford compound 1 (58 mg, 22% yield).

[0331] 1H NMR (400MHz, CDCl3) δ7.53(s,1H),7.08-7.04(m,1H),6.87-6.81(m,2H),6.41(s,1H),3.96-3.92(m,4H),3.84-3.78(m,2H),3.69(s,2H) ),3.68-3.66(m,2H),2.80-2.71(m,4H),2.01-1.86(m,3H),1.39-1.27(m,2H),1.10-0.99(m,1H),0.67-0.60(m,2H),0.31-0.26(m,2H).

[0332] LC-MS (ESI): m / z = 477.5 [M+H] + .

[0333] Example 2:

[0334] first step:

[0335] 1D (200 g, 0.56 mmol) and triethylamine (227 mg, 2.24 mmol) were dissolved in dichloromethane (1 mL). p-Nitrophenyl chloroformate (124 mg, 0.62 mmol) was added dropwise under a nitrogen atmosphere and ice-cooled. The mixture was allowed to react overnight at room temperature. After the reaction was complete, 25 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford 2A (178 mg, 61% yield).

[0336] LC-MS (ESI): m / z = 524.6 [M+H] + .

[0337] Step 2:

[0338] Oxetane-3-ol (101 mg, 1.36 mmol) was dissolved in tetrahydrofuran (4 mL). 60% sodium hydride (27 mg, 0.68 mmol) was added under a nitrogen atmosphere and ice-cooled. After stirring for 15 min, a solution of 2A (178 mg, 0.34 mmol) in DMF (3 mL) was added dropwise and allowed to react at room temperature for 2 h. After the reaction was complete, 15 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (15 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 afford compound 2 (47 mg, 30% yield).

[0339] 1 H NMR(400MHz, CDCl3)δ7.53(s,1H),7.09-7.04(m,1H),6.87-6.81(m,2H),6.41(s,1H),5.36-5.28(m,1H),4.83-4.79(m,2H),4.61-4.56(m, 2H),4.15-4.09(m,2H),3.96-3.92(m,4H),3.71-3.63(m,4H),2.88-2 .66(m,2H),2.04-1.96(m,1H),1.86-1.77(m,2H),1.25-1.14(m,2H).

[0340] LC-MS (ESI): m / z = 459.1 [M+H] + .

[0341] Example 3:

[0342] first step:

[0343] In a 1000 mL single-necked flask, 3A (12 g, 161.99 mmol) was dissolved in dry dichloromethane (480 mL). Triethylamine (40.98 g, 404.98 mmol) was added under ice-cooling. After the addition, p-nitrophenyl chloroformate (39.18 g, 194.39 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was washed twice with saturated aqueous sodium carbonate (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 5:1) to obtain compound 3B (18 g, 46% yield).

[0344] Step 2:

[0345] In a 500 mL single-necked flask, compound 3B (18 g, 75.26 mmol) was dissolved in dry dichloromethane (360 mL). Triethylamine (26.65 g, 263.41 mmol) was added under ice-cooling. After the addition, 4-hydroxymethylpiperidine (13.00 g, 122.89 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (300 mL). The organic phase was washed twice with water (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3C (14.4 g).

[0346] Step 3:

[0347] In a 500 mL single-necked flask, compound 3C (14.4 g, 66.90 mmol) was dissolved in dry dichloromethane (250 mL). Triethylamine (23.70 g, 234.17 mmol) was added under ice-cooling. After the addition, p-toluenesulfonyl chloride (14.03 g, 73.59 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (300 mL). The organic phase was washed twice with water (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 2:1) to obtain compound 3D (20 g, 81% yield).

[0348] Step 4:

[0349] 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 mixture was reacted at room temperature for 3 h. LCMS analysis showed that the reaction of the starting material 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 4D (0.3 g, yield: 91%).

[0350] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0351] Step 5:

[0352] Compound 4D (150 mg, 0.57 mmol) was dissolved in DMF (10 mL), and 3D (211 mg, 0.57 mmol) and potassium carbonate (158 mg, 1.14 mmol) were added. The mixture was stirred at 80°C overnight. The reaction was completed by TLC. Water (20 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain compound 3 (48 mg, yield 18.3%).

[0353] 1H NMR(400MHz, CDCl3)δ7.59(s,1H),7.11-7.07(m,1H),6.72-6.69(m,1H),6.48(s,1H),5.43-5.35(m,1H),4.91-4.84(m,2H),4.68-4.63(m,2H) ,4.23-4.14(m,2H),3.76-3.70(m,2H),3.65(s,2H),3.58(s,2H),2.96 -2.89(m,4H),2.10-2.00(m,1H),1.94-1.83(m,2H),1.36-1.20(m,4H).

[0354] LC-MS (ESI): m / z = 461.2 [M+H] +.

[0355] Example 4:

[0356] first step:

[0357] 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 mixture was reacted at room temperature for 3 h. LCMS analysis showed that the reaction of the starting material 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 4A (0.3 g, yield: 91%).

[0358] LC-MS (ESI): m / z = 264.1 [M+H] + .

[0359] Step 2:

[0360] Compound 4A (150 mg, 0.57 mmol) was dissolved in DMF (10 mL), and 3D (211 mg, 0.57 mmol) and potassium carbonate (158 mg, 1.14 mmol) were added. The mixture was stirred at 80°C overnight. The reaction was completed by TLC. Water (20 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to obtain compound 4 (56 mg, yield 21.3%).

[0361] 1H NMR(400MHz, CDCl3)δ7.59(s,1H),7.13-7.09(m,1H),6.81-6.76(m,1H),6. 48(s,1H),5.44-5.34(m,1H),4.92-4.83(m,2H),4.69-4.61(m,2H),4.24-4. 14(m,2H),3.80(s,2H),3.77-3.70(m,2H),3.59(s,2H),2.91-2.87(m,2H), 2.79-2.75(m,2H),2.10-2.00(m,1H),1.96-1.80(m,2H),1.35-1.20(m,4H).

[0362] LC-MS (ESI): m / z = 461.60 [M+H] + .

[0363] Example 5:

[0364] first step:

[0365] In a 500 mL single-necked flask, 5A (20 g, 169.21 mmol) was dissolved in glacial acetic acid (200 mL). Paraformaldehyde (5.08 g, 169.21 mmol) was added under ice-cooling. After the addition, a 40% hydrobromic acid-glacial acetic acid solution (100 mL, 169.21 mmol) was slowly added dropwise under ice-cooling. After stirring at room temperature for 30 min, the mixture was slowly heated to 80°C and allowed to react overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate (500 mL). The organic phase was washed three times with water (300 mL), twice with saturated sodium bicarbonate solution (100 mL), and once with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:0) to afford compound 5B (28 g, 54% yield).

[0366] Step 2:

[0367] Compound 5B (28 g, 92.10 mmol) was dissolved in ethanol (280 ml), and potassium carbonate (44.55 g, 322.82 mmol) was added. Benzylamine (24.67 g, 230.25 mmol) was slowly added dropwise under an ice bath. The mixture was allowed to react at 80°C for 4 hours. After the reaction was complete, the reaction solution was padded with celite, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 40:1) to obtain compound 5C (9.4 g, 40% yield).

[0368] Step 3:

[0369] Compound 5C (9.40 g, 92.10 mmol) was dissolved in methanol (940 ml), and palladium on carbon (0.8 g, 7.52 mmol) was added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight at 40°C. After the reaction was complete, the reaction solution was padded with celite, filtered, and the filtrate was concentrated to obtain compound 5D (4.6 g).

[0370] Step 4:

[0371] In a 1000 mL single-necked flask, 5E (12 g, 161.99 mmol) was dissolved in dry dichloromethane (480 mL). Triethylamine (40.98 g, 404.98 mmol) was added under ice-cooling. After the addition, p-nitrophenyl chloroformate (39.18 g, 194.39 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was washed twice with saturated aqueous sodium carbonate (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 5:1) to provide compound 5F (18 g, 46% yield).

[0372] Step 5:

[0373] In a 500 mL single-necked flask, compound 5F (18 g, 75.26 mmol) was dissolved in dry dichloromethane (360 mL). Triethylamine (26.65 g, 263.41 mmol) was added under ice-cooling. After the addition, 4-hydroxymethylpiperidine (5G) (13.00 g, 122.89 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (300 mL). The organic phase was washed twice with water (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5H (14.4 g).

[0374] Step 6:

[0375] In a 500 mL single-necked flask, compound 5H (14.4 g, 66.90 mmol) was dissolved in dry dichloromethane (250 mL). Triethylamine (23.70 g, 234.17 mmol) was added under ice-cooling. After the addition, p-toluenesulfonyl chloride (14.03 g, 73.59 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (300 mL), and the organic phase was washed twice with water (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 2:1) to obtain compound 5I (20 g, 81% yield).

[0376] Step 7:

[0377] In a 250 mL single-necked flask, compound 5I (9.5 g, 25.72 mmol) was dissolved in dry N,N-dimethylformamide (125 mL). Potassium carbonate (12.44 g, 90.02 mmol) and kojic acid (14.03 g, 73.59 mmol) were added. After stirring at room temperature for 30 min, the mixture was slowly heated to 100°C and allowed to react overnight. Upon completion of the reaction, the reaction solution was diluted with ethyl acetate (500 mL). The organic phase was washed three times with water (375 mL) and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:1) to afford compound 5J (8.4 g, 96% yield).

[0378] Step 8:

[0379] In a 100 mL single-necked flask, compound 5J (250 mg, 0.74 mmol) was dissolved in dry dichloromethane (15 mL). Triethylamine (262 mg, 2.59 mmol) was added under ice-cooling. After the addition, methanesulfonyl chloride (127 mg, 1.11 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (100 mL). The organic phase was washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5K (310 mg).

[0380] Step 9:

[0381] In a 100 mL single-necked flask, compound 5K (310 mg, 0.74 mmol) was dissolved in dry dichloromethane (15 mL). Triethylamine (260 mg, 2.59 mmol) was added under ice-cooling. After the addition, compound 5D (140 mg, 0.89 mmol) was slowly added under ice-cooling and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (100 mL). The organic phase was washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 30%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 5.

[0382] LCMS m / z=481.2[M+H] + .

[0383] Example 6:

[0384] first step:

[0385] Compound 6A (4.0 g, 13.4 mmol) and trimethylsilyl acetylene (13.2 g, 134 mmol) were dissolved in 50 mL of tetrahydrofuran. Bis(triphenylphosphine)palladium dichloride (941 mg, 1.34 mmol) and triethylamine (5.5 g, 53.6 mmol) were added and the mixture was sealed and reacted at 50°C for 4 h. After completion of the reaction, the reaction solution was added dropwise to 100 mL of ice water and extracted with dichloromethane (200 mL x 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 15:1) to obtain the target compound 6B (3.6 g, 85% yield).

[0386] LCMS(ESI): m / z=260.1[M+H-tBu]

[0387] Step 2:

[0388] Compound 6B (3.60 g, 11.4 mmol) was dissolved in 10 mL of anhydrous dioxane. 10 mL of 4 M hydrochloric acid in dioxane was added and the mixture was allowed to react at room temperature for 8 h. LCMS confirmed the completion of the reaction and the absence of hydrochloric acid addition product. Excess solvent was removed by vortexing, and the residue 6C (TMS protecting group partially removed in this step) was used directly in the next step (2.38 g).

[0389] LCMS (ESI): m / z = 216.2 [M+H]

[0390] Step 3:

[0391] Crude product 6C (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 completion of the reaction, the mixture was filtered, and the filtrate was concentrated. The target compound 6D (1.39 g, 83% yield over two steps) was isolated by silica gel column chromatography (PE:EA = 1:1).

[0392] LCMS (ESI): m / z = 144.2 [M+H]

[0393] Step 4:

[0394] Compound 6D (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 and allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was added dropwise to 20 mL of ice water and extracted with dichloromethane (50 mL x 3). The organic phases were combined, concentrated, and separated by silica gel column chromatography to yield the target compound 6E (DCM:MeOH = 15:1) (620 mg, 24% yield).

[0395] LCMS (ESI): m / z = 268.3 [M+H]

[0396] Step 5:

[0397] Using 6E and 5I as raw materials, compound 6 was obtained by referring to the synthesis procedure of step 7 of Example 5.

[0398] LC-MS (ESI): m / z = 465.3 [M+H] + .

[0399] 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),7.25-7.16(m,4H),6.49(s,1H),5.16-5.08(m,1H),4.25-4.12(m,4H),4.07(s,4H),4 .02-3.97(m,2H),3.79(s,2H),3.75-3.71(m,2H),2.89(s,5H),2.09-2.02(m,1H),1.93-7.84(m,2H),1.33-1.21(m,2H).

[0400] Example 7:

[0401] first step:

[0402] 5-(Trifluoromethyl)isoindole (0.45 g, 2.42 mmol) and Intermediate 1 (0.47 g, 2.93 mmol) were dissolved in acetonitrile (20 mL), and DIPEA (0.47 g, 3.63 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using a Biotage Isolera One medium-pressure prep system (12 g silica gel column, eluent: 0-8% MeOH / DCM) to afford Compound 7B (0.38 g, 50.4% yield).

[0403] LC-MS (ESI): m / z = 312.3 [M+H] + .

[0404] Step 2:

[0405] Compound 7B (0.37 g, 1.19 mmol) and intermediate 2 (0.42 g, 1.43 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.21 g, 1.55 mmol) was added, and the reaction was allowed to proceed at 80°C overnight. LCMS showed that the reaction of the starting material was complete, and the reaction solution was poured into ice water for quenching. The product 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 using a medium-pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 7C (0.26 g, yield 42.9%).

[0406] LC-MS(ESI):m / z=409.2[M+H-100] + .

[0407] Step 3:

[0408] Compound 7C (0.26 g, 0.51 mmol) was dissolved in DCM (10 mL) and trifluoroacetic acid (1 mL) was added. The mixture was allowed to react at room temperature for 1 hour. LCMS confirmed the complete reaction. The reaction solution was concentrated to afford compound 7D (0.20 g), which was used directly in the next step without purification.

[0409] LC-MS (ESI): m / z = 409.1 [M+H] +.

[0410] Step 4:

[0411] In a 50 mL single-necked flask at 0°C, sodium hydride (0.02 g, 0.48 mmol), dry tetrahydrofuran (10 mL), and 3,3-difluorocyclobutanol (0.078 g, 0.72 mmol) were added. After stirring for 15 minutes, carbonyldiimidazole (0.078 g, 0.48 mmol) was added. After stirring for 1 hour, a solution of compound 7D (0.13 g, 0.24 mmol) and triethylamine (0.025 g, 0.24 mmol) in tetrahydrofuran was added. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a Biotage Isolera One medium-pressure prep system (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 7 (40 mg, yield 30.7%).

[0412] LC-MS (ESI): m / z = 543.2 [M+H] + .

[0413] 1 H NMR (400MHz, CDCl3): δ7.59(s,1H),7.52-7.49(m,2H),7.46-7.30(m,1H),6.49(s,1H),4.92 -4.85(m,1H),4.21-4.14(m,2H),4.09(s,4H),3.79(s,2H),3.73-3.68(m,2H),3.03-2.99(m, 2H),2.90-2.82(m,2H),2.68-2.63(m,2H),2.09-2.03(m,1H),1.90-1.87(m,2H),1.30-1.21(m,2H).

[0414] Example 8:

[0415] first step:

[0416] 6A (1 g, 3.36 mmol), cyclopropylboronic acid (576 mg, 6.72 mmol), bis(triphenylphosphine palladium dichloride) (236 mg, 0.34 mmol), and potassium phosphate (2.14 g, 10.08 mmol) were dissolved in a mixture of toluene (20 mL) and water (2 mL) and reacted at 100°C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated sodium bicarbonate solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to afford 8B (570 mg, 66% yield).

[0417] LC-MS(ESI):m / z=204.1[M+H-56] + .

[0418] Step 2:

[0419] 8B (570 mg, 2.20 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (8 mL) and allowed to react 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 the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford 8C (335 mg, 96% yield).

[0420] LC-MS (ESI): m / z = 160.1 [M+H] + .

[0421] Step 3:

[0422] 8C (335 mg, 2.11 mmol), Intermediate 1 (370 mg, 2.32 mmol), and N,N-diisopropylethylamine (639 mg, 6.33 mmol) were dissolved in acetonitrile (15 mL) and allowed to react overnight at room temperature. After completion, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 8D (382 mg, 64% yield).

[0423] LC-MS (ESI): m / z = 283.3 [M+H] +.

[0424] Step 4:

[0425] 8D (200 mg, 0.71 mmol), Intermediate 2 (229 mg, 0.78 mmol), and potassium carbonate (294 mg, 2.31 mmol) were dissolved in DMF (10 mL) and reacted at 70°C under a nitrogen atmosphere for 3 h. After completion of the reaction, the mixture was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford 8E (268 mg, 79% yield).

[0426] LC-MS (ESI): m / z = 481.3 [M+H] +.

[0427] Step 5:

[0428] 8E (268 mg, 0.56 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (5 mL) and allowed to react at room temperature for 1 h. Upon completion, the solvent was removed by rotary evaporation under reduced pressure. The residue was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford 8F (200 mg, 94% yield).

[0429] Step 6:

[0430] 8F (200 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (210 mg, 1.59 mmol) and HATU (264 mg, 0.69 mmol) were added, and the mixture was stirred at room temperature for 10 min. Cyclopropylacetic acid (53 mg, 0.53 mmol) was then added, and the mixture was allowed to react at room temperature for 1 h. 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 x 3). The combined organic layers were washed with saturated brine (25 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 afford compound 8 (60 mg, 25% yield).

[0431] 1 H NMR(400MHz,CD3Cl)δ7.59(s,1H),7.09-7.06(m,1H),6.96-6.92(m,1H),6.90(s,1H),6.48(s,1H),4.73 -4.67(m,1H),3.99(s,4H),3.90-3.85(m,1H),3.78-3.73(m,3H),3.71-3.65(m,1H),3.09-3.01(m,1H), 2.63-2.55(m,1H),2.30-2.73(,2H),2.19-2.08(m,1H),2.04-1.97(m,1H),1.92-1.81(m,2H),1.28-1.1 8(m,2H),1.09-0.99(m,1H),0.97-0.91(m,2H),0.68-0.63(m,2H),0.59-0.53(m,2H),0.20-0.15(m,2H).

[0432] LC-MS (ESI): m / z = 463.2 [M+H] +.

[0433] Example 9:

[0434] first step:

[0435] 9A (500 mg, 2.18 mmol) and N,N-diisopropylethylamine (845 mg, 6.54 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (374 mg, 3.27 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react overnight at room temperature. After completion, 30 mL of saturated sodium bicarbonate solution was added to quench the reaction mixture. The mixture was then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with 1 M dilute hydrochloric acid (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 9B (580 mg).

[0436] 1 H NMR(400MHz,CD3Cl)δ4.61(s,1H),4.08-4.00(m,2H),3.69(s,1H),2.95(s, 3H),1.85-1.75(m,1H),1.67-1.50(m,6H),1.38(s,9H),1.30-1.16(m,2H).

[0437] LC-MS(ESI):m / z=252.2[M+H-56] + .

[0438] Step 2:

[0439] 9B (436 mg, 1.42 mmol), 7B (400 mg, 1.29 mmol), and potassium carbonate (535 mg, 3.87 mmol) were dissolved in DMF (10 mL) and reacted at 60°C under a nitrogen atmosphere overnight. After completion of the reaction, the mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford 9C (470 mg, 70% yield).

[0440] LC-MS(ESI):m / z=423.1[M+H-100] + .

[0441] Step 3:

[0442] 9C (470 mg, 0.90 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (8 mL) and allowed to react at room temperature for 1 h. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure and concentrated to afford crude product 9D (350 mg, 92%), which was used directly in the next step without further purification.

[0443] LC-MS (ESI): m / z = 423.4 [M+H] + .

[0444] Step 4:

[0445] Cyclopropylcarboxylic acid (48 mg, 0.56 mmol) was dissolved in DMF (6 mL), and N-methylimidazole (69 mg, 0.84 mmol) and TCFH (86 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 10 min, followed by the addition of 9D (120 mg, 0.28 mmol) and allowed to react at room temperature for 1 h. 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 x 3). The combined organic layers were washed with saturated brine (25 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 afford compound 9 (33 mg, 24% yield).

[0446] 1 H NMR(400MHz,CD3Cl)δ7.61(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.33-7.30(m,1H),6.49(s,1H),6.00(s,1H),4.14-4.08(m,5H),3 .81-3.77(m,4H),1.97-1.90(m,1H),1.76-1.59(m,6H),1.55-1.44(m,2H),1.42-1.33(m,1H),0.98-0.93(m,2H),0.74-0.68(m,2H).

[0447] LC-MS (ESI): m / z = 491.3 [M+H] + .

[0448] Example 10:

[0449] first step:

[0450] 9D (100 mg, 0.24 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol) were dissolved in dichloromethane (8 mL). Cyclopropylmethylsulfonyl chloride (56 mg, 0.36 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react overnight at room temperature. 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 x 3). The organic layers were combined, washed with saturated brine (25 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 compound 10 (25 mg, yield: 19%).

[0451] 1H NMR(400MHz,CD3Cl)δ7.55-7.52(m,2H),7.48(s,1H),7.35-7.33(m,1H),6 .49(s,1H),4.68(s,1H),4.43(s,4H),4.04(s,2H),3.69-3.61(m,3H),2.8 9-2.86(m,2H),1.90-1.83(m,1H),1.78-1.73(m,2H),1.69-1.59(m,4H),1 .45-1.35(m,2H),1.12-1.03(m,1H),0.66-0.60(m,2H),0.34-0.30(m,2H).

[0452] LC-MS (ESI): m / z = 541.3 [M+H] + .

[0453] Example 11:

[0454] first step:

[0455] Compound 11A (20.0 g, 103 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (24.6 g, 113 mmol), and N,N-diisopropylethylamine (26.6 g, 206 mmol) were added to a 500 mL round-bottom flask. N-methylpyrrolidone (150 mL) was then added and the mixture was heated to 130°C and allowed to react overnight. After cooling to room temperature, the reaction mixture was poured into water (600 mL) and extracted with ethyl acetate (100 mL x 5). The organic phases were combined and washed three times with water (150 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 50 / 50) to obtain the target compound 11B (21.3 g, yield: 52.9%).

[0456] LC-MS (ESI): m / z = 390.1 [M+H] +

[0457] Step 2:

[0458] Compound 11B (21.3 g, 54.6 mmol) and potassium tert-butoxide (12.2 g, 109 mmol) were dissolved in tert-butanol (150 mL) and heated to 80°C with continuous stirring for 3 hours. After the reaction, the temperature was cooled to room temperature and quenched with water (400 mL). The mixture was extracted with ethyl acetate (100 mL x 5). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 70 / 30) to obtain the target compound 11C (19.4 g, 96.0% yield).

[0459] LC-MS (ESI): m / z = 370.1 [M+H] +

[0460] Step 3:

[0461] Compound 11C (1.80 g, 4.86 mmol) was dissolved in dichloromethane (24 mL) at room temperature, and trifluoroacetic acid (8 mL) was added. Stirring was continued at room temperature for 1 hour. After the disappearance of the starting material by LCMS monitoring, the mixture was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 11D (2.45 g), which was used directly in the next reaction without purification.

[0462] LC-MS (ESI): m / z = 270.1 [M+H] + .

[0463] Step 4:

[0464] The crude trifluoroacetate salt of compound 11D (2.45 g) obtained in the previous step was dissolved in dichloromethane (60 mL) under an ice-water bath. Triethylamine (2.95 g, 29.2 mmol) and methylsulfonyl chloride (836 mg, 7.30 mmol) were added sequentially, and the reaction was maintained at 0°C for 2 h. After completion of the reaction, as monitored by LCMS, saturated aqueous ammonium chloride (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 90 / 10) to afford compound 11E (1.58 g, 93.5% yield over two steps).

[0465] LC-MS (ESI): m / z = 348.1 [M+H] + .

[0466] Step 5:

[0467] Under nitrogen, compound 11E (400 mg, 1.15 mmol), 7B (536 mg, 1.72 mmol), X-Phos-Pd-G2 (181 mg, 0.230 mmol), cesium carbonate (749 mg, 2.30 mmol), and potassium iodide (381 mg, 2.30 mmol) were dissolved in 1,4-dioxane (30 mL) and heated to 100°C overnight. After completion of the reaction, as monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 85 / 15), and then separated and purified by preparative HPLC to afford the racemic compound 11 (24 mg, 3.6% yield).

[0468] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative HPLC conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content ranging from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[0469] 1 H NMR(400MHz,DMSO-d6)δ9.68-9.21(m,1H),8.44(d,1H),7.63(d,1H),7.61-7.55(m,2H),7.48(d,1H),6.45(s,1H),4.69-4.62(m,1 H),4.42(dd,1H),4.11-4.05(m,4H),4.02(dd,1H),3.92(s,2H),3.72-3.55(m,3H),2.98-2.88(m,4H),2.83(td,1H),2.65(t,1H).

[0470] LC-MS (ESI): m / z = 579.3 [M+H] + .

[0471] Example 12:

[0472] first step:

[0473] 7D (300 mg, 0.67 mmol) and triethylamine (203 mg, 2.01 mmol) were dissolved in 5 ml of dichloromethane. 3-Butyne-1-sulfonyl chloride (152 mg, 1.00 mmol) was added under ice-cooling and allowed to react for 1 hour. After completion of the reaction, the excess solvent was removed by rotary evaporation and the mixture was purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to obtain the target compound 12 (142 mg, 39% yield).

[0474] LCMS (ESI): m / z = 525.3 [M+H] +

[0475] 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.63(s,1H),7.59-7.55(m,1H),7.49-7.45(m,1H),6.39(s,1H),4.03(s,4H),3.81(s,2H),3.72(d, 2H),3.62(d,2H),3.27-3.20(m,2H),3.00-2.96(m,1H),2.96-2.82(m,2H),2.64-2.55(m,2H),1.88-1.78(d,3H),1.35-1.21(m,2H).

[0476] Example 13:

[0477] first step:

[0478] To a 250 mL single-necked flask were added 13A (10.0 g, 46.3 mmol), 1,2-difluoro-4-nitrobenzene (7.3 g, 46.3 mmol), potassium hydroxide (7.8 g, 138.9 mmol), and N,N-dimethylformamide (100 mL). The reaction was allowed to proceed at room temperature for 6 hours, then the temperature was raised to 60°C for 24 hours. The filtrate was filtered, added with ethyl acetate (500 mL), and washed with water (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 20 / 100) afforded 13B (10.0 g, 64.5% yield).

[0479] LC-MS (ESI): m / z = 336.2 [M+H] + .

[0480] Step 2:

[0481] To a 250 mL single-necked flask were added 13B (10.0 g, 29.9 mmol), ethyl acetate (100 mL), and palladium on carbon (2 g) in sequence. The mixture was hydrogenated and reacted at room temperature for 12 h. After filtration, the filtrate was concentrated under reduced pressure to give crude product 13C (7.0 g).

[0482] LC-MS (ESI): m / z = 306.2 [M+H] + .

[0483] Step 3:

[0484] To a 100 mL single-necked flask were added acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous iodide (2.24 g, 11.8 mmol) in sequence. The mixture was heated to 65°C, and a solution of 13C (3.0 g, 9.8 mmol) in acetonitrile (10 mL) was added dropwise. After the addition was complete, the mixture was reacted at 65°C for 4 hours. After the heating was turned off, the reaction was continued for 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 20 / 100) to give 13D (0.4 g, yield: 12.6%).

[0485] LC-MS(ESI):m / z=361.2[M-56+H] + .

[0486] Step 4:

[0487] Compound 13D (2.0 g, 4.80 mmol) was dissolved in dichloromethane (40 mL) at room temperature, and trifluoroacetic acid (10 mL) was added. Stirring was continued at room temperature for 1 hour. After the disappearance of the starting material by LCMS monitoring, the mixture was concentrated under reduced pressure at 30°C to afford the crude trifluoroacetate salt of compound 13E (2.98 g), which was used directly in the next reaction without purification.

[0488] LC-MS (ESI): m / z = 317.1 [M+H] + .

[0489] Step 5:

[0490] The crude trifluoroacetate salt of compound 13E (2.98 g) obtained in the previous step was dissolved in dichloromethane (80 mL) under an ice-water bath. Triethylamine (2.92 g, 28.8 mmol) and methanesulfonyl chloride (1.10 g, 9.61 mmol) were added sequentially, and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, as monitored by LCMS, saturated aqueous ammonium chloride (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 65 / 35) to afford compound 13F (1.46 g, 77.1% yield).

[0491] LC-MS (ESI): m / z = 395.1 [M+H] + .

[0492] Step 5:

[0493] Under nitrogen, compound 13F (300 mg, 0.761 mmol), 7B (355 mg, 1.14 mmol), X-Phos-Pd-G2 (120 mg, 0.152 mmol), and cesium carbonate (496 mg, 1.52 mmol) were dissolved in 1,4-dioxane (30 mL) and heated to 100°C overnight. After completion of the reaction, monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 85 / 15), and then separated and purified by preparative HPLC to afford the racemic compound 13 (27 mg, 6.1% yield).

[0494] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative HPLC Conditions: a. Mobile Phase A, B Composition: Mobile Phase A: Acetonitrile; Mobile Phase B: Water (containing 0.1% trifluoroacetic acid); b. Gradient elution, Mobile Phase A content from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min. After preparation, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, and extract with ethyl acetate to obtain the product.

[0495] 1H NMR(400MHz,DMSO-d6)δ9.58-9.02(m,1H),7.66-7.51(m,4H),7.48(d,1H),7.03(d,1H),6.39(s,1H),4.36(dd,1H),4.0 7(s,3H),4.06-3.93(m,2H),3.90(s,2H),3.62(t,2H),3.45-3.18(m,2H,overlapped),2.97-2.78(m,5H),2.61(t,1H).

[0496] LC-MS (ESI): m / z = 578.2 [M+H] + .

[0497] Chromatographic analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6×50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Flow rate: 1.0 mL / min, run time: 10 min. Retention time: 3.650 min.

[0498] Example 14:

[0499] first step:

[0500] 14A (1.02 g, 4.45 mmol) and N-methylmorpholine (900 mg, 8.90 mmol) were dissolved in dichloromethane (20 mL). Methanesulfonyl chloride (610 mg, 5.34 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react overnight at room temperature. After completion, the reaction mixture was quenched by adding 30 mL of saturated sodium bicarbonate solution. The mixture was then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with 1 M dilute hydrochloric acid (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 14B (1.05 mg, 76.7% yield).

[0501] 1 H NMR (400MHz, CDCl3) δ4.38(s,1H),4.04-3.99(m,2H),3.37(s,1H),2.99(s,3H),2.13- 2.00(m,2H),1.92-1.80(m,2H),1.76-1.63(m,1H),1.43(s,9H),1.18-1.03(m,4H).

[0502] LC-MS(ESI):m / z=252.2[M+H-56] + .

[0503] Step 2:

[0504] Using 14B (470 mg, 1.53 mmol) as starting material, the procedure was followed by reference to Example 9 (second step) to give compound 14C (400 mg, yield: 50%).

[0505] LC-MS(ESI):m / z=467.50[M+H-56] + .

[0506] Step 3:

[0507] Using 14C (400 mg, 0.77 mmol) as starting material, the reaction was carried out according to Example 9 (step 3) to obtain crude compound 14D hydrochloride (472 mg), which was used directly in the next step without further purification.

[0508] LC-MS (ESI): m / z = 423.2 [M+H] + .

[0509] Step 4:

[0510] 14D (220 mg, 0.52 mmol) and triethylamine (158 mg, 1.56 mmol) were dissolved in dichloromethane (10 mL). Cyclopropylmethylsulfonyl chloride (96 mg, 0.62 mmol) was added dropwise under a nitrogen atmosphere and ice-cooled. The mixture was allowed to react overnight at room temperature. 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 x 3). The organic layers were combined, washed with saturated brine (25 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 afford compound 14 (51 mg, 18.1% yield).

[0511] LC-MS (ESI): m / z = 541.60 [M+H] + .

[0512] 1H NMR(400MHz, CDCl3)δ7.57(s,1H),7.52-7.48(m,1H),7.46(s,1H),7.33-7.28(m,1H ),6.48(s,1H),4.10(s,4H),4.08-4.03(m,1H),3.79(s,2H),3.68-3.64(m,2H),3.3 5-3.24(m,1H),2.97-2.91(m,2H),2.18-2.10(m,2H),2.00-1.94(m,2H),1.87-1.77 (m,1H),1.30-1.25(m,2H),1.18-1.13(m,2H),0.74-0.66(m,2H),0.43-0.37(m,2H).

[0513] Example 15:

[0514] first step:

[0515] 14D (220 mg, 0.52 mmol) and triethylamine (158 mg, 1.56 mmol) were dissolved in dichloromethane (8 mL). Cyclopropylcarbonyl chloride (65 mg, 0.62 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react overnight at room temperature. 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 x 3). The organic layers were combined, washed with saturated brine (25 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 compound 15 (72 mg, yield: 28.2%).

[0516] LC-MS (ESI): m / z = 491.50 [M+H] + .

[0517] 1 H NMR (400MHz, CDCl3) δ7.57(s,1H),7.52-7.47(m,1H),7.46(s,1H),7.33-7.29(m,1H),6.48(s,1H),5.45-5.40(m,1H),4.12(s,4H),3.80(s ,2H),3.78-3.72(m,1H),3.67-3.61(m,2H),2.10-1.94(m,4H),1.91- 1.81(m,1H),1.31-1.27(m,1H),1.20-1.07(m,4H),0.99-0.93(m,2H), 0.74-0.67(m,2H).

[0518] Example 16:

[0519] first step:

[0520] Kojic acid (10.0 g, 70.3 mmol) was dissolved in DMF (120 mL), and potassium carbonate (11.7 g, 84.4 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (30.2 g, 84.4 mmol) were added. The mixture was reacted at room temperature for 14 h. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 16B (17.0 g, yield: 88.2%).

[0521] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),6.69(s,1H),4.53(s,2H).

[0522] Step 2:

[0523] 16B (8.13 g, 29.7 mmol) and (E)-tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (10.0 g, 29.7 mmol) were dissolved in 1,4-dioxane (300 mL), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (2.2 g, 2.9 mmol), potassium carbonate (8.2 g, 59.3 mmol) and water (60 mL) were added. The atmosphere was purged with nitrogen three times and heated to 90°C for 3 h. The mixture was passed through a short silica gel column, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 16C (5.2 g, yield: 52%).

[0524] LC-MS(ESI):m / z=280.2[M+H-56] + .

[0525] Step 3:

[0526] 16C (1.5 g, 4.5 mmol) was dissolved in DCM (50 mL). Dess-Martin periodinane (2.28 g, 5.4 mmol) was added portionwise at room temperature. The reaction was allowed to proceed for two hours. The mixture was quenched with saturated sodium thiosulfate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered, and rotary evaporated. 16D (1.4 g, 94% yield) was obtained by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1).

[0527] LC-MS(ESI):m / z=278.2[M+H-56] + .

[0528] Step 4:

[0529] 16D (500 mg, 1.5 mmol) was dissolved in 1,2-dichloroethane (10 mL) and acetic acid (1 mL). 5-cyclopropyl-2,3-dihydro-1H-isoindole (0.29 g, 1.8 mmol) was then added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.41 g, 1.9 mmol) was added and allowed to react at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated. 16E (490 mg, 69% yield) was obtained by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1).

[0530] LC-MS(ESI):m / z=421.3[M+H-56] + .

[0531] Step 5:

[0532] 16E (490 mg, 1.0 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product 16F was directly used for the next reaction without purification.

[0533] Step 6:

[0534] The crude product 16F from the previous step was dissolved in DCM (20 mL), and triethylamine (0.31 g, 3.1 mmol) was added. After stirring at room temperature for five minutes, 2-cyclopropylacetyl chloride (0.15 g, 1.3 mmol) was added and allowed to react at room temperature for 1 hour. The reaction solution was quenched with water, and the aqueous phase was extracted with dichloromethane. The organic layers were combined and washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated. Silica gel column chromatography (eluting with ethyl acetate) afforded compound 16 (200 mg, 38% yield).

[0535] LC-MS (ESI): m / z = 459.3 [M+H] + .

[0536] 1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.09(d,1H),6.95-6.89(m,2H),6.70-6.61(m,1H),6 .34(s,1H),6.13(d,1H),4.39(d,1H),3.95-3.71(m,7H),3.04(t,1H),2.59(t,1H),2.38- 2.28(m,1H),2.25(d,2H),1.93-1.85(m,1H),1.77-1.65(m,2H),1.30-1.21(m,1H),1.19- 1.12(m,1H),0.97-0.86(m,3H),0.65-0.56(m,2H),0.46-0.40(m,2H),0.13-0.09(m,2H).

[0537] Example 17:

[0538] first step:

[0539] 17A (1 g, 9.13 mmol) was dissolved in THF (15 mL), cooled to 0°C, and methanesulfonyl chloride (2.61 g, 22.82 mmol) was slowly added dropwise. The reaction was continued at this temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford crude 17B (1.2 g), which was used directly in the next reaction.

[0540] Step 2:

[0541] Crude 17B (1.2 g) was added to a 2 M hydroxide solution (10 mL) and stirred at room temperature for 2 hours. The pH was adjusted to neutral and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude product. This crude product was purified using a Biotage Isolera One medium-pressure prep system (12 g silica gel column, eluent: 0-5% MeOH / DCM) to afford the target compound 17C (0.52 g) in a two-step yield of 41.8%.

[0542] Step 3:

[0543] Compound 17C (120 mg, 0.78 mmol) and CDI (84 mg, 0.6 mmol) were dissolved in THF (10 mL) and stirred at room temperature for half an hour. TEA (350 mg, 3.46 mmol) and 7D (160 mg, 0.4 mmol) were then added, and the temperature was raised to 60°C for overnight reaction. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified using a medium-pressure prep system, Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM), to obtain the target compound 17 (80 mg, 34.4% yield).

[0544] LC-MS (ESI): m / z = 586.1 [M+H] + .

[0545] 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),7.52-7.44(m,2H),7.33-7.28(m,1H),6.49(s,1H),5.17-5.09(m,1H),4.23-4.13(m, 4H),4.10(s,4H),4.02-3.97(m,2H),3.79(s,2H),3.76-3.71(m,2H),2.89(s,5H),1.93-1.85(m,2H),1.33-1.21(m,3H).

[0546] Example 18:

[0547] first step:

[0548] 18A (1.2 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), and N,N-diisopropylethylamine (3.9 g, 30 mmol) and tert-butyl bromoacetate (2.3 g, 12 mmol) were added. The mixture was allowed to react at room temperature for 18 h. After completion, 25 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to afford 18B (1.0 g, 50% yield).

[0549] 1 H NMR (400MHz, CDCl3) δ4.11-4.05(m,1H),3.84-3.72(m,2H),3.25(s,3H),3.20(s,2H),3.04-2.94(m,2H),1.46(s,9H).

[0550] Step 2:

[0551] To 18B (1.0 g, 5 mmol) was added dilute hydrochloric acid (10 mL, 6 M). After stirring at room temperature for 1 h, the solvent was removed on a rotary evaporator at 60°C to give the product 18C (400 mg).

[0552] LC-MS (ESI): m / z = 145.2 [M+H] + .

[0553] Step 3:

[0554] 16D (1.5 g, 74.5 mmol) was dissolved in DCM (20 mL), and 5-trifluoromethylisoindoline hydrochloride (1.1 g, 5.0 mmol), triethylamine (0.5 g, 5.0 mmol) and sodium acetate borohydride (1.4 g, 6.8 mmol) were added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, 10 mL of water was added to the reaction solution, and the mixture was extracted with DCM (20 mL × 2). The organic layers were combined, washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 18D (1.8 g, yield: 79.3%).

[0555] LC-MS (ESI): m / z = 505.5 [M+H] + .

[0556] Step 4:

[0557] Compound 18D (1.5 g, 3.0 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (6 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 18E (1.3 g), which was used directly in the next step.

[0558] Step 5:

[0559] 18E (202 mg, 0.50 mmol) was dissolved in DMF (10 mL), and 18C (86.4 mg, 0.6 mmol) and N-methylimidazole (164 mg, 2 mmol) were added. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (168 mg, 0.6 mmol) was added at 0°C, and the mixture was stirred at room temperature for 20 min. After the reaction was complete, 20 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 × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 18 (40 mg, yield: 15%).

[0560] 1 H NMR (400MHz, CD3OD) δ8.23(s,1H),7.77-7.65(m,2H),7.58(d,1H),6.67-6.61(m,2H),6.24(d,1H),4.78(s,4H),4. 59-3.90(m,10H),3.67(d,1H),3.33(d,3H),3.17(t,1H),2.80(t,1H),2.42(s,1H),1.85(t,2H),1.51-1.31(m,2H).

[0561] LC-MS (ESI): m / z = 531.2 [M+H] + .

[0562] Example 19:

[0563] first step:

[0564] Compound 19A (0.60 g, 1.77 mmol) and TEA (0.54 g, 5.33 mmol) were dissolved in DCM (15 mL), and methanesulfonyl chloride (0.16 mL, 2.09 mmol) was added. The mixture was reacted at room temperature for 0.5 h. After the reaction, the reaction mixture was used directly in the next step without further treatment.

[0565] Step 2:

[0566] To the reaction mixture from the previous step, 5-isoindoline pentafluoride hydrochloride (470 mg, 1.68 mmol) was added and dissolved in dichloromethane (15 mL). Triethylamine (0.51 mg, 5.04 mmol) was then added and allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 19C (550 mg, 57.7% yield over two steps).

[0567] LC-MS(ESI):m / z=467.5[M+H-100] + .

[0568] Step 3:

[0569] Compound 19C (0.55 g, 0.98 mmol) was dissolved in DCM (10 mL), and dioxane hydrochloride solution (4 mol / L, 5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction solution was directly dried to obtain compound 19D (530 mg).

[0570] LC-MS (ESI): m / z = 467.1 [M+H] + .

[0571] Step 4:

[0572] 17C (0.14 g, 0.93 mmol) was dissolved in tetrahydrofuran (15 mL), and N,N'-Carbonyldiimidazole (0.15 g, 0.93 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hour, and then triethylamine (0.25 g, 2.47 mmol) was added and stirring was continued for 0.5 hour. Then, 19D (330 mg, 0.61 mmol) was added to the reaction system, and the temperature was raised to 60°C and the reaction was continued for 16 hours. The reaction solution was directly dried by rotary evaporation, and the crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 19 (180 mg, yield: 48.4%).

[0573] LC-MS (ESI): m / z = 644.9 [M+H] + .

[0574] 1 H NMR(400MHz, CDCl3)δ7.63(d,1H),7.60(s,2H),7.28(d,1H),6.48(s,1H),5.19-5.07(m,1H),4.23-4.05(m ,8H),4.00(dd,2H),3.78(s,2H),3.73(d,2H),2.84(d,5H),2.14-2.01(m,1H),1.89(d,2H),1.27(qd,2H).

[0575] Example 20:

[0576] first step:

[0577] Intermediate 1 (15.0 g, 93.43 mmol) and imidazole (12.7 g, 187 mmol) were dissolved in DCM (100 mL). tert-Butyldimethylsilyl chloride (15.49 g, 102.77 mmol) was added dropwise under an ice bath and allowed to react at room temperature for 1 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to obtain 20A (20.0 g, yield: 77.9%).

[0578] LC-MS (ESI): m / z = 275.1 [M+H] + .

[0579] Step 2:

[0580] 20A (20.0 g, 72.78 mmol) was dissolved in DMF (30 mL), followed by the addition of sodium azide (5.2 g, 80.06 mmol) and the reaction was allowed to react at room temperature overnight. After 16 h, 50 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to afford 20B (19.0 g, 92.7% yield).

[0581] LC-MS (ESI): m / z = 282.3 [M+H] + .

[0582] Step 3:

[0583] 20B (19.0 g, 67.52 mmol) was dissolved in tetrahydrofuran (100 mL). Triphenylphosphine (26.61 g, 101.47 mmol) was added portionwise under ice-cooling. After stirring for 10 min, 2.5 mL of pure water was slowly added dropwise and the mixture was allowed to react at 50°C overnight. After the reaction was complete, the mixture was cooled to room temperature and 50 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated brine (100 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 afford 20C (12 g, yield: 69.6%).

[0584] LC-MS (ESI): m / z = 256.3 [M+H] + .

[0585] Step 4:

[0586] 20C (1.2 g, 4.7 mmol), 2,3-bis(chloromethyl)thiophene (847 mg, 4.7 mmol), potassium iodide (156 mg, 0.94 mmol), and potassium carbonate (1.95 g, 14.1 mmol) were dissolved in acetonitrile (60 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 and 40 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 20D (300 mg, 17.5% yield).

[0587] LC-MS (ESI): m / z = 364.2 [M+H] + .

[0588] Step 5:

[0589] 20D (300 mg, 0.83 mmol) was dissolved in methanol (10 mL), and potassium carbonate (343 mg, 2.49 mmol) was added. The mixture was allowed to react at room temperature overnight. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in EA (20 mL). The organic phase was washed with water (15 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain 20E (200 mg, yield: 97.2%).

[0590] LC-MS (ESI): m / z = 250.2 [M+H] + .

[0591] Step 6:

[0592] 20E (200 mg, 0.80 mmol) was dissolved in dry DMF (10 mL), and tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (259 mg, 0.88 mmol) was added. The mixture was stirred until homogeneous, and potassium carbonate (331 mg, 2.4 mmol) was added. The reaction was allowed to react at 80°C for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. After cooling to room temperature, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 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 (DCM:MeOH (v / v) = 15:1) to obtain 20F (100 mg, yield: 27.9%).

[0593] LC-MS (ESI): m / z = 447.2 [M+H] + .

[0594] Step 7:

[0595] 20F (100 mg, 0.22 mmol) was dissolved in DCM (10 mL) at room temperature. A solution of hydrochloric acid in dioxane (0.5 mL, 2 mmol, 4 M) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction was stopped upon disappearance of the starting material by TLC monitoring. The reaction solution was concentrated without purification to afford 20G (70 mg).

[0596] LC-MS (ESI): m / z = 347.2 [M+H] + .

[0597] Step 8:

[0598] At room temperature, 1-(Methylsulfonyl)azetidin-3-ol (61 mg, 0.40 mmol) was dissolved in dry THF (10 mL). CDI (64.8 mg, 0.40 mmol) was added and stirred at room temperature for 30 min. Triethylamine (0.5 mL) was added, followed by 20G (70 mg, 0.20 mmol). The reaction was allowed to react at 80°C for 16 h. The reaction was stopped by TLC monitoring, after the disappearance of the starting material. The reaction mixture was cooled to room temperature, and 20 mL of water was added. 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 (DCM:MeOH (v / v) = 15:1) to obtain compound 20 (5 mg, yield: 4.7%).

[0599] 1 H NMR (400MHz, CDCl3) δ7.59-7.58(d,1H),7.24-7.23(d,1H),6.82-6.80(d,1H),6.48(s,1H),5.16 -5.10(m,1H),4.19-4.10(m,6H),4.02-3.97(m,4H),3.83(s,2H),3.75-3.69(m,2H),2.89(s,3H), 2.82-2.76(t,2H),2.08-2.01(m,1H),1.90-1.73(t,4H).

[0600] LC-MS (ESI): m / z = 524.1 [M+H] + .

[0601] Example 21:

[0602] first step:

[0603] Compound 19D (200 mg, 0.37 mmol) and triethylamine (150 mg, 1.48 mmol) were dissolved in dichloromethane (15 mL). Cyclopropylacetyl chloride (0.066 mg, 0.55 mmol) was added dropwise under an ice-water bath. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the product was concentrated and then purified on a silica gel column (dichloromethane:methanol (v / v) = 20:1) to afford compound 21 (62 mg, 30.5% yield).

[0604] LC-MS (ESI): m / z = 549.9 [M+H] + .

[0605] 1H NMR(400MHz, CDCl3)δ7.63(d,1H),7.59(s,2H),7.29(s,1H),6.48(s,1H),4.70(d,1H),4.08(d,4H),3.88(d,1H),3.82-3.65(m,4H),3.05(t, 1H),2.59(t,1H),2.28(d,2H),2.19-2.06(m,1H),2.00(d,1H),1.84(d ,1H),1.30-1.18(m,2H),1.09-0.98(m,1H),0.56(dt,2H),0.18(q,2H).

[0606] Example 22:

[0607] first step:

[0608] 20G (70 mg, 0.20 mmol), 2-cyclopropylacetic acid (40 mg, 0.40 mmol), and NMI (20 mg, 0.24 mmol) were dissolved in dry DCM (10 mL) at room temperature and stirred at room temperature for 30 min. TCFH (67.2 mg, 0.24 mmol) was added and the reaction continued for 1 hour. The reaction was stopped by TLC monitoring upon the disappearance of the starting material. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were 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 (DCM:MeOH (v / v) = 15:1) to afford compound 22 (15 mg, 17.3% yield).

[0609] 1 H NMR (400MHz, CDCl3) δ7.63-7.62(t,1H),7.35-7.32(m,1H),7.02-6.97(m,1H),6.72-6.67 (t,1H),3.90-3.83(m,3H),3.80-3.69(m,4H),3.48(s,2H),3.08-3.02(t,1H),2.63-2.57 (t,1H),2.29-2.27(d,2H),2.25-2.20(m,1H),2.18-2.10(m,1H),2.03-1.99(m,2H),1.89 -1.83(m,1H),1.68-1.60(m,1H),1.09-1.01(d,2H),0.58-0.54(m,2H),0.20-0.15(m,2H).

[0610] LC-MS (ESI): m / z = 429.2 [M+H]+ .

[0611] Example 23:

[0612] first step:

[0613] To a 50 mL single-necked flask were added compound 13F (600 mg, 1.52 mmol), pinacol diboron (1.16 g, 4.56 mmol), bistriphenylphosphine palladium dichloride (214 mg, 0.304 mmol), and potassium acetate (298 mg, 3.04 mmol) in sequence. After purging with nitrogen, N,N-dimethylformamide (30 mL) was added by injection. The temperature was raised to 100°C and the reaction was allowed to proceed overnight. After the disappearance of the starting material, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 93 / 7 to 75 / 25) to give 23A (309 mg, yield: 51.5%).

[0614] LC-MS (ESI): m / z = 395.2 [M+H] + .

[0615] Step 2:

[0616] Compound 7B (650 mg, 2.09 mmol) and potassium carbonate (866 mg, 6.26 mmol) were dissolved in N,N-dimethylformamide (20 mL). N-phenylbis(trifluoromethanesulfonyl)imide (1.49 g, 4.18 mmol) was added with stirring and allowed to react at room temperature for approximately 4 hours. After the disappearance of the starting material by TLC, the reaction was quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 65 / 35) to afford compound 23B (908 mg, 98.1% yield).

[0617] LC-MS (ESI): m / z = 444.1 [M+H] + .

[0618] Step 3:

[0619] Under nitrogen, compound 23A (270 mg, 0.685 mmol), 23B (364 mg, 0.822 mmol), bistriphenylphosphine palladium dichloride (96.1 mg, 0.137 mmol), and potassium carbonate (189 mg, 1.37 mmol) were dissolved in 1,4-dioxane (20 mL). Water (10 drops) was added, and the mixture was heated to 100°C and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 85 / 15), followed by SFC separation and purification to afford the racemic compound 23 (65.2 mg, 17.0% yield).

[0620] SFC purification method: 1. Instrument: Waters 150Prep-SFC F; 2. Chromatographic column: Chiralcel AD column 50×4.6mm ID, 3μm; 3. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in IPA and ACN; 4. Gradient: B 5-50%; 5. Flow rate: 100mL / min, cycle time: 3.60min.

[0621] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.64(s,1H),7.58(d,1H),7.48(d,1H),7.06(dd,1H),7.03-6.94(m,2H),6.42(s,1H),4.36(d d,1H),4.07(s,4H),4.02-3.91(m,2H),3.85(s,2H),3.66-3.57(m,2H),3.24-3.16(m,1H),2.93(s,4H),2.78(td,1H),2.60(t,1H).

[0622] LC-MS (ESI): m / z = 562.3 [M+H] + .

[0623] Chromatographic analysis conditions: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6×50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Flow rate: 1.0 mL / min, run time: 10 min. Retention time: 3.573 min.

[0624] Example 24:

[0625] first step:

[0626] 24A (1 g, 5.36 mmol) and triethylamine (1.63 g, 16.08 mmol) were dissolved in dichloromethane (20 mL). Methanesulfonyl chloride (798 mg, 6.97 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react at room temperature for 1 h. After completion, the reaction was quenched by adding 30 mL of saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford 24B (1.18 g, 83% yield).

[0627] LC-MS(ESI):m / z=165.2[M+H-100] + .

[0628] Step 2:

[0629] 24B (1.18 g, 4.46 mmol) was dissolved in dichloromethane and added to a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) under an ice bath. The mixture was allowed to react at room temperature for 30 min. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. After drying, compound 24C (705 mg) was obtained and used directly in the next step without further purification.

[0630] Step 3:

[0631] 7B (1 g, 3.21 mmol) and triethylamine (0.97 g, 9.67 mmol) were dissolved in tetrahydrofuran (15 mL). Trifluoromethanesulfonic anhydride (1.09 g, 3.86 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react at room temperature for 4 h. After completion, the reaction mixture was quenched by the addition of 30 mL of saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to afford 24D (850 mg, 60% yield).

[0632] LC-MS (ESI): m / z = 444.0 [M+H] + .

[0633] Step 4:

[0634] 24D (300 mg, 0.68 mmol), XPhos-Pd-G2 (54 mg, 0.068 mmol), and lithium chloride (35 mg, 0.82 mmol) were dissolved in 1,4-dioxane (8 mL). Under a nitrogen atmosphere, propenyltributyltin (338 mg, 1.02 mmol) was added dropwise at room temperature. The reaction was allowed to react at 100°C overnight. After completion of the reaction, the mixture was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 24E (188 mg, 82% yield).

[0635] LC-MS (ESI): m / z = 336.2 [M+H] + .

[0636] Step 5:

[0637] 24E (188 mg, 0.56 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL). Potassium osmate dihydrate (21 mg, 0.056 mmol) and sodium periodate (300 mg, 1.40 mmol) were then added and allowed to react at room temperature for 5 h. After completion of the reaction, 25 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (15 mL x 5). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 24F (140 mg, 74% yield).

[0638] LC-MS (ESI): m / z = 338.1 [M+H] + .

[0639] Step 6:

[0640] 24F (140 mg, 0.42 mmol) and 24C (69 mg, 0.42 mmol) were dissolved in methanol (8 mL). Sodium triacetoxyborohydride (356 mg, 1.68 mmol) was added portionwise and allowed to react at room temperature overnight. After the reaction was complete, 30 mL of saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate (15 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford compound 24 (35 mg, 17% yield).

[0641] 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.10-7.07(m,1H),6.93-6.91(m,2H),6.37(s,1H),3.89(s,4H),3.7 8-3.69(m,4H),3.60-3.55(m,2H),2.85(s,3H),2.76-2.69(m,2H),1.93-1.80(m,5H),1.35-1.24(m,2H).

[0642] LC-MS (ESI): m / z = 486.1 [M+H] + .

[0643] Example 25:

[0644] Step 1: Compound 25a (1.8 g, 7.6 mmol) was added to a 100 mL single-necked flask and dissolved in nitrogen-methylpyrrolidone (10 mL). Cesium carbonate (5.4 g, 16.7 mmol) was then added and heated to 130°C overnight. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 25b (0.89 g, 40%).

[0645] LC-MS(ESI):m / z=220.1[M+H-56] + .

[0646] Step 2: Compound 25b (0.89 g, 3.2 mmol) was added to a 100 mL single-necked bottle, dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3.0 mL) was added. After reacting at room temperature for 2 h, the mixture was concentrated to obtain compound 25c (1.0 g, 100%).

[0647] LC-MS (ESI): m / z = 176.1 [M+H] + .

[0648] Step 3:

[0649] 25A (173 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and DIEPA (154 mg, 1.2 mmol) and bis(4-nitrophenyl) carbonate (365 mg, 1.2 mmol) were added. The mixture was stirred at room temperature for 30 min to obtain a dichloromethane solution of 25B for use.

[0650] Step 4:

[0651] Compound 25C (396 mg, 1.0 mmol, obtained from 25c according to the synthetic route of 8F) was dissolved in dichloromethane (10 mL). DIEPA (258 mg, 2.0 mmol) and the 25B solution were added and stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 1) to afford 25D (350 mg, 59% yield).

[0652] LC-MS (ESI): m / z = 596.7 [M+H] + .

[0653] Step 5:

[0654] Compound 25D (350 mg, 0.6 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 25E (295 mg, yield: 98%), which was used directly in the next step.

[0655] Step 6:

[0656] 25E (295 mg, 0.6 mmol) was dissolved in DCM (10 mL), and triethylamine (182 mg, 1.8 mmol) and trifluoromethanesulfonyl chloride (118 mg, 0.7 mmol) were added. The mixture was stirred at room temperature for 20 min. After concentration, the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford compound 25 (100 mg, 29% yield).

[0657] LC-MS (ESI): m / z = 574.6 [M+H] + .

[0658] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.09(d,1H),6.89(d,2H),6.48(s,1H),5.18-5.06(m,1H),4.19-4.15(m,4H),4.04-3 .96(m,6H),3.81-3.72(m,4H),2.89-2.72(m,6H),2.07-2.03(m,1H),1.89(d,2H),1.32-1.22(m,2H),0.82-0.70(m,4H).

[0659] Example 26:

[0660] first step:

[0661] 18E (808 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and a solution of DIEPA (387 mg, 3.0 mmol) and 25B (1.0 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and the product was purified by silica gel column chromatography (PE / EA = 1 / 2) to afford 26A (920 mg, 77% yield).

[0662] LC-MS (ESI): m / z = 603.6 [M+H] + .

[0663] Step 2:

[0664] Compound 26A (920 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 26B (890 mg), which was used directly in the next step.

[0665] Step 3:

[0666] 26B (890 mg, 1.4 mmol) was dissolved in DCM (10 mL), and triethylamine (565 mg, 5.6 mmol) and methanesulfonyl chloride (171 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 20 min. After concentration, the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford compound 25 (300 mg, 37% yield).

[0667] LC-MS (ESI): m / z = 581.6 [M+H] + .

[0668] 1 H NMR(400MHz, CDCl3)δ7.80(s,1H),7.50(d,1H),7.46(s,1H),7.31(d,1H),6.58-6.52(m,1H),6.42(s,1H),6.18(d,1H),5.20-5.07 (m,1H),4.22-4.05(m,8H),4.01-3.96(m,2H),3.79(s,2H),2.97-2.73(m,5H),2.39-2.21(m,1H),1.79(d,2H),1.45-1.34(m,2H).

[0669] 19 F NMR(377MHz, CDCl3)δ-60.07(s).

[0670] Example 27:

[0671] first step:

[0672] Dissolve cyclopropanol (116 mg, 2.0 mmol) in dichloromethane (10 mL), add DIEPA (308 mg, 2.4 mmol) and bis(4-nitrophenyl) carbonate (730 mg, 2.4 mmol), and stir at room temperature for 30 min to obtain a dichloromethane solution of 27B for use.

[0673] Step 2:

[0674] 25C (792 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL) and a solution of DIEPA (516 mg, 4.0 mmol) and 27B (446 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and the product was purified by silica gel column chromatography (PE / EA = 1 / 1) to afford 27 (400 mg, 42% yield).

[0675] LC-MS (ESI): m / z = 480.6 [M+H] + .

[0676] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.12-7.05(m,1H),6.92-6.85(m,2H),6.47(s,1H),4.16(s,1H),4.09-4.03(m,1H),3.99(d,4H),3.75(s, 2H),3.74-3.66(m,3H),6.92-6.85(m,2H),2.10-1.92(m,1H),1.85(d ,2H),1.73(s,1H),1.22(d,2H),0.80-0.70(m,4H),0.70-0.59(m,4H).

[0677] Example 28:

[0678] first step:

[0679] 17A (0.30 g, 4.10 mmol) was added to dichloromethane (10 mL) and saturated sodium bicarbonate (10 mL). Chloroacetyl chloride (0.55 g, 4.93 mmol) was added dropwise under ice-cooling, and the reaction was stirred for 2 hours. The reaction solution was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The residue was purified using a Biotage Isolera One medium-pressure prep system (12 g silica gel column, eluent: 0-30% EA / PE) to afford compound 28B (0.41 g, 66.8% yield).

[0680] LC-MS (ESI): m / z = 150.2 [M+H] + .

[0681] 1 H NMR (400MHz, CD3OD-d4): δ4.63-4.57(m,1H),4.51-4.46(m,1H),4.26-4.21(m,1H),4.08-4.04(m,1H),4.02(s,2H),3.82-3.78(m,1H).

[0682] Step 2:

[0683] Compound 28B (0.054 g, 0.36 mmol) and compound 7D (0.1 g, 0.24 mmol) were dissolved in DMF (10 mL), and potassium carbonate (0.049 g, 0.35 mmol) was added. The mixture was reacted at 70°C overnight. After completion of the reaction of the starting materials, LCMS analysis showed that the reaction solution was quenched by pouring into ice water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a medium-pressure preparation apparatus Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 28 (0.050 g, yield 39.9%).

[0684] LC-MS (ESI): m / z = 522.2 [M+H] + .

[0685] 1 H NMR (400MHz, CDCl3): δ7.58(s,1H),7.50-7.48(m,1H),7.47-7.45(m,1H),7.31- 7.29(m,1H),6.49(s,1H),4.70-4.64(m,1H),4.47-4.43(m,1H),4.30-4.25(m,1H ),4.11-4.08(m,5H),3.90-3.86(m,1H),3.78(s,2H),3.71-3.70(m,2H),3.02(s, 2H),2.93-2.90(m,2H),2.10-2.05(m,2H),1.89-1.82(m,3H),1.44-1.35(m,2H).

[0686] Example 29:

[0687] first step:

[0688] Cyclopropanol (0.045 g, 0.78 mmol) was dissolved in tetrahydrofuran (15 mL), and CDI (0.13 g, 0.78 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hour, and then triethylamine (0.21 g, 2.08 mmol) was added and stirring was continued for 0.5 hour. Then, 19D (280 mg, 0.52 mmol) was added to the reaction system, and the temperature was raised to 60°C and the reaction was continued for 16 hours. The reaction solution was directly spin-dried, and the crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 19 (60 mg, yield: 20.9%).

[0689] LC-MS (ESI): m / z = 551.2 [M+H] + .

[0690] Example 30:

[0691] first step:

[0692] 16D (750 mg, 2.25 mmol) was dissolved in 1,2-dichloroethane (20 mL), followed by the addition of 5-cyclopropyloxyisoindoline trifluoroacetate (780 mg, 2.70 mmol). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (572 mg, 2.7 mmol) was added and allowed to react at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated. Silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) afforded 30A (482 mg, 43% yield).

[0693] LC-MS(ESI):m / z=437.3[M+H-56] + .

[0694] Step 2:

[0695] 30A (482 mg, 0.98 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product 30B was directly used for the next reaction without purification.

[0696] Step 3:

[0697] The crude product 30B from the previous step was dissolved in DCM (20 mL), and N,N-diisopropylethylamine (379 mg, 2.94 mmol) was added. After stirring at room temperature for five minutes, 27B (328 mg, 1.47 mmol) was added and allowed to react at room temperature for 1 hour. The reaction solution was quenched with water, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered, and rotary evaporated. The product was then purified by silica gel column chromatography (eluting with ethyl acetate) to afford compound 30 (200 mg, 43% yield).

[0698] LC-MS (ESI): m / z = 477.7 [M+H] + .

[0699] 1 H NMR(400MHz, CDCl3)δ7.79(s,1H),7.08(d,1H),6.91-6.86(m,2H),6.56-6.46(m,1H),6.41(s,1H),6.20-6.13(m,1H),4.25-3.93(m,6H),3 .75(s,2H),3.73-3.67(m,1H),2.85-2.74(m,2H),2.33-2.19(m,1H), 1.74(d,2H),1.45-1.25(m,3H),0.79-0.71(m,4H),0.72-0.64(m,4H).

[0700] Example 31:

[0701] first step

[0702] 18E (808 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and a solution of DIEPA (516 mg, 4.0 mmol) and 27B (446 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 2) to afford compound 31 (360 mg, 37% yield).

[0703] LC-MS (ESI): m / z = 488.5 [M+H] + .

[0704] 1H NMR (400MHz, CDCl3) δ7.79(s,1H),7.49(d,1H),7.45(s,1H),7.30(d,1H),6.55-6.50(m,1H),6.41(s,1H),6.17(d,1H ),4.33-3.89(m,7H),3.78(s,2H),2.82-2.76(m,2H),2.27-2.23(m,1H),1.74(d,2H),1.36(d,2H),0.69-0.67(m,4H).

[0705] 19 F NMR(376MHz, CDCl3)δ-60.07(s).

[0706] Example 32:

[0707] first step:

[0708] Cyclopropanol (57 mg, 0.98 mmol) and N,N'-carbonyldiimidazole (119 mg, 0.73 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 30 min. 7D (200 mg, 0.49 mmol) and triethylamine (198 mg, 1.96 mmol) were then added. The mixture was reacted at 70°C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and 30 mL of water was added. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford compound 32 (68 mg, 28% yield).

[0709] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.52-7.49(m,1H),7.46(s,1H),7.32-7.30(m,1H),6.49(s,1H),4.29-3.96(m,7H),3.80 (s,2H),3.73-3.70(m,2H),2.81-2.73(m,2H),2.09-1.98(m,1H),1.89-1.81(m,2H),1.28-1.17(m,2H),0.70-0.64(m,4H).

[0710] LC-MS (ESI): m / z = 493.2 [M+H] + .

[0711] Example 33:

[0712] first step:

[0713] 14D (550 mg, 1.30 mmol) and triethylamine (526 mg, 5.20 mmol) were dissolved in dichloromethane (10 mL). Deuterated acetyl chloride (117 mg, 1.43 mmol) was added dropwise under a nitrogen atmosphere and ice-cooled. The mixture was allowed to react at room temperature for 1 hour. 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 x 3). The combined organic layers were washed with saturated brine (25 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 afford compound 33 (287 mg, 47.2% yield).

[0714] LC-MS (ESI): m / z = 467.2 [M+H] + .

[0715] 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.73-7.67(m,1H),7.65-7.61(m,1H),7.60-7.54(m,1H),7.50-7.43(m,1H),6.38(s,1H ),4.02(s,4H),3.80(s,2H),3.66-3.60(m,2H),3.51-3.42(m,1H),1.89-1.77(m,4H),1.71-1.60(m,1H),1.23-1.00(m,4H).

[0716] Example 34:

[0717] first step:

[0718] Compound 34A (460 mg, 1.54 mmol, synthesized from 25c by the method of intermediate 8D) and 14B (520 mg, 1.69 mmol) were used as starting materials and the synthesis procedure of the second step of Example 9 was followed to obtain 34B (573 mg, yield: 73%).

[0719] LC-MS (ESI): m / z = 511.2 [M+H] + .

[0720] Step 2:

[0721] Using 34B (570 mg) as starting material, the synthesis procedure of the third step of Example 9 was referred to to obtain 34C (420 mg, yield: 91%).

[0722] LC-MS (ESI): m / z = 411.8 [M+H] + .

[0723] Step 3:

[0724] Using 34C (420 mg, 1.02 mmol) as starting material, compound 34 (340 mg, yield: 70%) was synthesized by referring to the synthesis procedure of the fourth step of Example 9.

[0725] 1 H NMR(400MHz, CDCl3)δ7.56(s,1H),7.10-7.07(m,1H),6.91-6.75(m,2H),6.47(s,1H),4.01-3.97(m,4H),3.81-3.68(m,4H),3.66 -3.63(m,2H),2.07-2.04(m,2H),2.00-1.96(m,2H),1.89-1.81(m,1H),1.31-1.06(m,6H),0.97-0.92(m,2H),0.78-0.67(m,5H).

[0726] LC-MS (ESI): m / z = 479.2 [M+H] + .

[0727] Example 35:

[0728] first step:

[0729] 1-Methylpyrazole-4-carboxylic acid (179 mg, 1.42 mmol) and triethylamine (478 mg, 4.72 mmol) were dissolved in dichloromethane (20 mL). HATU (673 mg, 1.77 mmol) was added under a nitrogen atmosphere and ice-cooled. The mixture was stirred for 5 minutes, and compound 14D (500 mg, 1.18 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours. 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 x 3). The organic layers were combined, washed with saturated brine (25 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 35 (398 mg, yield: 63.6%).

[0730] LC-MS (ESI): m / z = 531.1 [M+H] + .

[0731] 1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.09(s,1H),7.83-7.80(m,1H),7.81-7.75(m, 1H),7.65-7.61(m,1H),7.61-7.55(m,1H),7.50-7.45(m,1H),6.39(s,1H),4.03(s,4H),3.83(s,3H),3.81(s,2H), 3.73-3.66(m,1H),3.66-3.63(m,2H),1.91-1.82(m,4H),1.72-1.64(m,1H),1.38-1.25(m,2H),1.16-1.03(m,2H).

[0732] Example 36 and Example 37:

[0733] first step:

[0734] 36A (400 mg, 1.66 mmol) was dissolved in tetrahydrofuran (10 mL), and borane tetrahydrofuran complex (5 mL, 1 M in THF) was slowly added dropwise under ice-cooling. The reaction was continued under ice-cooling for 2 h. After completion, 1 M aqueous hydrogen chloride solution (2 mL) was added to the reaction solution to quench the reaction. Subsequently, 20 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford 36B (310 mg, 82% yield).

[0735] LC-MS(ESI):m / z=172.1[M+H-56] + .

[0736] Step 2:

[0737] 36B (310 mg, 1.36 mmol) and triethylamine (410 mg, 4.08 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (187 mg, 1.63 mmol) was added dropwise under a nitrogen atmosphere in an ice bath. The mixture was allowed to react at room temperature for 1 h. After completion, the reaction was quenched by adding 30 mL of saturated sodium bicarbonate solution. The mixture was then extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 25:1) to afford 36C (295 mg, 71% yield).

[0738] LC-MS(ESI):m / z=250.1[M+H-56] + .

[0739] Step 3:

[0740] 36C (295 mg, 0.97 mmol), 7B (302 mg, 0.97 mmol), and potassium carbonate (402 mg, 2.91 mmol) were dissolved in DMF (8 mL) and reacted at 70°C overnight under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to afford 36D (380 mg, 75% yield).

[0741] LC-MS(ESI):m / z=465.5[M+H-56] + .

[0742] Step 4:

[0743] 36D (380 mg, 0.73 mmol) was dissolved in dichloromethane (10 mL) and added dropwise to a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) under an ice bath. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the crude product 36E (300 mg, 97% yield) was obtained after concentration. This product was used directly in the next step without further purification.

[0744] LC-MS (ESI): m / z = 421.1 [M+H] + .

[0745] Step 5:

[0746] 1-(Methylsulfonyl)azetidin-3-ol (73 mg, 0.48 mmol) and N,N'-carbonyldiimidazole (117 mg, 0.72 mmol) were dissolved in tetrahydrofuran (6 mL) and stirred at room temperature for 30 min. The reaction mixture was then reacted with 36E (200 mg, 0.48 mmol) and triethylamine (194 mg, 1.92 mmol) at 70°C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, and 25 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford 36F (121 mg, 43% yield).

[0747] 36F was separated and purified by preparative HPLC to give compound 36 (41 mg) and compound 37 (21 mg).

[0748] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative HPLC conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content ranging from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[0749] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6×50 mm, 3 μm; 3. Mobile phase: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Acquisition time: 10 min; 6. Flow rate: 1.0 mL / min. Retention time: Compound 36: tR = 3.327 min; Compound 37: tR = 3.318 min.

[0750] Compound 36: 1 H NMR (400MHz, CDCl3) δ7.68-7.62(m,1H),7.51-7.48(m,1H),7.46(s,1H),7.32-7.30(m,1H) ),6.49-6.49(m,1H),5.18-5.09(m,1H),4.27-4.23(m,1H),4.19-4.12(m,2H),4.09(s,4H) ,4.03-3.94(m,3H),3.88-3.75(m,3H),3.43-3.31(m,1H),3.26-3.21(m,1H),2.89(s,3H) ,2.82(s,1H),2.67-2.56(m,1H),1.98-1.88(m,1H),1.83-1.74(m,1H),1.63-1.58(m,2H).

[0751] LC-MS (ESI): m / z = 598.9 [M+H] + .

[0752] Compound 37: 1H NMR (400MHz, CDCl3) δ7.63(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.32-7.29(m,1H),6. 48(s,1H),5.18-5.11(m,1H),4.30-4.25(m,1H),4.19-4.14(m,2H),4.09(s,4H),4.04-3 .96(m,2H),3.81-3.68(m,4H),3.37-3.31(m,1H),3.12-3.07(m,1H),2.89(s,3H),2.75- 2.71(m,1H),2.28-2.18(m,1H),1.98-1.86(m,1H),1.63-1.59(m,3H),1.35-1.28(m,1H).

[0753] LC-MS (ESI): m / z = 598.9 [M+H] + .

[0754] Example 38:

[0755] first step:

[0756] Using intermediate 1 (1 g, 6.28 mmol) and intermediate 3 (synthesized according to document WO2007087231A2) as raw materials and following the procedure of Example 1 (first step), compound 38A (820 mg, yield: 49.4%) was obtained.

[0757] LC-MS (ESI): m / z = 265.1 [M+H] + .

[0758] Step 2:

[0759] Using 38A (820 mg, 3.10 mmol) as starting material, the procedure was carried out according to Example 1 (second step) to obtain compound 38B (544 mg, yield: 38.0%).

[0760] LC-MS (ESI): m / z = 462.2 [M+H] + .

[0761] Step 3:

[0762] Using 38B (544 mg, 1.18 mmol) as starting material, the procedure was followed as in Example 1 (step 3) to obtain crude compound 38C hydrochloride (873 mg), which was directly used for the next step without further purification.

[0763] Step 4:

[0764] Using 38C (450 mg) as starting material, the procedure was carried out according to Example 20 (step 8) to give compound 38 (65 mg, yield: 11.8%).

[0765] LC-MS (ESI): m / z = 446.40 [M+H] + .

[0766] 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),6.46(s,1H),4.32-4.06(m,4H),4.06-4.04(m,1H),4.04-4.01(m,2H),3.84(s,2H),3.75 -3.68(m,2H),2.83-2.72(m,2H),2.71(s,3H),2.09-2.00(m,1H),1.89-1.81(m,2H),1.28-1.17(m,2H),0.72-0.64(m,4H).

[0767] Example 39:

[0768] first step:

[0769] Cyclopropanol (17 mg, 0.28 mmol) and triphosgene (83 mg, 0.28 mmol) were dissolved in dry DCM (10 mL) at room temperature. Triethylamine (85 mg, 0.84 mmol) was added dropwise under ice-cooling. After stirring at 0°C for 30 min, 20G (50 mg, 0.14 mmol) was added. After stirring, the mixture was allowed to react at room temperature for 1 hour. The reaction was stopped by TLC monitoring of the disappearance of the starting material. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH (v / v) = 15:1) to afford compound 39 (10 mg, 16.1% yield).

[0770] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.24(s,1H),6.82-6.81(d,1H),6.48(s,1H),4.15-4.01(m,7H),3.86 (s,2H),3.72-3.70(d,2H),2.80-2.73(m,2H),2.08-1.98(m,3H),1.86-1.83(d,,2H),0.68-0.67(d,4H).

[0771] LC-MS (ESI): m / z = 431.1 [M+H] + .

[0772] Example 40:

[0773] first step:

[0774] Compound 34 (200 mg, 0.42 mmol) was dissolved in tetrahydrofuran (6 mL). 60% sodium hydride (34 mg, 0.63 mmol) was added portionwise under a nitrogen atmosphere and ice-bathed. The mixture was stirred at room temperature for 30 min, followed by the slow dropwise addition of iodomethane (118 mg, 0.63 mmol) and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was slowly added dropwise to a 1M aqueous solution of hydrogen chloride (10 mL) to quench the reaction. 10 mL of water was then added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford compound 40 (55 mg, 27% yield).

[0775] 1 H NMR(400MHz, CDCl3)δ7.56(s,1H),7.11-7.08(m,1H),6.91-6.76(m,2H),6.48(s,1H),4.03-3.99(m,4H),3.82-3.69(m,4H),3.67-3.63 (m,2H),3.21(s,3H),2.08-2.05(m,2H),2.01-1.96(m,2H),1.89-1.82(m,1H),1.33-1.07(m,6H),0.98-0.92(m,2H),0.79-0.69(m,5H).

[0776] LC-MS (ESI): m / z = 493.4 [M+H] + .

[0777] Example 41:

[0778] first step:

[0779] (R)-(-)-3-Hydroxytetrahydrofuran (70.49 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and N,N'-carbonyldiimidazole (0.13 g, 0.80 mmol) was added at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 4.5 hours, triethylamine (0.16 g, 1.58 mmol) was added dropwise at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 2 hours, 18E (160 mg, 0.40 mmol) was added dropwise at 0-5°C. The reaction was continued at 60°C overnight. After the reaction was complete, the reaction solution was concentrated and purified by preparative HPLC to obtain compound 41 (85 mg, 40% yield).

[0780] LC-MS (ESI): m / z = 519.7 [M+H] + .

[0781] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.63(s,1H),7.58-7.56(d,1H),7.48-7 .46(d,1H),6.69-6.63(dd,1H),6.36(s,1H),6.15-6.11(d,1H),5.13-5.11( m,1H),4.03-3.95(m,6H),3.81-3.65(m,6H),2.83(s,2H),2.28-2.25(m,1H) ,2.17-2.05(m,1H),1.91-1.87(m,1H),1.71-1.68(d,2H),1.27-1.17(m,2H).

[0782] Example 42:

[0783] first step:

[0784] (S)-(-)-3-Hydroxytetrahydrofuran (70.49 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and N,N'-carbonyldiimidazole (0.13 g, 0.80 mmol) was added at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 4.5 hours, triethylamine (0.16 g, 1.58 mmol) was added dropwise at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 2 hours, 18E (160 mg, 0.40 mmol) was added dropwise at 0-5°C. The reaction was continued at 60°C overnight. After the reaction was complete, the reaction solution was concentrated and purified by preparative HPLC to obtain compound 42 (90 mg, 40% yield).

[0785] LC-MS (ESI): m / z = 519.7 [M+H] + .

[0786] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.63(s,1H),7.58-7.56(d,1H),7.48-7 .46(d,1H),6.69-6.63(dd,1H),6.36(s,1H),6.15-6.11(d,1H),5.13-5.11( m,1H),4.03-3.95(m,6H),3.82-3.65(m,6H),2.84(s,2H),2.28-2.25(m,1H) ,2.13-2.06(m,1H),1.92-1.86(m,1H),1.71-1.68(d,2H),1.27-1.17(m,2H).

[0787] Example 43:

[0788] first step

[0789] 16D (333.0 mg, 2.25 mmol) was dissolved in 1,2-dichloroethane (20 mL), followed by the addition of 5D (174.9 mg, 1.1 mmol). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (466.0 mg, 2.2 mmol) was added and allowed to react overnight at room temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with saturated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and rotary evaporated. Silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) afforded 43A (300.0 mg, 63.0% yield).

[0790] LC-MS (ESI): m / z = 477.2 [M+H] + .

[0791] Step 2

[0792] Compound 43A (300.0 mg, 0.62 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (2.0 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 43B (310.0 mg), which was used directly in the next step.

[0793] LC-MS (ESI): m / z = 377.2 [M+H] + .

[0794] Step 3

[0795] Cyclopropanol (44.0 mg, 0.75 mmol) was dissolved in tetrahydrofuran (5.0 mL), and CDI (120.0 mg, 0.75 mmol) was added. The reaction was stirred at room temperature for 0.5 h. Then, a solution of 43B (310.0 mg, 0.62 mmol) in tetrahydrofuran (5.0 mL) and triethylamine (191.0 mg, 1.9 mmol) were added. The mixture was heated to 60°C and reacted overnight. The reaction was complete by TLC. After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to give compound 43 (102.0 mg, yield: 35%).

[0796] LC-MS (ESI): m / z = 461.2 [M+H] + .

[0797] 1 H NMR(400MHz, CDCl3)δ7.79(s,1H),7.04(s,2H),6.55-6.49(m,1H),6.42(d,1H),6.17(d,1H),4.45-3.86(m,7H),3 .78(d,2H),2.94-2.71(m,6H),2.32-2.15(m,1H),2.11-2.04(m,2H),1.74(d,2H),1.36(d,2H),0.69-0.67(m,4H).

[0798] Example 44:

[0799] first step:

[0800] Kojic acid (1.00 g, 7.04 mmol) was dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (1.95 g, 14.08 mmol), 44A (2.47 g, 8.45 mmol), and potassium iodide (0.12 g, 0.70 mmol) were added at room temperature and allowed to react overnight at 85°C. After completion of the reaction, water (50 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (50 mL x 2). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4, (v / v)) to afford 44B (256 mg, 10% yield).

[0801] LC-MS(ESI):m / z=298.4[M-56+H] + .

[0802] Step 2:

[0803] 44B (256 mg, 0.72 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.36 g, 3.60 mmol) and methanesulfonyl chloride (0.99 g, 0.86 mmol) were added at 0-5°C. The mixture was allowed to react at room temperature for 30 minutes, and then 5D (197 mg, 0.86 mmol) was added and allowed to react at room temperature overnight. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to afford compound 44C (220 mg, 61% yield).

[0804] LC-MS (ESI): m / z = 495.3 [M+H] + .

[0805] Step 3:

[0806] Dissolve 44C (100 mg, 0.20 mmol) in 1,4-dioxane (0.5 mL) and add 4N HCl in 1,4-dioxane (10 mL) at room temperature. Allow to react at room temperature for 2.5 hours. Upon completion, concentrate the reaction mixture to yield crude product 44D, which was used directly in the next step.

[0807] Step 4:

[0808] Crude product 44D was dissolved in dichloromethane (5 mL). Triethylamine (0.10 g, 1.00 mmol) and cyclopropylcarbonyl chloride (0.31 g, 0.30 mmol) were added dropwise to the reaction system at room temperature. The reaction was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by preparative HPLC to afford compound 44 (15 mg, 16% yield).

[0809] LC-MS (ESI): m / z = 463.5 [M+H] + .

[0810] 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.91-7.89(d,1H),7.06(s,2H),6.36(s,1H),3.87(s,4H),3.75(s,2H),3.64-3.62(d,2H),3.51(m,1H),2. 82-2.78(t,4H),2.04-1.96(m,2H),1.83-1.81(d,4H),1.66(m,1H),1.5 2-1.47(m,1H),1.24-1.14(m,2H),1.09-1.00(m,2H),0.64-0.59(m,4H).

[0811] Example 45:

[0812] first step:

[0813] Compound 35 (281 mg, 0.53 mmol) was dissolved in dry DMF (5 mL) at room temperature. NaH (42 mg, 1.06 mmol) was added under ice-cooling and stirred for 10 minutes. Methyl iodide (113 mg, 0.79 mmol) was then added to the reaction system. The temperature was raised to room temperature and the reaction was continued for 6 hours before stopping the reaction. The reaction was quenched by adding water (10 mL) and extracted with EA (15 mL). The layers were separated and the aqueous phase was washed twice with EA (10 mL). The organic phases were combined and washed twice with saturated sodium chloride solution (20 mL). The organic phases were dried, concentrated, and purified by column chromatography (DCM:MeOH = 15:1) to afford compound 45 (17 mg, yield: 6.1%).

[0814] LC-MS (ESI): m / z = 545.4 [M+H] + .

[0815] 1 H NMR (400MHz, DMSO-d6) δ8.12-8.08(m,2H),7.83-7.81(m,1H),7.80-7.76(m,1H),7. 69-7.66(m,1H),7.54-7.49(m,1H),7.08-7.03(m,1H),5.32(s,1H),4.40-4.30(m,1H ),3.83(s,3H),3.72-3.67(m,2H),3.67-3.65(m,2H),2.35(s,3H),2.04-1.98(m,1H) ,1.97(s,2H),1.92-1.83(m,4H),1.71(s,1H),1.36-1.27(m,2H),1.19-1.08(m,2H).

[0816] Example 46:

[0817] first step:

[0818] Compound 33 (187 mg, 0.40 mmol) was used in the same manner as in Example 45 (first step) to obtain compound 46 (20 mg, yield: 10.4%).

[0819] LC-MS (ESI): m / z = 481.3 [M+H] + .

[0820] 1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.72-7.68(m,1H),7.67(s,1H),7.5 4-7.48(m,1H),7.08-7.03(m,1H),5.32(s,1H),4.41-4.28(m,1H),3.72-3 .66(m,1H),3.66-3.62(m,2H),3.52-3.44(m,1H),2.35(s,3H),2.03-1.9 8(m,1H),1.97(s,2H),1.87-1.79(m,4H),1.74(s,1H),1.20-1.02(m,4H).

[0821] Example 47:

[0822] first step:

[0823] 34B (160 mg, 0.39 mmol), 2-methylthiazole-4-carboxylic acid (61 mg, 0.43 mmol), and NMI (96 mg, 1.17 mmol) were dissolved in dry DCM (10 mL) at room temperature and stirred for 10 min. TCFH (130 mg, 0.46 mmol) was then added and the reaction continued for 1 hour. The reaction was stopped by TLC monitoring upon the disappearance of the starting material. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH (v / v) = 15:1) to afford compound 47 (20 mg, 9.6% yield).

[0824] 1 H NMR (400MHz, CDCl3) δ7.92(s,1H),7.58(s,1H),7.18-7.16(d,1H),7.10-7.08(d,1H),6.90-6.88(d,1H),6.48(s,1H),4.03-4. 00(d,4H),3.76(s,2H),3.69-3.67(d,2H),2.71(s,3H),2.15-2.12(d,2H),2.04-2.01(d,2H),1.37-1.14(m,8H),0.75(s,4H).

[0825] LC-MS (ESI): m / z = 536.3 [M+H] + .

[0826] Example 48:

[0827] first step:

[0828] (S)-(-)-3-Hydroxytetrahydrofuran (68.00 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (130 mg, 0.77 mmol) was added. The mixture was allowed to react at room temperature for 4 h. Triethylamine (120 mg, 1.23 mmol) was then added dropwise. After 2 h of reaction, compound 41E (120 mg, 0.31 mmol) was added dropwise in an ice-water bath. The reaction system was heated to 60°C and stirred overnight. LCMS confirmed the complete reaction. The reaction solution was concentrated and purified by preparative HPLC to yield compound 48 (50 mg, 32% yield).

[0829] LC-MS (ESI): m / z = 507.80 [M+H] + .

[0830] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.13(d,2H),6.99-6.91(m,1H),6.89-6.82(m,1H ),6.69-6.61(m,1H),6.34(s,1H),6.13(d,1H),5.15-5.08(m,1H),4.00-3.86(m,6H), 3.80-3.64(m,7H),2.94-2.76(m,2H),2.31-2.21(m,1H),2.15-2.05(m,1H),1.94-1.8 4(m,1H),1.72-1.64(m,2H),1.28-1.16(m,2H),0.79-0.71(m,2H),0.65-0.57(m,2H).

[0831] Example 49:

[0832] first step:

[0833] Compound 49A (1.00 g, 4.25 mmol) was dissolved in DMF (20 mL), and cyclobutane bromide (690 mg, 5.10 mmol) and cesium carbonate (3.46 g, 10.63 mmol) were added sequentially. The reaction solution was stirred at 90°C overnight under nitrogen. After TLC monitoring of the reaction completion, the reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was extracted twice with 30 mL of dichloromethane. The combined organic phases were dried, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to provide compound 49B (600 mg, 48.8% yield).

[0834] LC-MS(ESI):m / z=234.2[M-56+H] +

[0835] Step 2:

[0836] Compound 49B (600 mg, 2.07 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. After reacting at room temperature for half an hour, the reaction solution was concentrated under reduced pressure to obtain crude compound 49C (800 mg), which was used directly in the next reaction.

[0837] LC-MS (ESI): m / z = 190.2 [M+H] +

[0838] Step 3:

[0839] Compound 49C (540 mg, 2.39 mmol) was dissolved in acetonitrile (8 mL), and (2-chloromethyl)-5-hydroxy-4H-pyran-4-one (365 mg, 2.27 mmol) and triethylamine (730 mg, 7.18 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5) to afford compound 49D (580 mg, 77.4% yield).

[0840] LC-MS (ESI): m / z = 314.1 [M+H] +

[0841] Step 4:

[0842] Compound 49D (580 mg, 1.85 mmol) was dissolved in DMF (15 mL), and tert-butyl 4-bromopiperidine-1-carboxylate (540 mg, 2.05 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were added. The reaction solution was stirred at 85°C for 16 h, then cooled to room temperature, 60 mL of water was added, and the mixture was extracted three times with 40 mL of dichloromethane. The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5) to obtain compound 49E (900 mg, 95.2% yield).

[0843] LC-MS (ESI): m / z = 511.5 [M+H] +

[0844] Step 5:

[0845] Compound 49E (900 mg, 1.76 mmol) was dissolved in dichloromethane (8 mL), and dioxane hydrochloride solution (2 mL) was added. After reacting at room temperature for half an hour, the reaction solution was concentrated under reduced pressure to obtain crude compound 49F (850 mg), which was used directly in the next reaction.

[0846] LC-MS (ESI): m / z = 411.2 [M+H] +

[0847] Step 6:

[0848] Cyclopropanol (210 mg, 3.58 mmol) was dissolved in DMF (10 mL), and carbonyldiimidazole (580 mg, 3.58 mmol) and triethylamine (730 mg, 7.18 mmol) were added. The mixture was stirred at room temperature for 40 min, and 49F (850 mg, 1.76 mmol) was added. The reaction mixture was transferred to 85°C and stirred under nitrogen for 16 h. The reaction mixture was cooled to room temperature, 60 mL of water was added, and the mixture was extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried, and concentrated, and then separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5), followed by further reverse phase preparation (acetonitrile / water (v / v) = 5 / 95 to 95 / 5) to give compound 49 (80 mg, yield: 9.05%).

[0849] 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.11-7.08(m,1H),6.72(s,1H),6.69-6.64(m,1H ),6.36(s,1H),4.66-4.59(m,1H),4.00-3.95(m,2H),3.89-3.86(m,5H),3.75(s,2H), 3.69-3.68(m,2H),2.81-2.75(m,2H),2.43-2.36(m,2H),2.05-1.96(m,2H),1.93-1.8 7(m,1H),1.77-1.70(m,3H),1.66-1.59(m,1H),1.16-1.07(m,2H),0.63-0.60(m,4H).

[0850] LC-MS (ESI): m / z = 495.3 [M+H] +

[0851] Example 50:

[0852] first step:

[0853] 6-BOC-6-azaspiro[2.5]octane-1-carboxylic acid (0.14 g, 0.54 mmol), compound 7D (0.22 g, 0.54 mmol), and methylimidazole (0.089 g, 1.08 mmol) were dissolved in DMF (10 mL) and stirred for 10 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.23 g, 0.81 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a Biotage Isolera One medium-pressure prep system (12 g silica gel column, eluent: 0-50% EA / PE) to afford compound 50A (0.215 g, yield 61.66%).

[0854] LC-MS (ESI): m / z = 646.3 [M+H] + .

[0855] Step 2:

[0856] Compound 50A (0.215 g, 0.33 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. LCMS analysis confirmed the complete reaction. The reaction mixture was poured into ice water to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 50B (0.15 g), which was directly used for the next step without purification.

[0857] LC-MS (ESI): m / z = 546.1 [M+H] + .

[0858] Step 3:

[0859] Compound 50B (0.15 g, 0.27 mmol) and triethylamine (0.082 g, 0.81 mmol) were dissolved in dichloromethane (10 mL) at 0°C. After stirring for 15 minutes, methylsulfonyl chloride (0.037 g, 0.32 mmol) was added dropwise, and stirring was continued for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a medium-pressure preparator Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 50 (40 mg, yield 23.7%).

[0860] LC-MS (ESI): m / z = 624.7 [M+H] + .

[0861] 1 H NMR (400MHz, CDCl3): δ7.61(s,1H),7.51-7.49(m,1H),7.46(s,1H),7.32-7.30(m,1H),6.49(s,1H),4.69-4.60(m,1H),4.12(s,5H) ),3.81-3.66(m,4H),3.60-3.37(m,2H),3.21-2.93(m,4H),2.80(s,3H),2.67-2.62(m,1H),2.15-1.68(m,7H),1.43-1.13(m,4H).

[0862] Example 51:

[0863] first step:

[0864] 51A (3.4 g, 10 mmol) was dissolved in ethyl acetate (20 mL), and IBX (5.6 g, 20 mmol) was added and reacted at 80°C for 12 h. After the reaction was complete, the mixture was filtered and concentrated to obtain 51B (2.1 g).

[0865] LC-MS (ESI): m / z = 337.1 [M+H] + .

[0866] Step 2:

[0867] Compound 51C (540 mg, 2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.0 mL) was added. After reacting at room temperature for 15 min, the mixture was concentrated to obtain compound 51D (520 mg), which was used directly in the next step.

[0868] LC-MS (ESI): m / z = 169.2 [M+H] + .

[0869] Step 3:

[0870] 51B (606 mg, 1.8 mmol) was dissolved in DCE (20 mL), and 5-difluoromethylisoindoline hydrochloride (370 mg, 1.8 mmol), sodium acetate borohydride (763 mg, 3.6 mmol) and 1 drop of glacial acetic acid were added sequentially. The mixture was reacted at room temperature for 1 h. After the reaction was complete, 10 mL of water was added to the reaction solution, and the mixture was extracted with DCM (20 mL × 2). The organic layers were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to give 51E (735 mg, yield: 83%).

[0871] LC-MS (ESI): m / z = 169.2 [M+H] + .

[0872] Step 4:

[0873] Compound 51E (735 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3.0 mL) was added. The mixture was reacted at room temperature for 10 min and concentrated to obtain compound 51F (710 g), which was used directly in the next step.

[0874] Step 5:

[0875] 51F (710 mg, 1.4 mmol) was dissolved in dichloromethane (20 mL) and a solution of DIEPA (254 mg, 2.0 mmol) and 25B (0.6 g, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 2) to afford 51G (589 mg, 72% yield).

[0876] LC-MS (ESI): m / z = 590.6 [M+H] + .

[0877] Step 6:

[0878] Compound 51G (590 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. After reacting at room temperature for half an hour, the mixture was concentrated to obtain compound 51H (570 mg), which was used directly in the next step.

[0879] Step 7:

[0880] 51H (570 mg, 0.9 mmol) was dissolved in DCM (10 mL), and triethylamine (122 mg, 1.2 mmol) and methanesulfonyl chloride (137 mg, 1.2 mmol) were added. The mixture was stirred at room temperature for 20 min. After concentration, the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford compound 51 (120 mg, 24% yield).

[0881] LC-MS (ESI): m / z = 568.6 [M+H] + .

[0882] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),7.36(d,2H),7.29(s,1H),6.78-6.41(m,2H),5.29-5.00(m,1H),4.19-4.15(m,4H),4.08(s, 4H),4.02-3.98(m,2H),3.78(s,2H),3.73(d,2H),2.89(s,3H),2.79(s,2H),2.12-2.00(m,1H),1.89(d,2H),1.32-1.22(m,2H),

[0883] 19 F NMR(400MHz, CDCl3)δ-107.63(s).

[0884] Example 52:

[0885] first step:

[0886] Compound 18E (0.37 g, 0.91 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.28 g, 2.77 mmol) and cyclopropylacetyl chloride (0.22 g, 1.86 mmol) were added sequentially in an ice-water bath. After the addition was complete, the reaction was continued in an ice-water bath for 4 h. LCMS analysis showed that the reaction of the raw material was complete. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 52 (40 mg, yield: 9%).

[0887] LC-MS (ESI): m / z = 487.30 [M+H] + .

[0888] 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.62(s,1H),7.57(d,1H),7.46(d,1H),6.7 6-6.60(m,1H),6.36(s,1H),6.13(d,1H),4.38(d,1H),4.03(s,4H),3.90-3.74( m,3H),3.10-2.98(m,1H),2.64-2.54(m,1H),2.36-2.19(m,3H),1.77-1.62(m,2 H),1.31-1.09(m,2H),1.00-0.87(m,1H),0.48-0.38(m,2H),0.15-0.06(m,2H).

[0889] Example 53:

[0890] first step:

[0891] Compound 53A (5.4 g, 30 mmol) was dissolved in toluene (50 mL), and bis(cyclopentadienyl)zirconium dichloride (397 mg, 1.5 mmol) and pinacol borane (5.0 g, 39 mmol) were added sequentially. The mixture was reacted at 60°C for 18 h. After the reaction was complete, the mixture was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 53B (7.7 g, yield: 83%).

[0892] LC-MS (ESI): m / z = 310.2 [M+H] + .

[0893] Step 2:

[0894] 53B (7.7 g, 25 mmol) was dissolved in 1,4-dioxane (40 mL), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (1.8 mg, 2.5 mmol), cesium carbonate (16 g, 50 mmol), 16B (6.8 g, 25 mmol), and water (10 mL) were added. The atmosphere was purged with nitrogen three times and heated to 90°C for 3 h. The mixture was passed through a short silica gel column, eluted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 53C (4.6 g, yield: 60%).

[0895] LC-MS (ESI): m / z = 308.4 [M+H] + .

[0896] Step 3:

[0897] 53C (4.6 g, 15 mmol) was dissolved in ethyl acetate (50 mL), and IBX (8.4 g, 30 mmol) was added and reacted at 80°C for 12 h. After the reaction was complete, the mixture was filtered and concentrated to give 53D (4.3 g).

[0898] Step 4:

[0899] 53D (1.5 g, 5 mmol) was dissolved in DCE (20 mL), and 5-trifluoromethylisoindoline hydrochloride (1.1 g, 5.0 mmol), sodium acetate borohydride (1.4 g, 6.8 mmol), and 5 drops of glacial acetic acid were added sequentially. The mixture was reacted at room temperature for 1 h. After the reaction was complete, 10 mL of water was added to the reaction solution, and the mixture was extracted with DCM (20 mL × 2). The organic layers were combined, washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 53F (1.8 g, yield: 78%).

[0900] Step 5:

[0901] Compound 53F (1.8 g, 3.8 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (8.0 mL) was added. After reacting at room temperature for 10 min, the mixture was concentrated to obtain compound 53G (1.6 g), which was used directly in the next step.

[0902] LC-MS (ESI): m / z = 377.2 [M+H] + .

[0903] Step 6:

[0904] 53G (1.1 g, 3.0 mmol) was dissolved in dichloromethane (20 mL) and a solution of DIEPA (1.1 g, 8.0 mmol) and 27B (1.4 g, 6 mmol) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was concentrated and the product was purified by silica gel column chromatography (PE / EA = 1 / 1) to afford 53 (320 mg, 30% yield).

[0905] LC-MS (ESI): m / z = 461.1 [M+H] + .

[0906] 1H NMR (400MHz, CDCl3) δ7.81(s,1H),7.50(d,1H),7.46(s,1H),7.31(d,1H),6.89-6.83(m,1H),6.43(s,1H),6.18(d,1H ),4.16(t,2H),4.10(s,4H),4.07-3.98(m,1H),3.89-3.82(m,2H),3.79(s,2H),3.44-3.26(m,1H),0.79-0.56(m,4H).

[0907] 19 F NMR(400MHz, CDCl3)δ-60.08(s).

[0908] Example 54:

[0909] first step:

[0910] Compound 54 (66 mg, yield: 36%) was synthesized using 9D (150 mg, 0.36 mmol) and oxetane-3-carboxylic acid (44 mg, 0.43 mmol) as starting materials according to the fourth step of Example 9.

[0911] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.32-7.29(m,1H),6.48(s,1H),6.17-6.14(m,1H),4.89-4.85(m, 2H),4.81-4.77(m,2H),4.19-4.14(m,1H),4.09(s,4H),3.82-3.70(m,5H),1.93-1.88(m,1H),1.78-1.61(m,6H),1.57-1.46(m,2H).

[0912] LC-MS (ESI): m / z = 507.3 [M+H] + .

[0913] Example 55:

[0914] first step:

[0915] 2,2-Difluorocyclopropanecarboxylic acid (80 mg, 0.65 mmol), DIPEA (305 mg, 2.36 mmol), and HATU (270 mg, 0.71 mmol) were dissolved in dichloromethane (10 mL) and stirred in an ice-water bath under nitrogen for 10 minutes. 9D (250 mg, 0.59 mmol) was added, and the mixture was stirred in an ice-water bath for 5 minutes. The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was evaporated under reduced pressure. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 15:1) to obtain compound 55 (67 mg, 21.6%).

[0916] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0917] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.17-8.13(m,1H),7.63(s,1H),7.60-7.55(m,1H),7.49-7.45(m,1H),6.40(s,1H ),4.03(s,4H),3.85(s,1H),3.81(s,2H),3.74-3.68(m,2H),2.71-2.58(m,1H),1.92-1.74(m,3H),1.62-1.37(m,8H).

[0918] Example 56 and Example 57:

[0919] first step:

[0920] 1,1,1-Trifluoropropan-2-ol (223 mg, 1.96 mmol) and N,N'-carbonyldiimidazole (238 mg, 1.47 mmol) were dissolved in tetrahydrofuran (15 mL) and stirred at room temperature for 30 min. Then, 7D (400 mg, 0.98 mmol) and triethylamine (397 mg, 3.92 mmol) were added. The mixture was reacted at 70°C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and 30 mL of water was added. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to afford 56A (120 mg, 22% yield).

[0921] 56A was separated and purified by preparative HPLC to give compound 56 (36 mg, retention time: 3.940 min) and compound 57 (32 mg, retention time: 3.930 min).

[0922] Preparative HPLC separation and purification method: 1. Apparatus: Waters 2767 Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare a sample solution. 3. Preparative HPLC conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content ranging from 5% to 50%; c. Flow rate: 12 mL / min; d. Elution time: 30 min.

[0923] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT; 2. Column: Xtimate C18 4.6×50 mm, 3 μm; 3. Mobile phase system: A for 0.05% TFA in H2O; B for ACN; 4. Gradient: B 5-95%; 5. Acquisition time: 10 min; 6. Flow rate: 1.0 mL / min.

[0924] Compound 56: 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.50-7.47(m,1H),7.25-7.21(m,2H),6.49(s,1H),5.28-5.21(m,1H),4.31-4.13(m,2H) ,4.04(s,4H),3.77-3.72(m,4H),2.87-2.82(m,2H),2.07(s,1H),1.91-1.87(m,2H),1.41-1.39(m,3H),1.34-1.19(m,2H).

[0925] LC-MS (ESI): m / z = 549.3 [M+H] + .

[0926] Compound 57: 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.51-7.47(m,1H),7.26-7.22(m,2H),6.49(s,1H),5.28-5.22(m,1H),4.31-4.13(m,2H) ,4.05(s,4H),3.79-3.70(m,4H),2.88-2.83(m,2H),2.07(s,1H),1.92-1.88(m,2H),1.42-1.39(m,3H),1.34-1.20(m,2H).

[0927] LC-MS (ESI): m / z = 549.3 [M+H] + .

[0928] Example 58:

[0929] first step:

[0930] Compound 58A (1.0 g, 4.97 mmol) and triethylamine (1.51 g, 14.91 mmol) were added sequentially to dichloromethane (30 mL). Methanesulfonic anhydride (1.73 g, 9.94 mmol) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 58B (1.50 g), which was used directly in the next step without purification.

[0931] LC-MS (ESI): m / z = 280.1 [M+H] + .

[0932] Step 2:

[0933] Compound 58B (0.5 g, 1.79 mmol) was dissolved in anhydrous methanol (2 mL), and then a methanolic hydrochloric acid solution (5.0 mL, 4 M) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated to obtain crude compound 58C, which was used directly in the next step.

[0934] LC-MS (ESI): m / z = 180.1 [M+H] + .

[0935] Step 3:

[0936] Compound 58C (0.45 g, 2.51 mmol) and triethylamine (0.76 g, 7.53 mmol) were added sequentially to dichloromethane (30 mL). Cyclopropylcarbonyl chloride (0.34 g, 3.26 mmol) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 58D (0.4 g), which was used directly in the next step without purification.

[0937] LC-MS (ESI): m / z = 248.1 [M+H] + .

[0938] Step 4:

[0939] Compound 58D (0.4 g, 1.62 mmol), intermediate 7B (0.50 g, 1.62 mmol), and potassium carbonate (0.45 g, 3.24 mmol) were added to DMF (20 ml) in sequence, heated to 75°C and reacted overnight. The mixture was filtered, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified using Biotage Isolera One (20 g silica gel column, eluent: 0-10% dichloromethane / anhydrous methanol) to give compound 58 (100 mg, yield: 13%).

[0940] LC-MS (ESI): m / z = 463.2 [M+H] + .

[0941] 1 H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.15(s,1H),7.63(s,1H),7.56-7.58(m,1H),7.47(d,1H),6.39(s,1H),4.28-4.34(m ,1H),4.03(s,4H),3.88(d,2H),3.81(s,2H),2.52-2.56(m,1H),2.06-2.09(m,4H),1.47-1.51(m,1H),0.60-0.65(m,4H).

[0942] Example 59:

[0943] first step:

[0944] Compound 59A (1.0 g, 4.97 mmol) and triethylamine (1.51 g, 14.91 mmol) were added sequentially to dichloromethane (30 mL). Methanesulfonic anhydride (1.73 g, 9.94 mmol) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 59B (1.50 g), which was used directly in the next step without purification.

[0945] LC-MS (ESI): m / z = 280.1 [M+H] + .

[0946] Step 2:

[0947] Compound 59B (0.5 g, 1.79 mmol) was dissolved in anhydrous methanol (2 mL), and then a methanolic hydrochloric acid solution (5.0 mL, 4 M) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated to obtain crude compound 59C, which was used directly in the next step.

[0948] LC-MS (ESI): m / z = 180.1 [M+H] + .

[0949] Step 3:

[0950] Compound 59C (0.45 g, 2.51 mmol) and triethylamine (0.76 g, 7.53 mmol) were added sequentially to dichloromethane (30 mL). Cyclopropylcarbonyl chloride (0.34 g, 3.26 mmol) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 59D (0.5 g), which was used directly in the next step without purification.

[0951] LC-MS (ESI): m / z = 248.1 [M+H] + .

[0952] Step 4:

[0953] Compound 59D (0.5 g, 2.02 mmol), intermediate 7B (0.63 g, 2.02 mmol), and potassium carbonate (0.56 g, 4.04 mmol) were added to DMF (20 ml) in sequence, heated to 75°C and reacted overnight. The mixture was filtered, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified using Biotage Isolera One (20 g silica gel column, eluent: 0-10% dichloromethane / anhydrous methanol) to give compound 59 (130 mg, yield: 14%).

[0954] LC-MS (ESI): m / z = 463.2 [M+H] + .

[0955] 1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.15(s,1H),7.63(s,1H),7.56-7.58(m,1H),7.47(d,1H),6.41(s,1H),4.12-4.1 7(m,1H),4.03(s,4H),3.79-3.82(m,4H),2.29-2.36(m,3H),1.68-1.74(m,2H),1.50-1.54(m,1H),0.59-0.66(m,4H).

[0956] Example 60:

[0957] first step:

[0958] Compound 60A (1.0 g, 5.34 mmol) and triethylamine (1.62 g, 16.02 mmol) were weighed into a 100 mL single-necked flask and dissolved in dichloromethane (20 mL). Methanesulfonic anhydride (1.12 g, 6.43 mmol) was added and stirred at 25°C for 16 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). Water (20 mL) was added and stirred for 5 min. The mixture was extracted with dichloromethane (20 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: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 60B (1.2 g, 90% yield), which was used directly in the next step.

[0959] Step 2:

[0960] To a 100 mL single-necked flask, compound 7B (0.5 g, 1.61 mmol) and 60B (0.48 g, 1.93 mmol) were added and dissolved in DMF (20 mL). Potassium carbonate (0.66 g, 4.75 mmol) was added. After the addition was complete, the system was protected by nitrogen and stirred at 70°C for 16 h. LCMS analysis showed that the reaction of the starting material was complete. Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 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: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 60C (0.5 g, yield: 64%).

[0961] LCMS m / z=481.1[M+1] +

[0962] Step 3:

[0963] Compound 60C (0.5 g, 1.04 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (6 mL). Trifluoroacetic acid (3 mL) was added. After the addition was complete, the system was protected with nitrogen and stirred at 20°C for 2 h. LCMS analysis showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure to obtain the target compound 60D (0.4 g, crude product).

[0964] LCMS m / z=381.1[M+1] +

[0965] Step 4:

[0966] Carbonyldiimidazole (0.34 g, 2.1 mmol) and N-Boc-3-hydroxyazetidine (0.36 g, 2.1 mmol) were weighed into a 100 mL single-necked flask and dissolved in tetrahydrofuran (10 mL). The mixture was stirred at 25°C for 1 h, followed by the addition of 60D (0.4 g, 1.05 mmol) and triethylamine (0.32 g, 3.15 mmol). After the addition, the mixture was stirred at 70°C for 16 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 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: petroleum ether:ethyl acetate = 1:1) to obtain the title compound 60E (0.40 g, yield: 66%).

[0967] LCMS m / z=524.1[M-55] +

[0968] Step 5:

[0969] Compound 60E (0.4 g, 0.69 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (6 mL). Trifluoroacetic acid (3 mL) was added. After the addition was complete, the system was protected with nitrogen and stirred at 20°C for 4 h. LCMS analysis showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure to obtain the target compound 60F (0.4 g, crude product).

[0970] LCMS m / z=480.1[M+1] +

[0971] Step 6:

[0972] Compound 60F (300 mg, 0.73 mmol) and triethylamine (0.16 g, 1.58 mmol) were weighed and dissolved in dichloromethane (6 mL) in a 100 mL single-necked flask. Methanesulfonyl chloride (89 mg, 0.77 mmol) was added at 0°C. After addition, the system was protected with nitrogen and stirred at 0°C for 2 h. LCMS confirmed the complete reaction. Water (20 mL) was added, stirred for 5 min, and extracted with dichloromethane (20 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: petroleum ether:ethyl acetate = 1:1) to obtain the crude target compound. Preparative HPLC yielded compound 60 (35 mg, 12% yield).

[0973] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Samples were dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content ranging from 35% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 20 min.

[0974] LCMS m / z=558.2[M+1] +

[0975] 1 H NMR(400MHz,DMSO)δ8.20(s,1H),7.63(s,1H),7.57(d,1H),7.47(d,1H),6.42(s,1H),5.00-5.05 (m,2H),4.12-4.16(m,3H),4.00-4.03(m,7H),3.82-3.86(m,5H),3.04(s,3H),2.95-3.01(m,1H).

[0976] Example 61:

[0977] first step:

[0978] 61A (2.00 g, 8.96 mmol) was dissolved in dry toluene (60 mL), and pinacol borane (2.00 g, 15.61 mmol) was added dropwise. Bis(cyclopentadienyl)zirconium chloride (0.46 g, 1.79 mmol) was then added. After the addition, the atmosphere was replaced with nitrogen, and the mixture was stirred at 65°C for 18 h. TLC (petroleum ether:ethyl acetate = 2:1 (v / v)) confirmed the reaction was complete. The reaction solution was concentrated, and the crude product was used directly in the next step.

[0979] Step 2:

[0980] Compound 61B (3.14 g, 8.94 mmol) and 61a (3.96 g, 8.94 mmol, prepared using 7B as starting material according to the synthetic method of 16B) were dissolved in 1,4-dioxane (60 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.65 g, 0.89 mmol), potassium carbonate (4.32 g, 31.29 mmol), and water (12 mL) were added sequentially. After addition, the atmosphere was replaced with nitrogen three times and the reaction was stirred at 85°C for 18 h. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 61C (1.4 g, 30% yield).

[0981] LC-MS(ESI):m / z=463.10[M-56+H] + .

[0982] Step 3:

[0983] Compound 61C (800 mg, 1.54 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at room temperature for 2 h. The reaction was completed under TLC monitoring (petroleum ether:ethyl acetate = 1:1 (v / v)). The reaction solution was concentrated to obtain compound 61D (640 mg, crude product), which was used directly in the next step without purification.

[0984] LC-MS (ESI): m / z = 419.10 [M+H] + .

[0985] Step 4:

[0986] Compound 61D (640 mg, 1.53 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (542 mg, 5.35 mmol) and cyclopropionyl chloride (240 mg, 2.30 mmol) were added sequentially in an ice-water bath. After the addition was complete, the reaction was continued in an ice-water bath for 2 h. TLC monitoring (dichloromethane:methanol = 20:1 (v / v)) confirmed the completion of the reaction. The reaction solution was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the target compound 61 (87 mg, yield: 12%).

[0987] LCMS m / z=487.7[M+1] +

[0988] 1H NMR(400MHZ,DMSO-d6)δ8.30(s,1H),7.89(d,1H),7.62(s,1H),7.57(d,1H),7.47(d,1H),6.63(dd,1H),6.35(s,1H),6.11(d,1H ),4.03(s,4H),3.81(s,2H),3.49(s,1H),2.01(dd,1H),1.79(dd,4H),1.53-1.46(m,1H),1.26-1.15(m,4H),0.68-0.55(m,4H).

[0989] Example 62:

[0990] first step:

[0991] Compound 61D (485 mg, 1.16 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (411 mg, 4.06 mmol) and cyclopropylmethanesulfonyl chloride (269 mg, 1.74 mmol) were added sequentially in an ice-water bath. After the addition was complete, the reaction was continued in an ice-water bath for 7 h. TLC monitoring (dichloromethane:methanol = 20:1 (v / v)) confirmed the completion of the reaction. The reaction solution was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the target compound 67 (68 mg, yield: 11%).

[0992] LCMS m / z=537.8[M+1] +

[0993] 1 H NMR(400MHZ,DMSO-d6)δ8.30(s,1H),7.62(s,1H),7.57(d,1H),7.47(d,1H),6.99(d,1H),6.62(dd,1H),6.35(s,1H),6.09(d,1H),4.03(s,4 H),3.81(s,2H),3.07(s,1H),2.92(d,2H),1.92(d,3H),1.74(d,2H),1 .35-1.11(m,4H),1.00(qd,1H),0.59-0.52(m,2H),0.37-0.29(m,2H).

[0994] Example 63

[0995] first step:

[0996] Using 14D (200 mg, 0.47 mmol) and oxetane-3-carboxylic acid (58 mg, 0.56 mmol) as raw materials, referring to the synthesis procedure of the fourth step of Example 9, compound 63 (46 mg, yield: 23%) was synthesized.

[0997] 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.32-7.29(m,1H),6.48(s,1H),5.68-5.65(m,1H),4.87-4.83(m, 2H),4.79-4.75(m,2H),4.09(s,4H),3.83-3.75(m,3H),3.72-3.63(m,3H),2.08-1.96(m,4H),1.88-1.82(m,1H),1.26-1.08(m,4H).

[0998] LC-MS (ESI): m / z = 507.8 [M+H] + .

[0999] Example 64

[1000] first step:

[1001] Compound 64 was synthesized using Compound 14D and Compound 17C as raw materials by referring to the third step of Example 17.

[1002] LC-MS (ESI): m / z = 600.6 [M+H] + .

[1003] 1 H NMR (400MHz, CDCl3): δ7.57(s,1H),7.50(d,1H),δ7.46(s,1H),7.31(s,1H),6.48(s,1H),5.17-5.11(m,1H),δ4.68(s,1H),4.16(t,2H),4.10( s,4H),3.98-3.94(m,2H),3.79(s,2H),3.67(d,2H),3.48-3.40(m,1H) ,2.89(s,3H),2.08-1.97(m,4H),1.89-1.80(m,1H),1.23-1.10(m,4H).

[1004] Example 65:

[1005] first step:

[1006] Using (1R)-2,2-difluorocyclopropane-1-carboxylic acid (86 mg, 0.71 mmol) and compound 14D (250 mg, 0.54 mmol) as starting materials, referring to the first step of Example 55, compound 65 (61 mg, yield 19.6%) was obtained.

[1007] LC-MS (ESI): m / z = 527.2 [M+H] + .

[1008] 1 H NMR (400MHz, DMSO-d6) δ8.22-8.17(m,1H),8.12(s,1H),7.64-7.62(m,1H),7.59-7.55(m,1H),7.49-7.44(m,1H),6.39(s,1H),4.02(s ,4H),3.80(s,2H),3.66-3.61(m,2H),3.57-3.48(m,1H),1.90-1.77(m,6H),1.73-1.61(m,1H),1.27-1.12(m,3H),1.12-1.00(m,2H).

[1009] Example 66

[1010] first step:

[1011] Using (1S)-2,2-difluorocyclopropane-1-carboxylic acid (86 mg, 0.71 mmol) and compound 14D (250 mg, 0.54 mmol) as starting materials, referring to the first step of Example 55, compound 66 (53 mg, yield 17.1%) was obtained.

[1012] LC-MS (ESI): m / z = 527.2 [M+H] + .

[1013] 1 H NMR (400MHz, DMSO-d6) δ8.21-8.16(m,1H),8.12(s,1H),7.65-7.62(m,1H),7.59-7.56(m,1H),7.50-7.45(m,1H),6.39(s,1H),4.03(s ,4H),3.81(s,2H),3.66-3.61(m,2H),3.58-3.48(m,1H),1.92-1.77(m,6H),1.72-1.63(m,1H),1.27-1.12(m,3H),1.12-1.01(m,2H).

[1014] Example 67:

[1015] first step:

[1016] Using cyclopropanol (83 mg, 1.42 mmol) and compound 14D (300 mg, 0.65 mmol) as starting materials, referring to the fourth step of Example 19, compound 67 (135 mg, yield 37.5%) was obtained.

[1017] LC-MS (ESI): m / z = 507.1 [M+H] + .

[1018] 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.64-7.61(m,1H),7.59-7.55(m,1H),7 .49-7.45(m,1H),7.06-6.99(m,1H),6.38(s,1H),4.03(s,4H),3.94-3.88(m ,1H),3.80(s,2H),3.65-3.59(m,2H),3.25-3.17(m,1H),1.86-1.76(m,4H), 1.67-1.56(m,1H),1.22-0.98(m,4H),0.63-0.57(m,2H),0.57-0.50(m,2H).

[1019] Example 68

[1020] first step:

[1021] Using 14D (170 mg, 0.37 mmol) and 3-thiophenesulfonyl chloride (88 mg, 0.48 mmol) as starting materials, the procedure was followed by reference to Example 14 (step 4) to give compound 68 (57 mg, yield: 25%).

[1022] LC-MS (ESI): m / z = 569.1 [M+H] + .

[1023] 1H NMR(400MHz,DMSO-d6)δ8.14-8.11(m,1H),8.09(s,1H),7.75-7.71(m,1H),7 .63-7.61(m,1H),7.60-7.53(m,2H),7.48-7.45(m,1H),7.35-7.32(m,1H),6 .37(s,1H),4.02(s,4H),3.79(s,2H),3.60-3.56(m,2H),2.99-2.88(m,1H), 1.77-1.64(m,4H),1.62-1.52(m,1H),1.24-1.14(m,2H),1.02-0.91(m,2H).

[1024] Example 69, 70:

[1025] first step:

[1026] Isomer A and Isomer B were prepared using compound 50 as raw material by SFC.

[1027] SFC preparative method: Instrument: Waters 150Prep-SFC E preparative liquid chromatography; chromatographic column: Chiralcel AD column. The sample was dissolved in DMF and filtered through a 0.45 μm 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: 70% content, flow rate: 100 mL / min. Column pressure: 100 bar, column temperature: 25°C, absorption wavelength: 220 nm, cycle time: 3.0 min. Isomer A retention time: 1.247 min, set as compound 69. Isomer B retention time: 1.741 min, set as compound 70.

[1028] Isomer A:

[1029] LC-MS (ESI): m / z = 624.3 [M+H] + .

[1030] 1H NMR (400MHz, CDCl3): δ7.60(s,1H),7.51-7.49(m,1H),7.46(s,1H),7.32-7.30(m,1H),6.49(s,1H),4.69-4.61(m,1H),4.12(s,5H) ),3.81-3.66(m,4H),3.60-3.37(m,2H),3.22-2.93(m,4H),2.80(s,3H),2.67-2.62(m,1H),2.15-1.68(m,7H),1.43-1.15(m,4H).

[1031] Isomer B:

[1032] LC-MS (ESI): m / z = 624.7 [M+H] + .

[1033] 1 H NMR (400MHz, CDCl3): δ7.61(s,1H),7.51-7.49(m,1H),7.46(s,1H),7.32-7.30(m,1H),6.49(s,1H),4.68-4.60(m,1H),4.12(s,5H) ),3.81-3.66(m,4H),3.60-3.37(m,2H),3.21-2.93(m,4H),2.80(s,3H),2.68-2.62(m,1H),2.15-1.68(m,7H),1.43-1.14(m,4H).

[1034] Example 71

[1035] first step:

[1036] Using 14D (200 mg, 0.49 mmol) and 3-thiophenesulfonyl chloride (147 mg, 0.98 mmol) as starting materials, the procedure was followed by reference to Example 14 (step 4) to give compound 71 (140 mg, yield: 48.8%).

[1037] LC-MS (ESI): m / z = 585.2 [M+H] + .

[1038] 1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.65-7.61(m,1H),7.60-7.54(m,1H) ),7.49-7.45(m,1H),6.98-6.94(m,1H),6.39(s,1H),4.42-4.33(m,1H), 4.05-3.93(m,8H),3.83-3.76(m,4H),3.72-3.67(m,2H),2.99(s,3H),2. 77-2.65(m,2H),1.96-1.84(m,1H),1.75-1.66(m,2H),1.18-1.05(m,2H).

[1039] Example 72

[1040] first step:

[1041] Using 7D (150 mg, 0.37 mmol) and 72A (80 mg, 0.37 mmol) as starting materials, 72B (161 mg, yield: 72%) was synthesized by referring to the first step of Example 50.

[1042] Step 2:

[1043] Using 72B (161 mg, 0.27 mmol) as starting material, referring to the synthesis procedure of the second step of Example 50, 72C (113 mg, yield: 83%) was synthesized.

[1044] LC-MS (ESI): m / z = 506.2 [M+H] + .

[1045] Step 3:

[1046] Using 72C (113 mg, 0.22 mmol) as starting material and referring to the synthesis procedure of the third step of Example 50, compound 72 (34 mg, yield: 26%) was synthesized.

[1047] 1H NMR(400MHz, CDCl3)δ7.61(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.32-7.29(m,1H), 6.49(s,1H),5.08-5.05(m,1H),4.67-4.63(m,1H),4.09-4.02(m,5H),3.81-3.62(m,5H ),3.24-3.16(m,1H),3.03-2.92(m,4H),2.75-2.68(m,2H),2.67-2.58(m,1H),2.33-2. 22(m,2H),2.17-2.07(m,1H),1.98-1.94(m,1H),1.89-1.84(m,1H),1.29-1.15(m,2H).

[1048] LC-MS (ESI): m / z = 584.7 [M+H] + .

[1049] Example 73

[1050] first step:

[1051] Compound 73 was synthesized using 73A and 7D as raw materials and referring to the first step of the synthesis procedure in Example 50.

[1052] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.51-7.49(m,1H),7.46(s,1H),7.32 -7.30(m,1H),6.49(s,1H),4.66-4.63(m,1H),4.11(s,4H),3.80-3.68(m,5H),3.08 -3.01(m,2H),2.97-2.88(m,2H),2.76-2.61(m,3H),2.18-2.11(m,1H),2.02-1.99(m,1H),1.88-1.85(m,1H),1.29-1.15(m,2H).

[1053] LC-MS (ESI): m / z = 527.2 [M+H] + .

[1054] Example 74

[1055] first step:

[1056] Compound 74B (5.1 g, yield: 76.8%) was synthesized using 74A (3.5 g, 24.93 mmol) according to the literature (Journal of Materials Chemistry C: Materials for Optical and Electronic Devices, Volume: 10, Issue: 42, Pages: 15861-15871, 2022).

[1057] Step 2:

[1058] At room temperature, 74B (5.1 g, 19.17 mmol) was dissolved in methanol (50 mL). Sodium borohydride (1.45 g, 38.34 mmol) was added portionwise under ice-cooling. The reaction was allowed to react at room temperature for 3 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. The reaction solution was concentrated, and the residue was redissolved in EA (50 mL). The organic phase was washed with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 74C (4.5 g, yield: 86.9%).

[1059] Step 3:

[1060] At room temperature, 74C (4.5 g, 16.66 mmol) was dissolved in dry DCM (50 mL). Sulfonyl chloride (3.96 g, 33.36 mmol) was added dropwise under ice-cooling. The reaction was allowed to react at room temperature for 2 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. The reaction solution was concentrated, and the residue was redissolved in DCM (50 mL). The organic phase was washed with water (50 mL x 2) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to afford 74D (3.5 g, 68.4% yield).

[1061] Step 4:

[1062] 74D (3.5 g, 11.40 mmol) was dissolved in dry DMF (20 mL) at room temperature. Sodium hydride (1.0 g, 24.97 mmol) was added under ice-cooling and stirred. p-Toluenesulfonamide (1.95 g, 11.4 mmol) was added and allowed to react at 0°C for 30 min. The mixture was then warmed to room temperature and allowed to react for 2 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. EA (40 mL) was added to the reaction solution, and the organic phase was washed with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to afford 74E (2.5 g, 54.1% yield).

[1063] LC-MS (ESI): m / z = 405.9 [M+H] + .

[1064] Step 5:

[1065] 74E (2.5 g, 6.17 mmol) was dissolved in dry DMF (20 mL) at room temperature. Cuprous iodide (1.53 g, 8.03 mmol) and HMPA (5.53 g, 30.85 mmol) were added. The mixture was stirred at room temperature for 10 min under a nitrogen atmosphere. Methyl fluorosulfonyldifluoroacetate (5.93 g, 30.81 mmol) was then added. The reaction was continued at 100°C under a nitrogen atmosphere for 3 h. The reaction was stopped by TLC monitoring of the disappearance of the starting material. After cooling to room temperature, EA (30 mL) was added to the reaction solution. The organic phase was washed with water (60 mL × 2) and saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to afford 74F (1.7 g, yield: 79.3%).

[1066] LC-MS (ESI): m / z = 348.3 [M+H] + .

[1067] Step 6:

[1068] At room temperature, a round-bottom flask was charged with 74F (1.7 g, 4.89 mmol), phenol (0.92 g, 9.78 mmol), and propionic acid (1.49 g, 1.5 mL, 20.05 mmol). 48% aqueous hydrobromic acid (20 mL) was then added. The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction was stopped by TLC monitoring of the disappearance of the starting material. After cooling to room temperature, water (10 mL) was added to the reaction solution. The aqueous phase was washed with diethyl ether (30 mL x 3) and concentrated without purification to afford the product 74G (1.2 g, 89.9% yield).

[1069] LC-MS (ESI): m / z = 194.1 [M+H] + .

[1070] Step 7:

[1071] Compound 74H (100 mg, yield: 55.5%) was synthesized using 74G (74.38 mg, 0.39 mmol) as starting material and referring to the synthesis method of the first step in Example 1.

[1072] LC-MS(ESI):m / z=415.1[M+H-100] + .

[1073] Step 8:

[1074] Compound 74I (75 mg, yield: 95.25%) was synthesized using 74H (100 mg, 0.19 mmol) as starting material and referring to the synthesis method of the third step of Example 1.

[1075] LC-MS (ESI): m / z = 415.2 [M+H] + .

[1076] Step 9:

[1077] Using 74I (75 mg, 0.18 mmol) as starting material, the target compound 74 (20 mg, yield: 18.8%) was synthesized by referring to the synthesis method of step 8 of Example 20.

[1078] LC-MS (ESI): m / z = 592.0 [M+H] + .

[1079] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.18(s,1H),6.47(s,1H),5.16-5.10(m,1H),4.21-4.15(m,6H),4.02-3.98(m,4H),3 .83(s,2H),3.74-3.72(d,2H),2.89(s,3H),2.84-2.75(m,2H),2.12-2.00(d,1H),1.90-1.87(d,2H),1.29-1.28(d,2H).

[1080] Example 75

[1081] first step:

[1082] Compound 75A was synthesized using 7D and 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid as raw materials and referring to the first step of the synthesis of Example 50.

[1083] LC-MS (ESI): m / z = 660.9 [M+H] + .

[1084] Step 2:

[1085] Compound 75B was synthesized using compound 75A as starting material and referring to the synthesis procedure of the second step of Example 50.

[1086] LC-MS (ESI): m / z = 560.7 [M+H] + .

[1087] Step 3:

[1088] Using 75B as starting material, compound 75 was synthesized by referring to the synthesis procedure of the third step of Example 50.

[1089] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.49(d,J=8.0Hz,1H),7.45(s,1H),7.31(d,J=8.0Hz,1H),6.48(s, 1H),4.63(d,J=13.6Hz,1H),4.09(s,4H),3.79(s,2H),3.77-3.67(m,3H),3.24-3.15(m,3H),3.12-3. 09(m,2H),2.97(td,J=13.2,2.4Hz,1H),2.75(s,3H),2.61(td,J=12.8,2.8Hz,1H),2.17-2.08(m,3H) ,2.05-1.96(m,3H),1.84(d,J=12.8Hz,1H),1.77-1.75(m,2H),1.69-1.66(m,2H),1.24-1.14(m,2H).

[1090] LC-MS (ESI): m / z = 638.3 [M+H] + .

[1091] Example 76

[1092] first step:

[1093] Compound 76 was synthesized using 76A and 7D as raw materials and referring to the first step of the synthesis procedure of Example 71.

[1094] LC-MS (ESI): m / z = 542.2 [M+H] + .

[1095] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.51-7.48(m,1H),7.46(s,1H),7.32 -7.30(m,1H),6.48(s,1H),4.66-4.65(m,1H),4.18-4.13(m,1H),4.10(s,4H),3.98-3.95(m,2H),3.79(s,2H),3.73-3.71(m,2H),3.04 -2.93(m,2H),2.85-2.78(m,2H),2.50-2.37(m,2H),2.08-2.04(m,1H),1.91-1.88(m,2H),1.32-1.22(m,4H).

[1096] Example 77

[1097] first step:

[1098] Compound 77A (1.20 g, 5.63 mmol) and triethylamine (1.71 g, 16.89 mmol) were weighed into a 100 mL single-necked flask and dissolved in dichloromethane (20 mL). Methanesulfonic anhydride (1.18 g, 6.76 mmol) was added and stirred at 25°C for 16 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). Water (20 mL) was added and stirred for 5 min. The mixture was extracted with dichloromethane (20 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: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 77B (1.5 g, yield: 91%), which was used directly in the next step.

[1099] Step 2:

[1100] To a 100 mL single-necked flask, compound 7B (1.50 g, 4.81 mmol) and 77B (1.40 g, 4.81 mmol) were added and dissolved in DMF (20 mL). Potassium carbonate (1.99 g, 14.43 mmol) was added. After the addition was complete, the system was protected with nitrogen and stirred at 70°C for 16 h. LCMS analysis showed that the reaction of the starting material was complete. Water (40 mL) was added, stirred for 5 min, and extracted with ethyl acetate (40 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: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 77C (0.90 g, yield: 37%).

[1101] LCMS m / z=451.2[M-55] +

[1102] Step 3:

[1103] Compound 77C (1.0 g, 1.97 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added. After the addition was complete, the system was protected with nitrogen and stirred at 20°C for 2 h. LCMS analysis showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure to obtain the target compound 77D (0.8 g, crude product).

[1104] LCMS m / z=407.1[M+1] +

[1105] Step 4:

[1106] Carbonyldiimidazole (0.40 g, 2.47 mmol) and N-Boc-3-hydroxyazetidine (0.43 g, 2.47 mmol) were weighed into a 100 mL single-necked flask and dissolved in tetrahydrofuran (20 mL). The mixture was stirred at 25°C for 1 h, followed by the addition of 77D (0.50 g, 1.23 mmol) and triethylamine (0.37 g, 3.65 mmol). After the addition, the mixture was stirred at 70°C for 16 h. TLC (petroleum ether:ethyl acetate = 1:1) indicated complete reaction. Water (20 mL) was added, stirred for 5 min, and extracted with ethyl acetate (20 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: petroleum ether:ethyl acetate = 1:1) to obtain the title compound 77E (0.40 g, 53% yield).

[1107] LCMS m / z=550.1[M-55] +

[1108] Step 5:

[1109] Compound 77E (0.4 g, 0.66 mmol) was added to a 100 mL single-necked flask and dissolved in dichloromethane (6 mL). Trifluoroacetic acid (3 mL) was added. After the addition was completed, the system was protected with nitrogen and stirred at 20°C for 4 h. LCMS analysis showed that the reaction of the raw material was complete. The reaction solution was concentrated under reduced pressure to obtain the target compound 77F (0.3 g, crude product).

[1110] LCMS m / z=506.1[M+1] +

[1111] Step 6:

[1112] Compound 77F (300 mg, 0.59 mmol) and triethylamine (0.18 g, 1.78 mmol) were weighed and dissolved in dichloromethane (6 mL) in a 100 mL single-necked flask. Methanesulfonyl chloride (81 mg, 0.71 mmol) was added at 0°C. After addition, the system was protected with nitrogen and stirred at 0°C for 2 h. LCMS confirmed the complete reaction. Water (20 mL) was added, stirred for 5 min, and extracted with dichloromethane (20 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: petroleum ether:ethyl acetate = 1:1) to obtain the crude target compound. Preparative HPLC yielded compound 77 (35 mg, 12% yield).

[1113] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm); Sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonia); b. Gradient elution, mobile phase A content ranging from 40% to 80%; c. Flow rate: 15 mL / min; d. Elution time: 20 min.

[1114] LCMS m / z=584.2[M+1] +

[1115] 1 H NMR(400MHZ,DMSO-d6)δ8.12(s,1H),7.63(s,1H),7.57(d,1H),7.47(d, 1H),6.40(s,1H),4.99-5.05(m,1H),4.10-4.16(m,2H),4.02(s,4H),3.8 1-3.87(m,4H),3.77(d,2H),3.58(d,1H),3.49(d,1H),3.41-3.45(m,1H ),3.33-3.38(m,1H),3.04(s,3H),1.58-1.65(m,2H),1.00-1.05(m,1H).

[1116] Example 78:

[1117] first step:

[1118] N-Bromosuccinimide (4.67 g, 26.26 mmol) and silver fluoride (7.57 g, 59.68 mmol) were added to a mixture of acetonitrile (90 mL) and water (10 mL). 78A (5.00 g, 23.87 mmol) was added at room temperature and allowed to react overnight at 80°C. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1, v / v) to afford 78B (5.50 g, 74% yield).

[1119] LC-MS (ESI): m / z = 252.2 [M-56] + .

[1120] Step 2:

[1121] 78B (3.00 g, 9.73 mmol) was dissolved in 1,4-dioxane (30 mL). Bis(pinacol)diboron (3.71 g, 14.60 mmol), tricyclohexylphosphine (0.27 g, 0.96 mmol), and potassium acetate (3.36 g, 24.31 mmol) were added at room temperature. The atmosphere was purged with nitrogen three times after the addition. Tris(dibenzylidene-BASE acetone)dipalladium (0.89 g, 0.97 mmol) was then added. The atmosphere was purged with nitrogen three times after the addition. The reaction was allowed to react at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1, v / v) to afford 78C (3.40 g, 98% yield).

[1122] LC-MS (ESI): m / z = 255.4 [M-100] + .

[1123] Step 3:

[1124] 41B (1.70 g, 3.83 mmol) was dissolved in 1,4-dioxane (30 mL) and water (6 mL). 78C (1.70 g, 4.79 mmol), potassium carbonate (1.32 g, 9.55 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.35 g, 0.48 mmol) were added at room temperature. After the addition, the atmosphere was replaced with nitrogen three times and the mixture was reacted at 90°C for 3 hr. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to afford 78D (0.60 g, 23% yield).

[1125] LC-MS (ESI): m / z = 467.6 [M-55] + .

[1126] Step 4:

[1127] Dissolve 78D (300 mg, 0.57 mmol) in dichloromethane (8 mL) and add trifluoroacetic acid (2 mL) at 0-5°C. Allow to react at room temperature for 2.5 hours. After completion of the reaction, concentrate the reaction mixture to afford crude 78E, which was used directly in the next step.

[1128] Step 5:

[1129] 1-Methanesulfonylazetidin-3-ol (232.67 mg, 1.54 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N'-carbonyldiimidazole (249.55 mg, 1.54 mmol) was added at room temperature. The reaction mixture was allowed to react at room temperature for 4.5 hours, followed by the dropwise addition of triethylamine (288.39 mg, 2.85 mmol) at room temperature. After the addition was complete and the reaction mixture was allowed to react at room temperature for 2 hours, a solution of 78E (240 mg, 0.57 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0-5°C. The mixture was allowed to react at 60°C overnight. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to yield compound 78 (195 mg, 57% yield).

[1130] LC-MS (ESI): m / z = 600.2 [M+H] + .

[1131] 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.62(s,1H),7.58-7.56(d,1H),7.48 -7.46(d,1H),6.41(s,1H),5.74-5.63(d,1H),5.07-5.01(m,1H),4.17-4.1 3(m,2H),4.10-4.05(m,6H),3.89-3.86(m,2H),3.83(s,2H),3.04(s,3H),3 .00-2.77(m,2H),2.66-2.49(m,1H),1.86-1.83(d,2H),1.43-1.40(d,2H).

[1132] Example 79:

[1133] first step:

[1134] Compound 79A (6.50 g, 35.90 mmol, synthesis reference: Organic Letters, 2012, vol. 14, #6, p. 1508-1511) was dissolved in N,N-dimethylformamide (65 mL). Sodium trihydride (3.59 g, 89.75 mmol) was added at 0-5°C and allowed to react at room temperature for 30 min. p-Toluenesulfonamide (6.15 g, 35.90 mmol) was then added at 0-5°C and allowed to react at room temperature for 3 hr. After completion of the reaction, water (200 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate (200 mL x 2). The organic phase was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to afford 79B (4.80 g, 47% yield).

[1135] LC-MS (ESI): m / z = 280.2 [M+H] + .

[1136] Step 2:

[1137] 79B (0.55 g, 1.97 mmol) was dissolved in acetonitrile (11 mL) and N-bromosuccinimide (385.68 mg, 2.17 mmol) was added at room temperature. The mixture was allowed to react at room temperature for 1.5 hr. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to afford 79C (0.50 g, 70% yield).

[1138] Step 3:

[1139] 79C (0.50 g, 1.40 mmol) was dissolved in 1,4-dioxane (16 mL) and water (2 mL). Methylboric acid (355.22 mg, 5.60 mmol) and potassium carbonate (967.47 mg, 7.00 mmol) were added at room temperature. After the addition, the atmosphere was purged with nitrogen three times. Tetrakis(triphenylphosphine)palladium (161.78 mg, 0.14 mmol) was added and the atmosphere was purged with nitrogen three times. The mixture was allowed to react at 100°C overnight. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to afford 79D (0.25 g, 60% yield).

[1140] LC-MS (ESI): m / z = 294.1 [M+H] + .

[1141] Step 4:

[1142] Phenol (385.159.99 mg, 1.70 mmol) was added to 79D (0.25 g, 0.85 mmol) and aqueous hydrogen bromide (1 mL) at room temperature and allowed to react overnight at 100°C. After completion of the reaction, the reaction solution was extracted with diethyl ether (15 mL x 2), and the aqueous phase was directly concentrated to obtain crude product 79E, which was directly reacted in the next step.

[1143] LC-MS (ESI): m / z = 140.1 [M+H] + .

[1144] Step 5:

[1145] 16C (0.18 g, 0.54 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (136.61 mg, 1.35 mmol) and methanesulfonyl chloride (92.79 mg, 0.81 mmol) were added at 0-5°C. The mixture was allowed to react at room temperature for 30 minutes, and then 79E (90.21 mg, 0.65 mmol) was added. The reaction was allowed to react at room temperature overnight. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to afford compound 79F (110 mg, 44% yield).

[1146] LC-MS (ESI): m / z = 401.4 [M-55] + .

[1147] Step 6:

[1148] Dissolve 79F (110 mg, 0.24 mmol) in dichloromethane (4 mL) and add trifluoroacetic acid (1 mL) at 0-5°C. Allow to react at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain crude product 79G, which was used directly in the next step.

[1149] Step 7:

[1150] Cyclopropanol (37.64 mg, 0.65 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N'-carbonyldiimidazole (105.07 mg, 0.65 mmol) was added at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 4.5 hours, triethylamine (121.43 mg, 1.20 mmol) was added dropwise at room temperature. After the addition was complete and the reaction was allowed to proceed at room temperature for 2 hours, a solution of crude product 79G in tetrahydrofuran (0.5 mL) was added dropwise at 0-5°C. The reaction was continued at 60°C overnight. After the reaction was complete, the reaction solution was concentrated and purified by preparative HPLC to yield compound 79 (5 mg, 4% yield).

[1151] LC-MS (ESI): m / z = 411.8 [M+H]+ .

[1152] 1 H NMR(400MHz,DMSO-d6)δ8.29(s,1H),6.6\6-6.61(dd,1H),6.58(s,1H),6.31(s,1H),6.13-6.09(d,1H),3.99-3.94(m,3H),3. 82-3.81(m,4H),2.83-2.77(t,2H),2.40(s,3H),2.25-2.21(m,1H),1.68-1.65(d,2H),1.28-1.14(m,4H),0.65-0.56(m,4H).

[1153] Example 80

[1154] first step:

[1155] 61D (320 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (153.81 mg, 1.52 mmol) and deuterated acetyl chloride (92.93 mg, 1.14 mmol) were added dropwise at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to yield compound 80 (160.00 mg, 45% yield).

[1156] LC-MS (ESI): m / z = 464.5 [M+H] + .

[1157] 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.69-7.67(d,1H),7.62(s,1H),7.58-7.56(d,1H),7.48-7.46(d,1H),6.66-6.60(dd,1H),6.3 5(s,1H),6.13-6.09(d,1H),4.03(s,4H),3.81(s,2H),3.48-3.45(m,1H),2.01-2.00(m,1H),1.82-1.74(m,4H),1.24-1.13(m,4H).

[1158] Example 81

[1159] first step:

[1160] 81A (2.6 g, 18.56 mmol) was dissolved in N,N-dimethylformamide (30 mL). Cesium carbonate (9.07 g, 27.84 mmol) and deuterated iodomethane (3.23 g, 22.27 mmol) were added sequentially at 0-5°C. The mixture was allowed to react overnight at room temperature. After completion, water (200 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed once with water (200 mL) and once with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to yield 81B (2.7 g, 92% yield).

[1161] LC-MS (ESI): m / z = 158.2 [M+H] + .

[1162] Step 2:

[1163] 81B (2.7 g, 17.18 mmol) was dissolved in ethanol (30 mL). A solution of sodium hydroxide (1.38 g, 34.61 mmol) in water (10 mL) was added sequentially at 0-5°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in water. The pH was adjusted to 2-3 with 1N hydrochloric acid. A large amount of off-white solid precipitated, which was filtered and the filter cake was concentrated to obtain 81C (1.30 g, 56% yield).

[1164] LC-MS (ESI): m / z = 130.2 [M+H] + .

[1165] Step 3:

[1166] 61D (350 mg, 0.84 mmol) and 81C (119.32 mg, 0.92 mmol) were dissolved in N,N-dimethylformamide (10 mL). N-methylimidazole (344.82 mg, 4.20 mmol) was added at 0-5°C and allowed to react for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (353.53 mg, 1.26 mmol) was then added at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to afford compound 81 (170.00 mg, 38% yield).

[1167] LC-MS (ESI): m / z = 530.7 [M+H] + .

[1168] 1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.09(s,1H),7.82(s,1H),7.77-7.75(d,1H),7.63(s,1H),7.58-7.56(d,1H),7.48-7.46(d,1H),6.68-6.62 (dd,1H),6.36(s,1H),6.15-6.11(d,1H),4.04(s,4H),3.82(s,2H),3.7 2-3.64(m,1H),2.07-2.03(m,1H),1.88-1.77(m,4H),1.39-1.19(m,4H).

[1169] Example 82

[1170] first step:

[1171] Methylsulfonamide (190 mg, 2.0 mmol) was dissolved in DCM (10 mL), and DIPEA (650 mg, 5 mmol) was added. The mixture was allowed to react at room temperature for 2 h. 7D (408 mg, 1.0 mmol) was then added and stirred at room temperature for 12 h. After the reaction was complete, 10 mL of water was added to the reaction solution, which was then extracted with DCM (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to afford compound 82 (150 mg, 28% yield).

[1172] LC-MS (ESI): m / z = 530.5 [M+H] + .

[1173] 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.62(s,1H),7.57(d,1H),7.47(d,1H),6.38(s,1H),4.22(d,2H),4.03(s,4H),3. 80(s,2H),3.67(d,2H),3.31(s,H),2.70(s,3H),1.92(s,2H),1.92-1.75(m,1H),1.69-1.55(m,2H),1.07-0.97(m,2H).

[1174] 19 F NMR(376MHz,DMSO)δ-58.34(s).

[1175] Example 83

[1176] first step:

[1177] Compound 16C (420 mg, 1.25 mmol) was dissolved in dry dichloromethane (20 mL). Triethylamine (316 mg, 3.13 mmol) was added under ice-cooling. Methanesulfonyl chloride (172 mg, 1.50 mmol) was then slowly added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A solution of compound 83A (218 mg, 1.51 mmol) and triethylamine (191 mg, 1.89 mmol) in dichloromethane (10 mL) was slowly added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, as monitored by TLC (petroleum ether:ethyl acetate = 1:1 (v / v)), the reaction mixture was diluted with dichloromethane (100 mL) and separated by addition of water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 83B (380 mg, 65% yield).

[1178] LC-MS(ESI):m / z=406.1[M-56+H] + .

[1179] Step 2:

[1180] Compound 83B (380 mg, 0.82 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for 2 h. The reaction was completed under TLC monitoring (petroleum ether:ethyl acetate = 1:1 (v / v)). The reaction solution was concentrated to obtain compound 83C (315 mg, crude product), which was used directly in the next step without purification.

[1181] LC-MS (ESI): m / z = 362.4 [M+H] + .

[1182] Step 3:

[1183] Cyclopropanol (101 mg, 1.74 mmol) and N,N'-carbonyldiimidazole (282 mg, 1.74 mmol) were dissolved in tetrahydrofuran (15 mL) and reacted at room temperature for 1 h. Triethylamine (308 mg, 3.04 mmol) was added dropwise under an ice-water bath and allowed to react at room temperature for 2 h. Compound 83C (315 mg, 0.87 mmol) was added to the above solution and allowed to react at 60°C overnight. TLC (dichloromethane:methanol = 10:1 (v / v)) confirmed the completion of the reaction. The reaction solution was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the target compound 83 (65 mg, 17% yield).

[1184] LCMS m / z=446.4[M+1]+

[1185] 1 H NMR(400MHZ,DMSO-d6)δ8.31(s,1H),7.72(s,1H),7.68(d,1H),7.46(d,1H),6.65(dd,1H),6.35(s,1H),6.12(d,1H),4.03(s,2 H),4.00(s,2H),3.99-3.83(m,3H),3.80(s,2H),2.81(t,2H),2.25(td,1H),1.67(d,2H),1.27-1.14(m,2H),0.66-0.56(m,4H).

[1186] Example 84

[1187] first step:

[1188] 61D (230 mg, 0.55 mmol) and 2-methyloxazole-4-carboxylic acid (76.90 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (10 mL). N-methylimidazole (225.77 mg, 2.75 mmol) was added at 0-5°C and allowed to react for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (231.48 mg, 0.83 mmol) was then added dropwise at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to yield compound 84 (65.00 mg, 22% yield).

[1189] LC-MS (ESI): m / z = 528.6 [M+H] + .

[1190] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.30(s,1H),7.88-7.85(d,1H),7.63(s ,1H),7.58-7.56(d,1H),7.48-7.46(d,1H),6.68-6.62(dd,1H),6.36(s,1H), 6.14-6.10(d,1H),4.04(s,4H),3.82(s,2H),3.72-3.67(m,1H),2.44(s,3H) ,2.03-2.01(m,1H),1.83-1.75(m,4H),1.50-1.42(m,2H),1.27-1.19(m,2H).

[1191] Example 85:

[1192] first step:

[1193] 61D (220 mg, 0.53 mmol) and 1-methyl-4-imidazolecarboxylic acid (73.52 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (10 mL). N-methylimidazole (217.56 mg, 2.65 mmol) was added at 0-5°C and allowed to react for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (233.06 mg, 0.80 mmol) was then added dropwise at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to yield compound 85 (90.00 mg, 32% yield).

[1194] LC-MS (ESI): m / z = 527.6 [M+H] + .

[1195] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(s,2H),7.60-7.56(m,2H),7.52-7.46(m,2H),6.69-6.63(dd,1H),6.36(s,1H),6.14-6.1 0(d,1H),4.04(s,4H),3.82(s,2H),3.72-3.65(m,4H),2.04-1.99(m,1H),1.85-1.76(m,4H),1.47-1.38(m,2H),1.28-1.19(m,2H).

[1196] Example 86

[1197] first step:

[1198] 61D (100.0 mg, 0.24 mmol) and 4-isoxazolecarboxylic acid (35.0 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred at 0°C. N-methylimidazole (110.0 mg, 1.38 mmol) was then added, followed by the slow addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (100.0 mg, 0.36 mmol). The mixture was allowed to react at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 86 (22.0 mg, 17.8% yield).

[1199] 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),8.54(s,1H),7.82(s,1H),7.50(d,1H),7.46(s,1H),7.31(d,1H),6.47-6.41(m,2H),6.21(d,1H),5.76( d,1H),4.10(s,4H),3.96-3.88(m,1H),3.79(s,2H),2.14-2.09(m,3H),1.92-1.88(m,2H),1.42-1.25(m,4H), LC-MS(ESI): m / z=514.3[M+H] + .

[1200] Example 87

[1201] first step:

[1202] 61D (100.0 mg, 0.24 mmol) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (40.0 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred at 0°C. N-methylimidazole (110.0 mg, 1.38 mmol) was then added, followed by the slow addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (100.0 mg, 0.36 mmol). The mixture was allowed to react at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 87 (28.0 mg, 22.1% yield).

[1203] 1 H NMR(400MHz, CDCl3)δ8.01(s,1H),7.81(s,1H),7.52(d,1H),7.47(s,1H),7.32(d,1H),6.98(d,1H),6.50(dd,1H),6.43(s,1H),6.18(d,1H) ,4.17-4.14(m,7H),3.96-3.90(m,1H),3.84(s,2H),2.14-2.09(m,3H),1.91-1.85(m,2H),1.42-1.29(m,4H), LC-MS(ESI):m / z=528.4[M+H] + .

[1204] Example 88

[1205] first step:

[1206] 61D (150.0 mg, 0.36 mmol) and 3,3-difluorocyclobutanecarboxylic acid (63.0 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (8 mL) and stirred at 0°C. N-methylimidazole (180.0 mg, 2.16 mmol) was then added, followed by the slow addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (150.0 mg, 0.54 mmol). The mixture was allowed to react at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 88 (50.0 mg, 25.8% yield).

[1207] 1 H NMR(400MHz, CDCl3)δ7.80(s,1H),7.49(d,1H),7.45(s,1H),7.30(d,1H),6.45(dd,1H),6.40(s,1H),6.17(d,1H),5.27(d,1H),4.09(s,4H),3. 78(s,2H),3.76-3.70(m,1H),2.91-2.82(m,2H),2.74-2.66(m,3H),2.0 6-2.00(m,3H),1.89-1.82(m,2H),1.37-1.27(m,2H),1.22-1.12(m,2H),

[1208] LC-MS (ESI): m / z = 537.7 [M+H] + .

[1209] Example 89

[1210] first step:

[1211] 61D (450.0 mg, 1.08 mmol) and (1S)-2,2-difluorocyclopropane-1-carboxylic acid (170.0 mg, 1.40 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 0°C. N-methylimidazole (530.0 mg, 6.48 mmol) was then added, followed by the slow addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (450.0 mg, 1.62 mmol). The mixture was reacted at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 89.

[1212] LC-MS (ESI): m / z = 523.6 [M+H] +

[1213] Example 90

[1214] first step:

[1215] 61D (450.0 mg, 1.08 mmol) and (1R)-2,2-difluorocyclopropane-1-carboxylic acid (170.0 mg, 1.40 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 0°C. N-methylimidazole (530.0 mg, 6.48 mmol) was then added, followed by the slow addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (450.0 mg, 1.62 mmol). The mixture was reacted at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 90.

[1216] LC-MS (ESI): m / z = 523.6 [M+H] + .

[1217] Example 91:

[1218] first step:

[1219] 91A (2.0 g, 11.6 mmol) was dissolved in DCM (40 mL), and triethylamine (1.8 g, 17.4 mmol) and TsCl (2.7 g, 13.9 mmol) were added sequentially, followed by stirring at room temperature for 4 h. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to afford 91B (2.5 g, 66% yield).

[1220] 1 H NMR (400MHz, CDCl3) δ7.78(d,2H),7.34(d,2H),3.83(d,2H),3.66(d,3H),2.45(s,3H),2.24-2.16(m ,1H),2.05-1.90(m,2H),1.88-1.73(m,2H),1.72-1.58(m,1H),1.44-1.34(m,2H),1.02-0.92(m,2H).

[1221] Step 2:

[1222] 91B (1.0 g, 3.1 mmol), 7B (0.8 g, 2.5 mmol), and cesium carbonate (2.0 g, 6.1 mmol) were dissolved in DMF (20 mL) and reacted at 80°C for 2 h. After completion of the reaction, 10 mL of water was added to the reaction solution, which was then extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3 / 1) to afford 91C (0.8 g, 56% yield).

[1223] LC-MS (ESI): m / z = 466.5 [M+H] + .

[1224] Step 3:

[1225] 91C (0.5 g, 1.1 mmol) was dissolved in THF (4 mL), and water (1 mL) and lithium hydroxide (0.2 g, 8.8 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the THF was removed by vacuum distillation, and the pH of the solution was adjusted to 3 with dilute hydrochloric acid. A gray solid precipitated and was filtered to obtain 91D (0.3 g, 52% yield).

[1226] Step 4:

[1227] 91D (0.2 g, 0.5 mmol) was dissolved in DMF (10 mL), and CDI (0.2 g, 1.3 mmol) was added. The mixture was reacted at 65°C for 1 h. The reaction solution was cooled to 0°C, and a solution of methylsulfonamide (250 mg, 2.6 mmol) and sodium hydroxide (88 mg, 2.2 mmol) in DMF (5 mL) was added. The mixture was reacted at room temperature for 3 h. The solvent was concentrated and the mixture was purified on a silica gel column (dichloromethane / methanol (v / v) = 10 / 1) to give compound 91 (50 mg, yield: 22%).

[1228] LC-MS (ESI): m / z = 529.5 [M+H] + .

[1229] 1 H NMR(400MHz, CDCl3)δ9.17(s,1H),7.63(s,1H),7.54-7.39(m,2H),7.31(d,1H),6.58(s,1H),4.11(s,4H),3.81(s,2H),3 .72(d,2H),3.28(s,3H),2.39-2.19(m,1H),2.05-1.99(m,4H),1.86-1.82(m,1H),1.60-1.49(m,2H),1.21-1.03(m,2H).

[1230] 19 F NMR(400MHz, CDCl3)δ-60.09(s,3F).

[1231] Example 92:

[1232] first step:

[1233] 18E (340 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (338.99 mg, 3.35 mmol) and deuterated acetyl chloride (65.54 mg, 0.80 mmol) were added dropwise at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to afford compound 92 (150.00 mg, 49% yield).

[1234] LC-MS (ESI): m / z = 450.2 [M+H] + .

[1235] 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.63(s,1H),7.55-7.56(d,1H),7.48-7.46(d,1H),6.69-6 .63(m,1H),6.36(s,1H),6.15-6.11(d,1H),4.37-4.34(d,1H),4.04(s,4H),3.82(s,3H),3.10- 3.03(m,1H),2.61-2.54(m,1H),2.35-2.28(m,1H),1.74-1.67(t,2H),1.34-1.24(m,1H),1.19-1.09(m,1H).

[1236] Example 93:

[1237] first step:

[1238] 16B (3.10 g, 11.31 mmol) was dissolved in 1,4-dioxane (30 mL) and water (6 mL). 61B (5.96 g, 16.96 mmol), potassium carbonate (4.69 g, 33.93 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.83 g, 1.13 mmol) were added at room temperature. After the addition, the atmosphere was replaced with nitrogen three times and the reaction was continued at 85°C for 4 hr. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3, (v / v)) to afford 93B (1.20 g, 30% yield).

[1239] LC-MS (ESI): m / z = 294.4 [M-55] +

[1240] Step 2:

[1241] 93B (0.55 g, 1.57 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (794.34 mg, 7.85 mmol) and methanesulfonyl chloride (215.81 mg, 1.88 mmol) were added at 0-5°C. The mixture was allowed to react at room temperature for 30 minutes, and then 79E (262.29 mg, 1.88 mmol) was added. The reaction was allowed to react at room temperature overnight. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to afford compound 93C (192 mg, 25% yield).

[1242] LC-MS (ESI): m / z = 471.8 [M+H] + .

[1243] Step 3:

[1244] Dissolve 93C (192 mg, 0.41 mmol) in 1,4-dioxane (4 mL) and add 4N hydrogen chloride in 1,4-dioxane (10 mL) dropwise at 0-5°C. Allow to react at room temperature for 2 hours. Upon completion, concentrate the reaction mixture to yield crude product 93D, which was used directly in the next step.

[1245] Step 4:

[1246] 93D (151.90 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.20 g, 2.02 mmol) and deuterated acetyl chloride (0.040 g, 0.49 mmol) were added dropwise at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to afford compound 93 (20.00 mg, 11% yield).

[1247] LC-MS (ESI): m / z = 416.2 [M+H] + .

[1248] 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.69-7.67(d,1H),6.65-6.59(m,2H),6.31(s,1H),6.12-6.08(d,1H),3.96(s,2H), 3.82-3.81(m,4H),3.50-3.41(m,1H),2.41(s,3H),2.00-1.90(m,1H),1.82-1.81(m,2H),1.74(s,2H),1.24-1.13(m,4H).

[1249] Example 94:

[1250] first step:

[1251] Compounds 61D (250 mg, 0.60 mmol) and 94A (92 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N-methylimidazole (200 mg, 2.40 mmol) and TCFH (250 mg, 0.90 mmol) were added in sequence. After the addition, the reaction was continued at room temperature for 3 h. LCMS analysis showed that the reaction of the raw materials was complete. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 94 (105 mg, yield: 35%).

[1252] LC-MS (ESI): m / z = 503.20 [M+H] +.

[1253] 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.73(d,1H),7.62(s,1H),7.57(d,1H),7.47(d,1H),6.70-6.55(m,1H),6.35(s,1H),6.11(d,1H),4. 76-4.44(m,4H),4.03(s,4H),3.81(s,2H),3.73-3.63(m,1H),3.58-3 .46(m,1H),2.08-1.96(m,1H),1.86-1.70(m,4H),1.26-1.14(m,4H).

[1254] Example 95:

[1255] first step:

[1256] 93B (0.90 g, 2.58 mmol) was dissolved in methanol (20 mL), and palladium on carbon (274.56 mg, 0.26 mmol) was added. After the addition, the atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2, (v / v)) to afford compound 95A (520 mg, 57% yield).

[1257] LC-MS (ESI): m / z = 295.3 [M-56] + .

[1258] Step 2:

[1259] 95A (0.25 g, 0.71 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (358.55 mg, 3.55 mmol) and methanesulfonyl chloride (133.45 mg, 0.85 mmol) were added at 0-5°C. The mixture was allowed to react at room temperature for 30 minutes. 5-Trifluoromethylisoindoline (157.21 mg, 0.84 mmol) was then added and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 2, (v / v)) to afford compound 95B (300 mg, 82% yield).

[1260] LC-MS (ESI): m / z = 521.3 [M+H] + .

[1261] Step 3:

[1262] Dissolve 95B (300 mg, 0.58 mmol) in 1,4-dioxane (4 mL) and add 4N hydrogen chloride in 1,4-diox...

Claims

1. A compound represented by formula (I), its stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl; Ring B is selected from The left side of the B ring is connected to L1; Ring C is selected from phenyl, 5-6 membered heteroaryl, 6-12 membered bicyclic carbocyclyl, 6-12 membered bicyclic heterocycloalkyl, 8-14 membered tricyclic heterocycloalkyl, and Ring C is not L1 is selected from W1-R La -W2, L1 is connected to A on the left side; L2 is selected from W3-R Lb -W4, the left side of L2 is connected to B, and L1 and L2 are not bonds at the same time; R La , R Lb are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, wherein the alkylene and alkenylene groups are optionally further substituted with 1 to 4 R L1 replace; R L1 are each independently selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkenyl, alkoxy, cycloalkyl optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-8 membered cycloalkyl, a 5-10 membered heterocycloalkyl, or a 5-6 membered heteroaryl; W1, W2, W3, and W4 are each independently selected from a bond, -O-, -S-, -NR W1 -, -Se-, -C(O)-; R W1 Selected from H, halogen, C 1-4 alkyl; R A Each is independently selected from halogen, =O, CN, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution; R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, =O, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 or =CH2 group substitution; R C Each is independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se- 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, -O-(CH2) p -C 3-6 Cycloalkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-8 membered cycloalkyl group; q is selected from 0 or 1; p is each independently selected from 0, 1, 2, 3, or 4; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; The condition is, (1) When ring A is selected from When R A Not -S(O)2-(CH2) 0-1 CH3, and Not for (2) When R A Selected from -S(O)2-(CH2) 0-1 When CH3, the A ring is not and Not for (3) When the C ring is selected from When R C is not H, and Not for (4) When R C When only H is selected, the C ring is not and Not for 2. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Ring A is selected from 4-8 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 3-6 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl, 7-8 membered bicyclic bridged heterocyclyl; The C ring is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-7-membered heterocycloalkylphenyl, 5-6-membered carbocyclylphenyl, 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 3-6-membered cycloalkyl, or 9-12-membered tricyclic heterocycloalkyl; R La , R Lb are each independently selected from a bond, C 1-2 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, wherein the alkylene and alkenylene groups are optionally further substituted with 1 to 4 R L1 replace; R L1 are each independently selected from halogen, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, the alkyl, alkoxy, cycloalkyl optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-6 membered cycloalkyl group; R W1 Selected from H, halogen, C 1-2 alkyl; R A Each is independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-NH-R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; R a Selected from deuterated C 1-2 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, C 1-2 Alkyl, OH, =O, -S(O)2-CH3, C 1-2 Alkoxy, deuterated C 1-2 Alkyl or =CH2 group substitution; R C Each is independently selected from H, CN, halogen, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -Se-halogenated C 1-2 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, -O-(CH2) p -C 3-6 Cycloalkyl or -(CH2) p -OC 3-6 Cycloalkyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; p is each independently selected from 0, 1, 2, or 3; m is selected from 1, 2, or 3; n is selected from 1, 2, or 3.

3. The compound of formula (I) according to claim 2, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Ring A is selected from 4-6 membered cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered heterocycloalkyl, 5 membered heterocycloalkyl and 6 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 5 membered heterocycloalkyl, 5 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered heterocycloalkyl spiro 6 membered heterocycloalkyl, 4 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered cycloalkyl spiro 6 membered heterocycloalkyl, 5 membered heterocycloalkyl and 5 membered cycloalkyl, 6 membered heterocycloalkyl and 5 membered cycloalkyl, 10-14 membered partially unsaturated tricyclic heterocycloalkyl; The C ring is selected from 5-7 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 3-6 membered Cycloalkyl, 9-12 membered tricyclic heterocycloalkyl; R A Each independently selected from halogen, =O, CN, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -NH-R a 、-C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; R a Selected from deuterated C 1-2 alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, OH, =O, C 1-2 Alkyl, deuterated C 1-2 Alkyl, C 1-2 Alkoxy, -S(O)2-CH3 or =CH2; p is each independently selected from 0, 1, or 2; m is selected from 1, 2, or 3; n is selected from 1, 2, or 3.

4. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Ring A is selected from one of the following structures: Ring C is selected from one of the following structures: L1 is selected from a bond, -(C 1-2 Alkylene)-O-, -(C 1-2 Alkylene)-Se-, C 1-2 Alkylene, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene, -O-, C 2-4 Alkyne, wherein the alkylene and alkenylene groups are optionally further substituted with 1-3 R L1 replace; L2 is selected from a bond, C 1-2 Alkylene, -NH-, -O-, the alkylene, alkenylene, cycloalkyl group may be further substituted by 1-3 R L1 replace; R L1 are each independently selected from halogen, 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, or two R on the same carbon atom or two adjacent carbon atoms L1 and its connecting atoms together form a 3-6 membered cycloalkyl group; R A Each independently selected from =O, C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-NH-R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-C(O)-(CH2) p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-2 alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3; R a Selected from deuterated C 1-2 Alkyl, ethynyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted with halogen, methyl, deuterated methyl, methoxy, ethoxy, OH, =O, -S(O)2-CH3 or =CH2; R C Each is independently selected from H, CN, F, Cl, Br, OH, -SF5, methyl, difluoromethyl, trifluoromethyl, ethyl, ethynyl, cyclopropyl, -O-cyclopropyl, -O-CH2-cyclopropyl, cyclobutyl, -O-cyclobutyl, -O-CH2-cyclobutyl, -Se-trifluoromethyl, or any two R C and its connecting atoms together form a 3-6 membered cycloalkyl group; p is each independently selected from 0, 1, or 2; m is selected from 1, or 2; n is selected from 1 or 2.

5. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: Select one of the following structures: Select one of the following structures: L1 is selected from a bond, -CH2-O-, -CH2-Se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, -O-、-C(CH3)=CH-、-CH=C(CH3)-、 L2 is selected from -CH2-.

6. The compound according to claim 1, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein the compound has the structure of formula (Ia) or (Ic): in, Xa is selected from CH or N; X b Selected from CH or N; The C1 ring is selected from 5-6 membered heteroaryl, phenyl or benzo 5-6 membered cycloalkyl.

7. The compound according to claim 6, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein R A Selected from -S(O)2-(CH2) 1-3 -R a 、-C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-(6-9 membered bicyclic heterocycloalkyl), -NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-SO2-(CH2) 1-2 -R a 、-NH-C(O)-OR a 、-NH-R a 、-C(O)-(CH2)p -(4-6 membered monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 membered monocyclic cycloalkyl), -NH-C(O)-NH-R a 、-C(O)-deuterated C 1-4 alkyl, -C(O)-NH-(4-6 membered monocyclic cycloalkyl), -C(O)-NH-(4-6 membered monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl, -NH-C(O) deuterated C 1-2 Alkyl, -NH-C(O)-NH-C 1-2 Alkyl or -NH-C(O)-C 1-2 Alkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally further substituted by 1-3 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -O-halogenated C 1-4 Alkyl, -NH-S(O)2-CH3 group substitution; R a Selected from deuterated C 1-4 Alkyl, C 2-4 Alkynyl, 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, =O, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3 or =CH2 group substitution; R C Selected from F, Cl, halogenated C 1-2 Alkyl, C 2-4 Alkynyl, 3-4 membered cycloalkyl, -OC 3-4 Cycloalkyl; L1 is selected from -(C 1-2 Alkylene)-O-, C 1-2 Alkylene, C 2-4 Alkenylene, -C(O)-NH-; n is selected from 1 or 2; p is selected from 0, 1 or 2.

8. The compound according to claim 6, its stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein R A Selected from -C(O)-O-(CH2) p -R a 、-C(O)-(CH2) 1-2 -Ra 、-NH-C(O)-(CH2) p -R a 、-N(CH3)-C(O)-(CH2) p -R a 、-NH-C(O)-OR a ; R a is selected from 3-5 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl are any further selected from 1 to 4 halogens, C 1-4 Alkyl, deuterated C 1-4 Alkyl, or -S(O)2-CH3 group substitution; R C Selected from F, Cl, CHF2, CF3, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl.

9. The compound according to claim 1 or 6, its stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, wherein L1 is selected from -CH=CH-.

10. The compound according to claim 1, its stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 1.

11. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

12. A pharmaceutical composition or pharmaceutical preparation according to claim 11, comprising 1-1500 mg of a compound according to any one of claims 1-10 or a stereoisomer, tautomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof and a carrier and / or excipient.

13. Use of the compound according to any one of claims 1 to 10, its stereoisomer, tautomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, or the composition according to claim 11 or 12 in the preparation of a medicament for treating / preventing a disease mediated by CYP11A1.

14. The use according to claim 13, wherein the CYP11A1-mediated disease is selected from the group consisting of treating steroid hormone-dependent cancers.

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