CYP11A1 inhibitors and their applications

Abstract

Compounds represented by formula (I), or their stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, and pharmaceutical compositions thereof, and their uses in the manufacture of pharmaceuticals for the treatment / prevention of CYP11A1-mediated diseases, wherein each group in formula (I) is as defined in the specification. [C1] TIFF2026513527000277.tif23156

Description

[Technical Field]

[0001] This application is, Priority rights to a prior application filed with the China National Intellectual Property Administration on March 29, 2023, with patent application number 202310320916.4 and title "CYP11A1 inhibitor and its uses," Priority rights to a prior application filed with the China National Intellectual Property Administration on April 20, 2023, with patent application number 202310428094.1 and title "CYP11A1 Inhibitor and Uses thereof", Priority rights to a prior application filed with the China National Intellectual Property Administration on June 7, 2023, with patent application number 202310667272.6 and title "CYP11A1 Inhibitor and Uses thereof", Priority rights to a prior application filed with the China National Intellectual Property Administration on July 6, 2023, with patent application number 202310821299.6 and title "CYP11A1 Inhibitor and Uses thereof", Priority rights to a prior application filed with the China National Intellectual Property Administration on August 4, 2023, with patent application number 202310979027.9 and title "CYP11A1 Inhibitor and Uses thereof", Priority rights to a prior application filed with the China National Intellectual Property Administration on August 22, 2023, with patent application number 202311059482.3 and title "CYP11A1 Inhibitor and Uses thereof", Priority rights to a prior application filed with the China National Intellectual Property Administration on September 20, 2023, with patent application number 202311216619.1 and title "CYP11A1 Inhibitor and Uses thereof", The applicant claims priority from a prior application filed with the China National Intellectual Property Administration on December 7, 2023, with patent application number 202311669033.0 and title "CYP11A1 Inhibitor and Uses Thereof". The contents of the above priority rights are incorporated herein by reference in their entirety.

[0002] <Technical field> The present invention belongs to the pharmaceutical field and, in particular, relates to small molecule compounds having CYP11A1 selective inhibitory activity, their stereoisomers, tautomers, deuterides, solvates, cocrystals or pharmaceutically acceptable salts, and their uses in the manufacture of pharmaceuticals for treating related diseases. [Background technology]

[0003] Cytochrome p450 monooxygenase 11a1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is primarily involved in catalytic reactions related to drug metabolism and the synthesis of cholesterol, steroids, and other lipids. The CYP11A1 protein is localized in the inner mitochondrial membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in steroid hormone synthesis. This reaction takes place in adrenal cortical mitochondria and is catalyzed by cytochrome CYP11A1 (also known as P450scc), and functions in conjunction with CYP11A1, further including Adx and AdR. CYP11A1, Adx, and AdR belong to the cholesterol hydroxylase / lyase system (CH / L) and catalyze the initiation step of steroid synthesis in mammals, namely the process of producing pregnenolone from cholesterol. Pregnenolone is an important precursor of steroid hormones. The reaction process involves three consecutive monooxygenation reactions: the formation of 22R-hydroxycholesterol (22HC), the formation of 20R,22R-dihydroxycholesterol, and the cleavage of C20-C22. Each monooxygenation reaction requires the involvement of two electrons and one molecular oxygen. The electrons are supplied by NADPH and transferred to P450scc via NADPH-AdR and Adx. Adx and P450scc can form a complex and act as a mobile electron transporter.

[0004] CYP11A1 is primarily expressed in the placenta and responds to the synthesis of placental hormones such as progesterone and testosterone, while also being highly expressed in the adrenal glands and testes, and hardly expressed in other tissues. Inhibiting CYP11A1 (which is a crucial enzyme upstream of CYP17a1 in steroid biosynthesis) can achieve complete blockade of steroid biosynthesis. Therefore, CYP11A1 inhibitors have enormous potential to treat steroid-dependent cancers, such as prostate cancer, even in the later stages of the disease, particularly in patients exhibiting hormone refractory disease. Recently, compounds with CYP11A1 inhibitory activity have been demonstrated to significantly inhibit tumor growth in vivo in a mouse CRPC xenograft model.

[0005] There is an urgent need to discover a CYP11A1 inhibitor that is highly active, safe, and has few side effects. Such an inhibitor would have good potential for clinical development and could be used to treat cancer or other proliferative disorders or diseases. [Overview of the Initiative]

[0006] The present invention provides low molecular weight compounds having CYP11A1 inhibitory activity, stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof, the compounds being as shown in formulas (I), (II), (Ia), (Ib), (Ic), (Id), and (I-d1). [ka] Xa is selected from CH or N, and in some embodiments, Xa is selected from CH, and in some embodiments, Xa is selected from N. X b is selected from CH or N, and in some embodiments, X b is selected from CH, and in some embodiments, X b It is selected from N, The C1 ring is selected from a 5-6 member heteroaryl group, a phenyl group, or a benzo-5-6 member cycloalkyl group. In some embodiments, the C1 ring is selected from a 5-6 member heteroaryl group or a phenyl group. In some embodiments, the C1 ring is selected from a 5 member heteroaryl group or a phenyl group. In some embodiments, the C1 ring is selected from a phenyl group. Ring A is selected from 4-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 6-12 membered bicyclic heterocycloalkyl groups, and 8-14 membered tricyclic heterocycloalkyl groups. In some embodiments, ring A is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 6-12 membered bicyclic heterocycloalkyl groups, and 8-14 membered tricyclic heterocycloalkyl groups. In some embodiments, ring A is selected from 4-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl groups, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl condensed 3-6 membered cycloalkyl groups, 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups, and 7-8 membered bicyclic crosslinked heterocyclic groups. In some embodiments, ring A is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl groups, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl condensed 3-6 membered cycloalkyl groups, 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups, and 7-8 membered bicyclic crosslinked heterocyclic groups. In some embodiments, ring A is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl groups, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. In some embodiments, ring A is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl groups, 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl spiro 4-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. In some embodiments, ring A is selected from 4-6 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, 6-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. In some embodiments, ring A is selected from 5-6 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, 6-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. In some embodiments, the A ring is selected from a 5-6 member cycloalkyl group, a 4-7 member monocyclic heterocycloalkyl group, a 5-member heterocycloalkyl condensed 5-member heterocycloalkyl group, a 5-member heterocycloalkyl condensed 6-member heterocycloalkyl group, a 5-member heterocycloalkyl spiro 5-member heterocycloalkyl group, a 5-member heterocycloalkyl spiro 6-member heterocycloalkyl group, a 4-member heterocycloalkyl spiro 6-member heterocycloalkyl group, a 5-member heterocycloalkyl condensed 5-member cycloalkyl group, and a 6-member heterocycloalkyl condensed 5-member cycloalkyl group. In some embodiments, ring A is [ka] One of these structures is selected, or [ka] Selected from, In some embodiments, ring A is [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, Ring B is [ka] Selected from, the left side of ring B is connected to L1, The C ring is selected from a phenyl group, a 5-6 membered heteroaryl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocycloalkyl group, and an 8-14 membered tricyclic heterocycloalkyl group, and ring C is [ka] Instead, In some embodiments, the C ring is selected from a phenyl group, a five-membered heteroaryl group, a six-membered heteroaryl group, a 5-7 membered heterocycloalkyl condensed phenyl group, a 5-6 membered carbocyclic condensed phenyl group, a 5-6 membered heterocycloalkyl condensed 5-6 membered heteroaryl group, a 5-6 membered heterocycloalkyl condensed 3-6 membered cycloalkyl group, or a 9-12 membered tricyclic heterocycloalkyl group, and ring C is [ka] Instead, In some embodiments, the C ring is selected from a 5-7 member heterocycloalkyl condensed phenyl group, a 5-6 member heterocycloalkyl condensed 5-6 member heteroaryl group, a 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl group, and a 9-12 member tricyclic heterocycloalkyl group, and ring C is [ka] Instead, In some embodiments, ring C is selected from a 5- to 7-member heterocycloalkyl-fused phenyl group, a 5- to 6-member heterocycloalkyl-fused 5- to 6-member heteroaryl group, and a 5- to 6-member heterocycloalkyl-fused 3- to 6-member cycloalkyl group, and ring C is [Chemical formula] not In some embodiments, ring C is [Chemical formula] selected from one of the structures of [Chemical formula] or selected from In some embodiments, ring C is [Chemical formula] selected from one of the structures of [Chemical formula] or selected from L1 is selected from W1-R La -W2. The left side of L1 is connected to A. L2 is selected from W3-R Lb -W4. The left side of L2 is connected to B. L1 and L2 are not simultaneously bonded. R La R Lb are each independently a bond, a C 1-4 alkylene group, a C 2-4 alkenylene group, or a C 2-4 alkynylene group, and the alkylene group and the alkenylene group are optionally further substituted with 1 to 4 R L1 . In some embodiments, R La R Lb are each independently a bond, a C 1-4 alkylene group, a C 2-4Selected from alkenylene groups, the alkylene group, alkenylene group optionally has 1 to 4 R L1 It is further replaced by, In some embodiments, R La , R Lb Each is independent, combined, C 1-2 Alkylene group, C 2-4 Selected from alkenylene groups, the alkylene group, alkenylene group optionally has 1 to 4 R L1 It is further replaced by, In some embodiments, R La , R Lb Each is independent, combined, C 1-2 Alkylene group, C 2-4 Selected from alkenylene groups, the alkylene group, alkenylene group optionally has 1 to 4 R L1 It is further replaced by, In some embodiments, R La , R Lb Each of these is independently selected from bond, -CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, or -C(CH3)=CH-, -CH=C(CH3)-, and the CH3, CH2, and CH are arbitrarily selected from 1 to 4 R L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkenyl group, alkoxy group, and cycloalkyl group may be further optionally substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. In some embodiments, R L1These are, independently, halogen and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkenyl group, alkoxy group, and cycloalkyl group may be further optionally substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from an alkoxy group and a 3-6 membered cycloalkyl group, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two adjacent R L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl alkyl group, C 2-4Alkenyl group, C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R L1 These are, independently, halogen and C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Selected from an alkoxy group and a 3-6 membered cycloalkyl group, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two adjacent R L1 And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups, 3-6 membered cycloalkyl groups, or two R groups on the same carbon atom or two adjacent carbon atoms. L1and the atoms to which they are attached together form a 3- to 6-membered cycloalkyl group, In some embodiments, R L1 is, independently of each other, halogen, C 1-2 alkyl group, halo C 1-2 alkyl group, C 2-4 alkenyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, selected from 3- to 6-membered cycloalkyl groups, or two Rs on the same carbon atom or two adjacent carbon atoms L1 and the atoms to which they are attached together form a 3- to 6-membered cycloalkyl group, In some embodiments, R L1 is, independently of each other, halogen, =O, C 1-2 alkyl group, halo C 1-2 alkyl group, C 2-4 alkenyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, selected from 3- to 6-membered cycloalkyl groups, or two Rs on the same carbon atom or two adjacent carbon atoms L1 and the atoms to which they are attached together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, In some embodiments, R L1 is, independently of each other, halogen, =O, C 1-2 alkyl group, halo C 1-2 alkyl group, C 2-4 alkenyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, selected from 3- to 6-membered cycloalkyl groups, or two adjacent Rs L1 and the atoms to which they are attached together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, In some embodiments, R L1is independently selected from F, Cl, Br, =O, methyl group, ethyl group, -CF3, -CHF2, -CH2F, vinyl group, propenyl group, methoxy group, ethoxy group, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, cyclobutyl group, or two adjacent Rs L1 and the atoms to which they are attached together form a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, W1, W2, W3, W4 are each independently a bond, -O-, -S-, -NR W1 -, -Se-, -C(O)-, In some embodiments, W1, W2, W3, W4 are each independently a bond, -O-, -S-, -NR W1 -, -Se-, In some embodiments, W1, W2, W3, W4 are each independently a bond, -O-, -S-, -NR W1 -, In some embodiments, W1, W2, W3, W4 are each independently a bond, -O-, -NR W1 -, In some embodiments, W1, W2, W3, W4 are each independently a bond, -O-, R W1 is H, halogen, C 1-4 alkyl group, In some embodiments, R<http: / / www.wipo.int / standards / XMLSchema / ST96 / XMLSchema / W1 is H, halogen, C 1-2 alkyl group, In some embodiments, R W1 is selected from H, F, Cl, Br, methyl group, ethyl group, In some embodiments, L1 is a bond, -(C 1-2 alkylene)-O-, C 1-2 alkylene group, -O-(C 1-2 alkylene)-, C 2-4 alkenylene group, -C(=O)-N(C 1-2 alkylene)-, -O-, -C(=O)-O-, C 2-4Selected from alkylene groups, the alkylene group or alkenylene group optionally contains 1 to 3 R L1 It is further replaced by, In some embodiments, L1 is bonded, -(C 1-2 Alkylene)-O-,C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene group, -C(=O)-N(C 1-2 The alkylene group and alkenylene group are selected from -, -O-, and -C(=O)-O-, and the alkylene group and alkenylene group are optionally selected to have 1 to 3 R L1 It is further replaced by, In some embodiments, L1 is bonded, -(C 1-2 Alkylene)-O-,-(C 1-2 Alkylene)-Se-, C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene group, -O-, C 2-4 Selected from alkylene groups, the alkylene group or alkenylene group optionally contains 1 to 3 R L1 It is further replaced by, In some embodiments, L1 is bonded, -(C 1-2 Alkylene)-O-,-(C 1-2 Alkylene)-Se-, C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 The group is selected from alkenylene groups and -O- groups, and the said alkylene group and alkenylene group may optionally have 1 to 3 R groups. L1 It is further replaced by, In some embodiments, L1 is selected from the bonds -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)-, and the CH3, CH2, CH are optionally one to three R L1 It is further replaced by, In some embodiments, L1 is a bond of -CH2-O-, -CH2-se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, [ka] -O-, -C(CH3)=CH-, -CH=C(CH3)-, [ka] Selected from, In some embodiments, L1 is a bond of -CH2-O-, -CH2-se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, [ka] Selected from -O-, In some embodiments, L1 is a bond, -CH2-O-, -CH=CH-, -CH2-, -CH2CH2-, [ka] Selected from -O-, In some embodiments, L1 is a bond, -CH2-O-, -CH=CH-, -CH2- [ka] Selected from, In some embodiments, L1 is selected from -CH2O- and -CH=CH-. In some embodiments, L1 is selected from -CH=CH-, L2 is a bond, C 1-2 The alkylene group is selected from -C(=O)-, -NH-, and -O-, and the alkylene group can optionally have 1 to 3 R L1 It is further replaced by, In some embodiments, L2 is bonded to C 1-2 Selected from alkylene groups, -NH-, and -O-, the alkylene group optionally has 1 to 3 R groups. L1 It is further replaced by, In some embodiments, L2 is selected from bonds, -CH2-, -CH2CH2-, -C(=O)-, -NH-, -O-, and the CH3, CH2 are optionally 1 to 3 R L1 It is further replaced by, In some embodiments, L2 is selected from -CH2-, R A These are, independently, halogen, =O, CN, COOH, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 Further substitution with 1 to 4 groups selected from alkyl groups and -NH-S(O)2-CH3, In some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3. In some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl alkyl group, -NH-R a-C(O)-(6-9 member bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a , -NH-C(O)-OR a -C(O)-(CH2) p -(4-6 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3. In some embodiments, R A These are independent of each other: =O, C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-2 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, cycloalkyl group, and heterocycloalkyl group 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. In some embodiments, R A is -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p-(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 Further substitution with 1 to 3 groups selected from alkyl groups and -NH-S(O)2-CH3, In some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl groups or -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 Further substitution with 1 to 4 groups selected from alkyl groups and -NH-S(O)2-CH3, In some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl alkyl group, -C(O)-6~8 member bicyclic heterocycloalkyl group, -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 and heterocycloalkyl group are selected from and are further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, and -S(O)2-CH3. In some embodiments, R AThese are, independently, halogen, CN, COOH, and C. 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -NH-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group may optionally be halogen, OH, NH2, CN, or -O-haloC. 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, In some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3. In some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -C(O)-(6-9 member bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a , -NH-C(O)-OR a -C(O)-(CH2) p -(4-6 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and -NH-S(O)2-CH3. In some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -NH-C(O)-(CH2) p -Ra -NH-SO2-(CH2) 1-2 -R a Selected from, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. In some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN. In some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN. In some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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 Selected from, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. In some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Selected from alkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN, in some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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 aThe alkyl group is selected from and the alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, and -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-HaroC 1-3 Selected from alkyl groups, the CH3 and CH2 groups are optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN. In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, and -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 Selected from, the CH3 and CH2 are further optionally substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, and -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-HaroC 1-3 Selected from alkyl groups, In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, and -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 Selected from, In some embodiments, R AThese are, independently, -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 group, -S(O)2-CH2-4~6 membered heterocycloalkyl group, -S(O)2-CH2-5~6 membered heteroaryl group, -S(O)2-(CH2)2-3~5 membered cycloalkyl group, -S(O)2-(CH2)2-4~6 member heterocycloalkyl group, -S(O)2-(CH2)2-5~6 member heteroaryl group, -C(O)-O-3~5 member cycloalkyl group, -C(O)-O-4~6 member heterocycloalkyl group, -C(O)-O-5~6 member heteroaryl group, -C(O)-O-CH2-3~5 member cycloalkyl group, -C(O)-O-CH2-4~6 member heterocycloalkyl group -CH2-C(O)-O-CH2-5~6 member heteroaryl group, -CH2-C(O)-3~5 member cycloalkyl group, -CH2-C(O)-4~6 member heterocycloalkyl group, -CH2-C(O)-5~6 member heteroaryl group, -(CH2)2-C(O)-3~5 member cycloalkyl group, -(CH2)2-C(O)-4~6 member heterocycloalkyl group, -(CH2)2-C(O)-5~6 member Heteroaryl group, -C(O)-CH2-3~5 member cycloalkyl group, -C(O)-CH2-4~6 member heterocycloalkyl group, -C(O)-CH2-5~6 member heteroaryl group, -C(O)-(CH2)2-3~5 member cycloalkyl group, -C(O)-(CH2)2-4~6 member heterocycloalkyl group, -C(O)-(CH2)2-5~6 member heteroaryl group, -C(O)-O-haloC 1-3 Selected from alkyl groups, the cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally further substituted with groups of F, Cl, Br, OH, methyl, or ethyl. In some embodiments, R AThese are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2(CH3)2, -S(O)2-CH2CH2CH3, -S(O)2-CH2-3~5 member cycloalkyl group, -S(O)2-CH2-4~6 member heterocycloalkyl group, -S(O)2-CH2-5~6 member heteroaryl group, -S(O)2-(CH2)2-3~5 member cycloalkyl group, -S(O)2-(CH2)2-4~6 -C(O)-O-CH2-5~6 member heteroaryl group, -C(O)-O-3~5 member cycloalkyl group, -C(O)-O-4~6 member heterocycloalkyl group, -C(O)-O-5~6 member heteroaryl group, -C(O)-O-CH2-3~5 member cycloalkyl group, -C(O)-O-CH2-4~6 member heterocycloalkyl group, -C(O)-O-CH2-5~6 member heteroaryl group, -CH2- C(O)-3~5 member cycloalkyl group, -CH2-C(O)-4~6 member heterocycloalkyl group, -CH2-C(O)-5~6 member heteroaryl group, -(CH2)2-C(O)-3~5 member cycloalkyl group, -(CH2)2-C(O)-4~6 member heterocycloalkyl group, -(CH2)2-C(O)-5~6 member heteroaryl group, -C(O)-CH2-3~5 member cycloalkyl group, -C(O)-CH2-4~6 member heteroalkyl group Selected from chloroalkyl groups, -C(O)-CH2-5~6 member heteroaryl groups, -C(O)-(CH2)2-3~5 member cycloalkyl groups, -C(O)-(CH2)2-4~6 member heterocycloalkyl groups, and -C(O)-(CH2)2-5~6 member heteroaryl groups, the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups are optionally further substituted with groups of F, Cl, Br, OH, methyl, or ethyl. In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-4~6 member heterocycloalkyl, -C(O)-O-3~5 member cycloalkyl, -C(O)-CH2-3~5 member cycloalkyl, -S(O)2-CH2-3~5 member cycloalkyl, and -C(O)-O-haloC 1-3Selected from alkyl groups, the cycloalkyl groups and heterocycloalkyl groups are optionally further substituted with groups of F, Cl, Br, OH, methyl, or ethyl. In some embodiments, R A Each of these is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-4~6 member heterocycloalkyl, -C(O)-O-3~5 member cycloalkyl, -C(O)-CH2-3~5 member cycloalkyl, and -S(O)2-CH2-3~5 member cycloalkyl, and the cycloalkyl and heterocycloalkyl groups are optionally further substituted with groups of F, Cl, Br, OH, methyl, or ethyl. In some embodiments, R A These are, independently, -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-oxetanyl group, -C(O)-O-azetidinyl group, -C(O)-O-cyclobutyl group, -C(O)-O-piperidinyl group, -C(O)-CH2-cyclopropyl group, -S(O)2-CH2-cyclopropyl group, -S(O)2-CH2-cyclobutyl group, -S(O)2-CH2-cyclopentyl group, and -C(O)-O-haloC 1-3 Selected from alkyl groups, the oxetanyl group, azetidinyl group, cyclobutyl group, piperidinyl group, cyclopropyl group, and cyclopentyl group are optionally further substituted with groups F, Cl, Br, OH, methyl group, and ethyl group. In some embodiments, R A Each of these groups is independently selected from -S(O)2-CH3, -S(O)2-CH2CH3, -C(O)-O-oxetanyl group, -C(O)-O-azetidinyl group, -C(O)-O-cyclobutyl group, -C(O)-O-piperidinyl group, -C(O)-CH2-cyclopropyl group, -S(O)2-CH2-cyclopropyl group, -S(O)2-CH2-cyclobutyl group, and -S(O)2-CH2-cyclopentyl group, and the oxetanyl group, azetidinyl group, cyclobutyl group, piperidinyl group, cyclopropyl group, and cyclopentyl group are optionally further substituted with groups F, Cl, Br, OH, methyl group, and ethyl group. In some embodiments, RA is -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 Selected from, In some embodiments, [ka] teeth, [ka] One of these structures is selected, or [ka] Selected from the following structure, [ka] This structure is selected from, or [ka] Selected from the following structure, [ka] Selected from, In some embodiments, [ka] teeth, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, In some embodiments, [ka] teeth, [ka] One of these structures is selected, In some embodiments, [ka] teeth, [ka] One of these structures is selected, R a is deuterated C 1-4 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, =O, or C 1-4 Alkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, -S(O)2-CH3, or =CH2, In some embodiments, R a is deuterated C 1-4 Alkyl alkyl group, C 2-4The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 Further substitution with 1 to 4 groups selected from alkyl groups and -S(O)2-CH3, In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 Further substitution with 1 to 4 groups selected from alkyl groups and -S(O)2-CH3, In some embodiments, R a The group is selected from a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally replaced with a halogen or C 1-4 Alkyl groups, deuterated C 1-4 Further substituted with alkyl groups or 1, 2, 3, or 4 groups selected from -S(O)2-CH3, In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, or C 1-4 Alkyl alkyl group, C 2-4 Alkynyl group, -O-halo C 1-4 Further substitution with 1 to 4 groups selected from alkyl groups and -S(O)2-CH3, In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, a 5 membered heteroaryl group, and a 6 membered heteroaryl group, wherein the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally replaced with a halogen or C. 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R a is deuterated C 1-2 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Alkyl, OH, =O, -S(O)2-CH3, C 1-2 Alkoxy group, deuterated C 1-2 Further substituted with an alkyl group, In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 Further substituted with an alkoxy group, In some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, In some embodiments, R a is deuterated C 1-2The group is selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5 membered heteroaryl groups, wherein the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can optionally be a halogen, OH, =O, or C. 1-2 Alkyl groups, deuterated C 1-2 Alkyl alkyl group, C 1-2 Further substitution with alkoxy groups, -S(O)2-CH3 groups, In some embodiments, R a is deuterated C 1-2 Selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5-6 membered heteroaryl groups, the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups are optionally further substituted with halogens, methyl groups, deuterated methyl groups, methoxy groups, ethoxy groups, OH, =O, and -S(O)2-CH3 groups. In some embodiments, R a The group is selected from an ethynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Alkyl alkyl group, C 1-2 Further substitution with alkoxy groups, -S(O)2-CH3 groups, In some embodiments, R a The group is selected from an ethynyl group, a 3-5 membered cycloalkyl group, or a 4-6 membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally further substituted with a halogen, a methyl group, a methoxy group, an ethoxy group, an OH group, or a -S(O)2-CH3 group. In some embodiments, R a The group is selected from a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Further substitution with alkyl groups, -S(O)2-CH3 groups, In some embodiments, R aThe group is selected from a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Further substituted with alkyl groups, in some embodiments, R a The cycloalkyl group is selected from 3-5 membered cycloalkyl groups and 4-6 membered heterocycloalkyl groups, and the cycloalkyl group and heterocycloalkyl group are optionally further substituted with F, Cl, Br, OH, a methyl group, an ethyl group, or a -S(O)2-CH3 group. In some embodiments, R a The cycloalkyl group is selected from 3-5 membered cycloalkyl groups and 4-6 membered heterocycloalkyl groups, and the cycloalkyl group and heterocycloalkyl group are optionally further substituted with groups such as F, Cl, Br, OH, methyl, or ethyl. In some embodiments, R a The group is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxacyclopentyl, and oxacyclopentyl groups, and the cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxacyclopentyl, and oxacyclopentyl groups are optionally further substituted with F, Cl, Br, OH, methyl, ethyl, or -S(O)2-CH3 groups. In some embodiments, R a The group is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxacyclopentyl, and oxacyclopentyl groups, and the cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxacyclopentyl, and oxacyclopentyl groups are optionally further substituted with groups F, Cl, Br, OH, methyl, or ethyl. R C These are H, CN, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl group, -Se-halo C 1-4Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-8 membered cycloalkyl group. In some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-8 membered cycloalkyl group. In some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q-P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl alkyl group, or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-8 membered cycloalkyl group. In some embodiments, R C These are H, CN, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl group, -Se-halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl alkyl group, or -(CH2) p -OC 3-6Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R C F, Cl, Halo C 1-2 Alkyl alkyl group, C 2-4 Alkynyl group, 3-4 membered cycloalkyl group, -OC 3-4 Selected from cycloalkyl groups, In some embodiments, R C This is selected from F, Cl, CHF2, CF3, ethynyl group, cyclopropyl group, cyclobutyl group, -O-cyclopropyl group, and -O-cyclobutyl group. In some embodiments, R C It is selected from CF3, In some embodiments, R C Each of these groups is independently selected from H, CN, F, Cl, Br, OH, -SF5, methyl group, difluoromethyl group, trifluoromethyl group, ethyl group, ethynyl group, cyclopropyl group, -O-cyclopropyl group, -O-CH2-cyclopropyl group, cyclobutyl group, -O-cyclobutyl group, -O-CH2-cyclobutyl group, -Se-trifluoromethyl group, or any two of these groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. In some embodiments, R CThese are, independently, 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, -OCH2CHF 2, -OCH2CF3, -OCHClCH3, -OCCl2CH3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, ethynyl group, =O, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, -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, [ka] Selected from, or any two of R C And the atoms to which they are linked together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, In some embodiments, R C Each of these groups is independently selected from H, F, Cl, Br, OH, methyl group, ethyl group, cyclopropyl group, cyclobutyl group, trifluoromethyl group, and ethynyl group, or any two of these groups. C And the atoms to which they are linked together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, In some embodiments, R C Each of these is independently selected from H, F, Cl, Br, OH, methyl group, ethyl group, cyclopropyl group, cyclobutyl group, or any two of R CAnd the atoms to which they are linked together form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, In some embodiments, [ka] teeth, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, q is selected from 0 or 1. In some embodiments, q is selected from 0, In some embodiments, q is selected from 1, p is independently selected from 0, 1, 2, 3, or 4. In some embodiments, p is independently selected from 0, 1, 2, or 3. In some embodiments, p is independently selected from 0, 1, or 2. m is selected from 1, 2, 3, or 4. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is selected from 1 or 2. In some embodiments, m is selected from 1, n is selected from 1, 2, 3, or 4. In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is selected from 1 or 2. In some embodiments, n is selected from 1, The conditions are, (1) Ring A [ka] If selected from, R A is -S(O)2-(CH2) 0-1 Not CH3, and [ka] teeth, [ka] Instead, (2)R A -S(O)2-(CH2) 0-1 If selected from CH3, ring A is, [ka] Rather, and [ka] teeth, [ka] Instead, (3) Ring C is [ka] If selected from, R C It is not H, and [ka] teeth, [ka] Instead, (4)R C If is selected from H only, then the C ring is [ka] Rather, and [ka] teeth, [ka] isn't it.

[0007] As a more specific first technical example of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, [ka] Ring A is selected from 4-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 6-12 membered bicyclic heterocycloalkyl groups, and 8-14 membered tricyclic heterocycloalkyl groups. In some embodiments, Ring A is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 6-12 membered bicyclic heterocycloalkyl groups, and 8-14 membered tricyclic heterocycloalkyl groups. Ring B is [ka] Selected from, the left side of ring B is connected to L1, The C ring is selected from a phenyl group, a 5-6 membered heteroaryl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocycloalkyl group, and an 8-14 membered tricyclic heterocycloalkyl group, and ring C is [ka] Instead, L1 is W1-R La - Selected from W2, the left side of L1 is connected to A, L2 is W3-R Lb - Selected from W4, the left side of L2 is connected to B, and L1 and L2 are not connected simultaneously. R La , R LbEach is independent, combined, C 1-4 Alkylene group, C 2-4 Alkenylene group or C 2-4 Selected from alkylene groups, the alkylene group and alkenylene group optionally contain 1 to 4 R L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkenyl group, alkoxy group, and cycloalkyl group may be further optionally substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and in some embodiments, R L1 These are, independently, halogen and C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkenyl group, alkoxy group, and cycloalkyl group may be further optionally substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and in some embodiments, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two R atoms on the same carbon atom or two adjacent carbon atoms. L1And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and in some embodiments, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from an alkoxy group and a 3-6 membered cycloalkyl group, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two adjacent R L1 And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. W1, W2, W3, and W4 are independent of each other, and are combined, -O-, -S-, and -NR. W1 -, -Se- or -C(O)- are selected, and in some embodiments, W1, W2, W3, W4 are independently bonded to -O-, -S-, -NR W1 - Selected from, R W1 H, halogen, C 1-4 Selected from alkyl groups, R A These are, independently, halogen, =O, CN, COOH, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 It is further substituted with 1 to 4 groups selected from alkyl groups, -NH-S(O)2-CH3, and in some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl groups or -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 It is further substituted with 1 to 4 groups selected from alkyl groups, -NH-S(O)2-CH3, and in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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 -Ra 、-C(O)-O-HaroC 1-4 Alkyl alkyl group, -C(O)-6~8 member bicyclic heterocycloalkyl group, -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group, halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -NH-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from the alkyl group, alkenyl group, and alkynyl group, optionally the halogen, OH, NH2, CN, and -O-haloC. 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-6 Alkenyl group, C 2-6 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4Alkyl group, -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-HaroC 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group may optionally be halogen, OH, NH2, CN, or -O-haloC. 1-4 Further substitution with 1 to 4 groups selected from alkyl groups, R a is deuterated C 1-4 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, =O, or C 1-4 Alkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 It is further substituted with 1 to 4 groups selected from alkyl groups, -S(O)2-CH3, or =CH2, and in some embodiments, R a is deuterated C 1-4 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 It is further substituted with 1 to 4 groups selected from alkyl groups, -S(O)2-CH3, and in some embodiments, R a C 2-4Selected from an alkynyl group, a 3- to 5-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, and a 5- to 6-membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally halogen, OH, C 1-4 alkyl group, C 1-4 alkoxy group, C 2-4 alkynyl group, -O-haloC 1-4 alkyl group, -S(O)2-CH3, and is further substituted with 1 to 4 groups selected therefrom. In some embodiments, R a is C 2-4 Selected from an alkynyl group, a 3- to 5-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, and a 5- to 6-membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally halogen, OH, C 1-4 alkyl group, C 2-4 alkynyl group, -O-haloC 1-4 alkyl group, -S(O)2-CH3, and is further substituted with 1 to 4 groups selected therefrom. R C is each independently H, CN, halogen, OH, C 1-4 alkyl group, haloC 1-4 alkyl group, -O-haloC 1-4 alkyl group, -Se-haloC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, =O, C 3-6 cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 alkyl)2, -(CH2) p -O-C 1-4 alkyl group, -O-(CH2) p -C 3-6 cycloalkyl group or -(CH2) p -O-C 3-6 cycloalkyl group, or any two Rs C and the atoms to which they are attached together form a 3- to 8-membered cycloalkyl group. In some embodiments, R C is each independently H, halogen, OH, C1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3- to 8-membered cycloalkyl group, and in some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl alkyl group, or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-8 membered cycloalkyl group. q is selected from 0 or 1. p is 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 conditions are, (1) Ring A [ka] If selected from, R A is -S(O)2-(CH2) 0-1 Not CH3, and [ka] teeth, [ka] Instead, (2)R A -S(O)2-(CH2) 0-1 If selected from CH3, ring A is, [ka] Rather, and [ka] teeth, [ka] Instead, (3) Ring C is [ka] If selected from, R C It is not H, and [ka] teeth, [ka] Instead, (4) R C If is selected from H only, then the C ring is [ka] Rather, and [ka] teeth, [ka] isn't it.

[0008] A more specific second technical example of the present invention is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, Ring A is selected from 4-8 member cycloalkyl groups, 4-7 member monocyclic heterocycloalkyl groups, 5-6 member heterocycloalkyl condensed 5-6 member heterocycloalkyl groups, 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl groups, 5-6 member heterocycloalkyl spiro 4-6 member cycloalkyl groups, 5-6 member heterocycloalkyl spiro 5-6 member cycloalkyl groups, 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl groups, 10-14 member partially unsaturated tricyclic heterocycloalkyl groups, and 7-8 member bicyclic crosslinked heterocyclic groups. Selected, in some embodiments, the A ring is a 5-8 member cycloalkyl group, a 4-7 member monocyclic heterocycloalkyl group, a 5-6 member heterocycloalkyl group condensed into a 5-6 member heterocycloalkyl group, a 4-6 member heterocycloalkyl spiro, a 5-6 member heterocycloalkyl spiro, a 4-6 member cycloalkyl group, a 5-6 member heterocycloalkyl spiro, a 5-6 member cycloalkyl group, a 5-6 member heterocycloalkyl group condensed into a 3-6 member cycloalkyl group, or a 10-14 member partially unsaturated tricyclic heterocycloalkyl group. The group is selected from 7-8 membered bicyclic crosslinked heterocyclic groups, and in some embodiments, the A ring is a 5-8 membered cycloalkyl group, a 4-7 membered monocyclic heterocycloalkyl group, a 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl group, a 4-6 membered heterocycloalkyl spiro 5-6 membered heterocycloalkyl group, a 5-6 membered heterocycloalkyl spiro 5-6 membered cycloalkyl group, a 5-6 membered heterocycloalkyl condensed 5-6 membered cycloalkyl group, a 10-14 member partially unsaturated tricyclic heterocycloalkyl group, or a 5-6 membered heterocyclo The alkylspiro is selected from 4-6 membered cycloalkyl groups, and in some embodiments, the A ring is selected from 5-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered heterocycloalkyl groups, 4-6 membered heterocycloalkylspiro 5-6 membered heterocycloalkyl groups, 5-6 membered heterocycloalkylspiro 5-6 membered cycloalkyl groups, 5-6 membered heterocycloalkyl condensed 5-6 membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. The C ring is selected from a phenyl group, a five-membered heteroaryl group, a six-membered heteroaryl group, a 5-7 member heterocycloalkyl-fused phenyl group, a 5-6 member carbocyclic group-fused phenyl group, a 5-6 member heterocycloalkyl-fused 5-6 member heteroaryl group, a 5-6 member heterocycloalkyl-fused 3-6 member cycloalkyl group, or a 9-12 member tricyclic heterocycloalkyl group, R La 、R Lb are each independently a bond, a C 1-2 alkylene group, a C 2-4 alkenylene group or a C 2-4 alkynylene group, and the alkylene group and the alkenylene group are optionally further substituted with 1 to 4 R L1 s, R L1 are each independently a halogen, =O, a C 1-2 alkyl group, a C 2-4 alkenyl group, a C 1-2 alkoxy group, or a 3-6 member cycloalkyl group, and the alkyl group, the alkoxy group, and the cycloalkyl group are optionally further substituted with 1 to 4 substituents selected from a halogen, CN, OH, and NH2, or two R L1 s on the same carbon atom or two adjacent carbon atoms and the atoms to which they are attached together form a 3-6 member cycloalkyl group. In some embodiments, R L1 are each independently a halogen, a C 1-2 alkyl group, a C 2-4 alkenyl group, a C 1-2 alkoxy group, or a 3-6 member cycloalkyl group, and the alkyl group, the alkoxy group, and the cycloalkyl group are optionally further substituted with 1 to 4 substituents selected from a halogen, CN, OH, and NH2, or two R L1 s on the same carbon atom or two adjacent carbon atoms and the atoms to which they are attached together form a 3-6 member cycloalkyl group. In some embodiments, R L1 are each independently a halogen, =O, a C 1-2 alkyl group, a C 2-4 alkenyl group, a C 1-2Selected from an alkoxy group and a 3-6 membered cycloalkyl group, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2, or two adjacent R L1 And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. R W1 H, halogen, C 1-2 Selected from alkyl groups, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a, -C(O)-deuterated C 1-4 Alkyl groups or -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl alkyl group, -C(O)-6~8 member bicyclic heterocycloalkyl group, -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from, the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, in some embodiments, R AThese are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -NH-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN. R a is deuterated C 1-2 Alkyl alkyl group, C 2-4The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Alkyl, OH, =O, -S(O)2-CH3, C 1-2 Alkoxy group, deuterated C 1-2 Further substituted with alkyl groups or =CH2 groups, in some embodiments, R a is deuterated C 1-2 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 Further substituted with an alkoxy group, in some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Alkyl, OH, -S(O)2-CH3, C 1-2 Further substituted with an alkoxy group, in some embodiments, R a C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C. 1-2 Further substitution with alkyl groups, OH groups, and -S(O)2-CH3 groups, R C These are H, CN, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl group, -Se-halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl groups or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R C These are H, halogen, OH, and C, respectively, independently. 1-4 Alkyl, halo C 1-4 Alkyl, -O-halo C 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, =O, C 3-6 Cycloalkyl group, -SCF3, -SF5, -(NH) q -P(O)(C 1-4 Alkyl)2,-(CH2) p -OC 1-4Alkyl alkyl group, or -(CH2) p -OC 3-6 Selected from cycloalkyl groups, or any two R groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. p is independently selected from 0, 1, 2, or 3. m is selected from 1, 2, or 3. n is selected from 1, 2, or 3. The other components are as described in the first technical proposal mentioned above.

[0009] A third, more specific technical example of the present invention is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, Ring A is selected from 4-6 member cycloalkyl groups, 4-7 member monocyclic heterocycloalkyl groups, 5 member heterocycloalkyl condensed 5-member heterocycloalkyl groups, 5 member heterocycloalkyl condensed 6-member heterocycloalkyl groups, 5 member heterocycloalkyl spiro 5-member heterocycloalkyl groups, 5 member heterocycloalkyl spiro 6-member heterocycloalkyl groups, 4 member heterocycloalkyl spiro 6-member heterocycloalkyl groups, 4 member cycloalkyl spiro 6-member heterocycloalkyl groups, 5 member cycloalkyl spiro 6-member heterocycloalkyl groups, 5 member heterocycloalkyl condensed 5-member cycloalkyl groups, 6 member heterocycloalkyl condensed 5-member cycloalkyl groups, and 10-14 member partially unsaturated tricyclic heterocycloalkyl groups. In some embodiments, Ring A is selected from 5-6 member cycloalkyl groups, 4-7 member monocyclic heterocycloalkyl groups, 5 member heterocycloalkyl condensed 5-member heterocycloalkyl groups, 5 member heterocycloalkyl condensed 6-member heterocycloalkyl groups, and 5 member heterocycloalkyl spiro 5-member heterocycloalkyl groups. The group is selected from a 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl group, a 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl condensed 5-membered cycloalkyl group, a 6-membered heterocycloalkyl condensed 5-membered cycloalkyl group, a 4-membered cycloalkyl spiro 6-membered heterocycloalkyl group, a 5-membered cycloalkyl spiro 6-membered heterocycloalkyl group, and a 10-14 member partially unsaturated tricyclic heterocycloalkyl group. In some embodiments, the A ring is selected from a 5-6 membered cycloalkyl group, a 4-7 membered monocyclic heterocycloalkyl group, a 5-membered heterocycloalkyl condensed 5-membered heterocycloalkyl group, a 5-membered heterocycloalkyl condensed 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl spiro 5-membered heterocycloalkyl group, a 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl group, a 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl condensed 5-membered cycloalkyl group, and a 6-membered heterocycloalkyl condensed 5-membered cycloalkyl group. The C ring is selected from a 5-7 member heterocycloalkyl condensed phenyl group, a 5-6 member heterocycloalkyl condensed 5-6 member heteroaryl group, a 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl group, or a 9-12 member tricyclic heterocycloalkyl group. In some embodiments, the C ring is selected from a 5-7 member heterocycloalkyl condensed phenyl group, a 5-6 member heterocycloalkyl condensed 5-6 member heteroaryl group, or a 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl group. R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl alkyl group, -NH-R a -C(O)-(6-9 member bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a , -NH-C(O)-OR a -C(O)-(CH2) p -(4-6 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C1-2 Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are, independently, halogen, =O, CN, COOH, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl group, -C(O)-(6-9 member bicyclic heterocycloalkyl), -N(CH3)-C(O)-(CH2) p -R a , -NH-C(O)-OR a -C(O)-(CH2) p -(4-6 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl groups or -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may be optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-4 Alkyl alkyl groups, -C(O)-6~8 membered bicyclic heterocycloalkyl groups, -N(CH3)-C(O)-(CH2) p -R a Selected from, the alkyl group, alkenyl group, alkynyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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 Selected from, or -C(O)-O-HALO-C 1-4Selected from alkyl groups, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN, in some embodiments, R A These are, independently, halogen, CN, COOH, and C. 2-4 Alkenyl group, C 2-4 Alkynyl group, -OC 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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 Selected from, the alkyl group, alkenyl group, and alkynyl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. R a is deuterated C 1-2 The group is selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5 membered heteroaryl groups, wherein the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can optionally be a halogen, OH, =O, or C. 1-2 Alkyl groups, deuterated C 1-2 Alkyl alkyl group, C 1-2 Further substituted with alkoxy groups, -S(O)2-CH3 or =CH2 groups, in some embodiments, R a is deuterated C 1-2 The group is selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5 membered heteroaryl groups, wherein the cycloalkyl group, heterocycloalkyl group, and heteroaryl group can optionally be a halogen, OH, or C. 1-2 Alkyl alkyl group, C 1-2 Further substituted with alkoxy groups, -S(O)2-CH3 groups, and in some embodiments, R aThe group is selected from an ethynyl group, a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Alkyl alkyl group, C 1-2 Further substituted with alkoxy groups, -S(O)2-CH3 groups, and in some embodiments, R a The group is selected from a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Further substituted with an alkyl group or a -S(O)2-CH3 group, in some embodiments, R a The group is selected from a 3-5 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, or a 5 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, OH, or C 1-2 Further substituted with an alkyl group, p is independently selected from 0, 1, or 2. m is selected from 1, 2, or 3. n is selected from 1, 2, or 3. The other components are as described in the second technical proposal mentioned above.

[0010] A fourth, more specific technical proposal of the present invention, is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, Ring A is, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, Ring C is, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, L1 is a bond, -(C 1-2 Alkylene)-O-,-(C 1-2 Alkylene)-Se-, C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene group, -C(=O)-N(C 1-2 Alkylene)-, -O-, -C(=O)-O- or C 2-4 Selected from alkylene groups, the alkylene group or alkenylene group optionally contains 1 to 3 R L1 Further replaced by, in some embodiments, L1 is bonded, -(C 1-2 Alkylene)-O-,-(C 1-2 Alkylene)-Se-, C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene group, -O- or C2-4 Selected from alkylene groups, the alkylene group or alkenylene group optionally contains 1 to 3 R L1 Further replaced by, in some embodiments, L1 is bonded, -(C 1-2 Alkylene)-O-,C 1-2 Alkylene group, -O-(C 1-2 Alkylene)-, C 2-4 Alkenylene group, -C(=O)-N(C 1-2 The alkylene group and alkenylene group are selected from -, -O-, and -C(=O)-O-, and the alkylene group and alkenylene group are optionally selected to have 1 to 3 R L1 It is further replaced by, L2 is a bond, C 1-2 The alkylene group is selected from -C(=O)-, -NH-, and -O-, and the alkylene group can optionally have 1 to 3 R L1 Further substituted, in some embodiments, L2 is bonded, C 1-2 Selected from alkylene groups, -NH-, and -O-, the alkylene group optionally has 1 to 3 R groups. L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups, 3-6 membered cycloalkyl groups, or two R groups on the same carbon atom or two adjacent carbon atoms. L1 And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R L1 These are, independently, halogen and C 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups, 3-6 membered cycloalkyl groups, or two R groups on the same carbon atom or two adjacent carbon atoms. L1And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R L1 These are, independently, halogen, =O, and C. 1-2 Alkyl, halo C 1-2 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-2 Alkoxy group, Halo C 1-2 Selected from alkoxy groups and 3-6 membered cycloalkyl groups, R A These are independent of each other: =O, C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-2 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C1-2 Selected from alkyl groups, the alkyl group, cycloalkyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are independent of each other: =O, C 1-4 Alkyl group, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-2 Alkyl groups or -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2Selected from alkyl groups, the alkyl group, cycloalkyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, -NH-S(O)2-CH3, in some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl alkyl group, -C(O)-6~8 member bicyclic heterocycloalkyl group, -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R a Selected from, the alkyl group, heterocycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -S(O)2-CH3, and in some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Alkyl group, -NH-C(O)-(CH2) p -R a -NH-SO2-(CH2) 1-2 -R aSelected from, the alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN, in some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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-HaroC 1-3 Selected from alkyl groups, the alkyl group is optionally further substituted with 1 to 4 groups selected from halogens, OH, NH2, and CN, in some embodiments, R A These are, independently, -S(O)2-C 1-4 Alkyl group, -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 selected from and the alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, and CN. R a is deuterated C 1-2 Selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5-6 membered heteroaryl groups, the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups are optionally further substituted with halogens, methyl groups, deuterated methyl groups, methoxy groups, ethoxy groups, OH, =O, -S(O)2-CH3, or =CH2 groups, in some embodiments, R a is deuterated C 1-2Selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5-6 membered heteroaryl groups, the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups are optionally further substituted with halogens, methyl groups, methoxy groups, ethoxy groups, OH, and -S(O)2-CH3 groups, in some embodiments, R a The group is selected from an ethynyl group, a 3-5 membered cycloalkyl group, or a 4-6 membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is optionally further substituted with a halogen, a methyl group, a methoxy group, an ethoxy group, an OH group, or a -S(O)2-CH3 group, in some embodiments, R a The cycloalkyl group is selected from 3-5 membered cycloalkyl groups and 4-6 membered heterocycloalkyl groups, and the cycloalkyl group and heterocycloalkyl group are optionally further substituted with a halogen, a methyl group, an OH group or a -S(O)2-CH3 group, in some embodiments, R a The cycloalkyl group is selected from 3-5 membered cycloalkyl groups and 4-6 membered heterocycloalkyl groups, and the cycloalkyl group and heterocycloalkyl group are optionally further substituted with halogen, methyl, or OH groups. R C Each of these groups is independently selected from H, CN, F, Cl, Br, OH, -SF5, methyl group, difluoromethyl group, trifluoromethyl group, ethyl group, ethynyl group, cyclopropyl group, -O-cyclopropyl group, -O-CH2-cyclopropyl group, cyclobutyl group, -O-cyclobutyl group, -O-CH2-cyclobutyl group, -Se-trifluoromethyl group, or any two of these groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R C Each of these groups is independently selected from H, F, Cl, Br, OH, -SF5, methyl group, difluoromethyl group, trifluoromethyl group, ethyl group, ethynyl group, cyclopropyl group, -O-cyclopropyl group, -O-CH2-cyclopropyl group, cyclobutyl group, -O-cyclobutyl group, -O-CH2-cyclobutyl group, or any two of these groups. CAnd the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R C Each of these groups is independently selected from H, F, Cl, Br, OH, methyl group, ethyl group, cyclopropyl group, cyclobutyl group, trifluoromethyl group, and ethynyl group, or any two of these groups. C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group, and in some embodiments, R C Each of these is independently selected from H, F, Cl, Br, OH, methyl group, ethyl group, cyclopropyl group, cyclobutyl group, or any two of R C And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. p is independently selected from 0, 1, or 2. m is selected from 1 or 2. n is selected from 1 or 2. The other components are as described in the third technical proposal mentioned above.

[0011] A fifth, more specific technical proposal of the present invention, is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, [ka] teeth, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, [ka] teeth, [ka] One of these structures is selected, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, or [ka] Selected from, L1 is a bond, -CH2-O-, -CH2-Se-, -CH=CH-, -CF=CH-, -CH2-, -CH2CH2-, [ka] -O- or -C(CH3)=CH-, -CH=C(CH3)- or [ka] Selected from, in some embodiments, L1 is a bond, -CH2-O-, -CH=CH-, -CH2-, -CH2CH2-, [ka] Selected from -O-, in some embodiments, L1 is -CH2-O-, -CH=CH-, bond, -CH2-, [ka] Selected from, in some embodiments, L1 is selected from -CH2-O-, -CH=CH-, L2 is selected from -CH2-, The other components are as described in the fourth technical proposal mentioned above.

[0012] A sixth, more specific technical proposal of the present invention, is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, wherein the compound has the structures of formulas (Ia) and (Ic). [ka] Here, Xa is selected from CH or N. X b It is selected from CH or N, The C1 ring is selected from a 5-6 member heteroaryl group, a phenyl group, or a benzo-5-6 member cycloalkyl group. The other bases are as described in one of the aforementioned technical proposals.

[0013] A more specific seventh technical proposal of the present invention is a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, wherein the compound has the structure of formula (Ia), [ka] Here, Xa is selected from CH or N. The other bases are as described in one of the aforementioned technical proposals.

[0014] As a more specific eighth technical proposal of the present invention, a compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, wherein the compound has the structure of formula (Ic), [ka] Here, Xa is selected from CH or N. X b It is selected from CH or N, The C1 ring is selected from a 5-6 member heteroaryl group, a phenyl group, or a benzo-5-6 member cycloalkyl group. The other bases are as described in one of the aforementioned technical proposals.

[0015] A ninth, more specific technical proposal of the present invention, is a compound represented by formula (I), (Ia), (Ic), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, R A is -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-HaroC 1-4Alkyl group, -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 member monocyclic heterocycloalkyl), -C(O)-(CH2) p -(4-6 member monocyclic cycloalkyl), -NH-C(O)-NH-R a , -C(O)-deuterated C 1-4 Alkyl group, -C(O)-NH-(4-6 member monocyclic cycloalkyl), -C(O)-NH-(4-6 member monocyclic heterocycloalkyl), -C(O)-NH-S(O)2-C 1-4 Alkyl alkyl groups, -NH-C(O) deuterated C 1-2 Alkyl alkyl group, -NH-C(O)-NH-C 1-2 Alkyl alkyl group or -NH-C(O)-C 1-2 Selected from alkyl groups, the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be halogen, OH, NH2, CN, -S(O)2-CH3, -O-haloC 1-4 Further substitution with 1 to 3 groups selected from alkyl groups and -NH-S(O)2-CH3, R a is deuterated C 1-4 Alkyl alkyl group, C 2-4 The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, =O, or C 1-4 Alkyl groups, deuterated C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-4 Alkynyl group, -O-halo C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups, -S(O)2-CH3, or =CH2, R C F, Cl, Halo C 1-2 Alkyl alkyl group, C 2-4 Alkynyl group, 3-4 membered cycloalkyl group, -OC 3-4 Selected from cycloalkyl groups, L1 is -(C 1-2 Alkylene)-O-,C 1-2 Alkylene group, C 2-4 Selected from alkenylene group, -C(O)-NH-, n is selected from 1 or 2. p is selected from 0, 1, or 2. The other bases are as described in one of the aforementioned technical proposals.

[0016] A more specific tenth technical proposal of the present invention is a compound represented by formula (I), (Ia), (Ic), its stereoisomer, tautomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt, R A is -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 Selected from, R a The group is selected from a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, C 1-4 Alkyl groups, deuterated C 1-4 Further substituted with 1 to 4 groups selected from alkyl groups or -S(O)2-CH3, R C This is selected from F, Cl, CHF2, CF3, ethynyl group, cyclopropyl group, cyclobutyl group, -O-cyclopropyl group, and -O-cyclobutyl group. The other bases are as described in one of the aforementioned technical proposals.

[0017] As a more specific eleventh technical proposal of the present invention, a compound represented by formula (I), (Ia), its stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, L1 is selected from -CH=CH-, The other bases are as described in one of the aforementioned technical proposals.

[0018] As a specific example of the present invention, a compound described in the present invention, its stereoisomer, tautomer, deuteride, solvate, cocrystal, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures.

[0019] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0020] The present invention further provides a pharmaceutical composition or pharmaceutical preparation comprising a compound described in any one of the preceding designs, its stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0021] Furthermore, the present invention provides a composition or pharmaceutical preparation comprising 1 to 1500 mg of any one of the above-described compounds, stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof, and a carrier and / or excipient.

[0022] The present invention further provides applications for the compound described in any one of the preceding plans, its stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, or composition described in any one of the preceding plans, in the manufacture of drugs for treating / preventing CYP11A1-mediated diseases, wherein the CYP11A1-mediated disease is a steroid hormone-dependent cancer, and more preferably a prostate cancer.

[0023] The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the aforementioned technical proposals or its stereoisomer, tautomer, deuteride, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount being preferably 1 to 1500 mg, and the disease being preferably prostate cancer. In some embodiments, the mammal described in the present invention includes humans.

[0024] The “effective dose” or “therapeutic effective dose” as described in this application comprises administering a sufficient amount of the compound disclosed herein that alleviates, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include 1-1500mg, 1-1400mg, 1-1300mg, 1-1200mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 1-500mg, 1-400mg, 1-300mg, 1-250mg, 1-200mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, and 5-1 500mg, 5~1000mg, 5~900mg, 5~800mg, 5~700mg, 5~600mg, 5~500mg, 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~150mg, 5~1 25mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10~1500mg, 10~1000mg, 10 ~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 1 0~125mg, 10~100mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20~1500mg, 20~1000 mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500mg, 20~400mg, 20~350mg, 20~300mg, 20~250mg, 20~200mg, 20~15 0mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40mg, 20~30mg, 50~1500mg, 50~1000mg,This includes, but is not limited to, the following dosage ranges: 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg, 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, and 100-200mg.

[0025] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of a compound described in the present invention, or its stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit formulation (the amount of the active ingredient in the unit formulation is also called the "formulation specification"). In some embodiments, the pharmaceutical composition is available in doses of 1-1500 mg, 5-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, This includes, but is not limited to, 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, and 1500 mg of the compound of the present invention or its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts.

[0026] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the compound of the present invention, or its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably prostate cancer.

[0027] A method for treating a disease in a therapeutic mammal, comprising administering to a subject a daily dose of 1 to 1500 mg / day of the compound of the present invention, or its stereoisomers, tautomers, deuterides, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients, wherein the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose is 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 7 This includes, but is not limited to, 5-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day, and in some embodiments, one The daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0028] The present invention relates to a kit, which may comprise a single-dose or multiple-dose composition comprising the compound of the present invention or its stereoisomer, deuteride, or pharmaceutically acceptable salt, wherein the amount of the compound of the present invention or its stereoisomer, deuteride, or pharmaceutically acceptable salt is the same as the amount in the pharmaceutical composition.

[0029] In the present invention, the amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt is, in each case, calculated in terms of the form of the free base.

[0030] "Formulation specifications" refer to the weight of the active ingredient contained in one unit formulation, one tablet formulation, or any other unit formulation.

[0031] Synthesis pathway Methods for producing CYP11A1 inhibitors are described in patent documents such as WO2018115591A1, and those skilled in the art can produce the compounds of the present invention by combining said documents with known organic synthesis techniques, the starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, including companies such as Taitan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Wuxing Kangde, and Bailingwei Technology.

[0032] Indexes of known chemical substances, compiled by the American Chemical Society's chemical information retrieval service, allow for the selective identification of specific and similar reactants. These indexes are available in many public and university libraries and online. For known chemicals not available in catalogs, it is optional to commission a custom chemical synthesizer to produce them, many of which are standard chemical suppliers (e.g., the companies listed above).

[0033] term Unless otherwise specified in this invention, the terms used in this invention have the following meanings.

[0034] In this specification, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0035] "Halogenation" or "halogen substitution" means that a hydrogen atom is substituted with one or more of the following selected from F, Cl, Br, I, or their isotopes, the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogens of the group being substituted, and unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and if the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens.

[0036] "Deuterated" or "deuterated product" refers to a situation in which a hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, or alkynyl group is substituted with at least one isotopic hydrogen atom. The upper limit of the number of deuterated groups is equal to the sum of the number of substituted hydrogen atoms in the group being substituted. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, preferably 1 to 20 deuterium atom substitutions, more preferably 1 to 10 deuterium atom substitutions, even more preferably 1 to 6 deuterium atom substitutions, and even more preferably 1 to 3 deuterium atom substitutions.

[0037] "Alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group, which unless otherwise specified, is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, even more preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and various branched isomers thereof.

[0038] "Alkylene group" refers to a divalent linear and branched saturated alkyl group, and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0039] "Cycloalkyl group" refers to a monovalent, non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group, which, unless otherwise specified, typically has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, [ka] or containing cycloheptyl, etc.

[0040] A "cycloalkylene group" is a divalent group of a "cycloalkyl group," and non-limiting examples include cyclopropylene groups, cyclobutylene groups, and the like.

[0041] A "heterocycle" or "heterocyclic group" 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 N, O, or S, and includes monocyclic heterocycles, bridging bicyclic heterocycles, fused bicyclic heterocycles, and spiro-dicyclic heterocycles, etc. 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. Its definition includes heterocycloalkyl groups and heteroaryl groups. The N and S in the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be linked to a heteroatom or carbon atom, and non-limiting examples include oxyranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, pyridadinyl group, imidazolyl group, piperidinyl group, morpholino group, thiomorpholino group, 1,3-dithianyl group, dihydrofuryl group, dihydro Ropyranil group, dithiolanil group, tetrahydrofuranil group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranil group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group and oxapiro[3.3]heptyl group, [ka] This includes, among others.

[0042] A "heterocyclylene group" is a divalent group corresponding to a "heterocyclic group," and non-limiting examples include imidazolyl groups, piperidinylene groups, and aziridinyl groups.

[0043] "Carbon ring" or "carbon ring group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbon ring group, including monocyclic carbon rings, bicyclic bridged rings, bicyclic parallel rings, and bicyclic spiro rings, and unless otherwise specified, has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl groups and aryl groups. In non-limiting examples, monocyclic carbon rings include cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, or phenyl groups. [ka] The double-ring bridge includes, [ka] Including such as, a biring parallel ring is, [ka] The biring spiro ring includes, [ka] This includes, among others.

[0044] An "aryl group" refers to an aromatic carbon ring. Non-limiting examples include phenyl groups, naphthyl groups, and the like.

[0045] An "alkynyl group" refers to a linear or branched monounsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, and propargyl groups.

[0046] An "alkenyl group" refers to a linear or branched monounsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, an alkenyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include vinyl groups, propenyl groups, allyl groups, 2-butenyl groups, and 1-butenyl groups.

[0047] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group, and unless otherwise specified, -OC 1-8 It is an alkyl group, preferably -OC 1-6 It is an alkyl group, more preferably -OC 1-4 It is an alkyl group, and more preferably -OC 1-2 It is an alkyl group. Non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group and cyclobutoxy group, etc. "Haloalkoxy group" refers to -O-haloalkyl groups, and unless otherwise specified, -O-haloC 1-8 It is an alkyl group, preferably -O-haloC 1-6 It is an alkyl group, more preferably -O-haloC 1-4 It is an alkyl group, and more preferably -O-haloC 1-2 It is an alkyl group. Non-restrictive examples include monofluoromethoxy groups, difluoromethoxy groups, trifluoromethoxy groups, difluoroethyloxy groups, etc.

[0048] "C 1-4 The alkylacyl group is C 1-4 This refers to alkyl-C(O)-. Non-limiting examples include formyl groups, acetyl groups, and propionyl groups.

[0049] "C 1-4 The alkylsulfonyl group is C 1-4This refers to alkyl-S(O)2-. Non-limiting examples include methanesulfonyl groups, ethylsulfonyl groups, and propylsulfonyl groups.

[0050] "Hetero-aromatic ring" or "heteroaryl group" refers to an aromatic heterocyclic ring. Non-limiting examples include pyrazolyl group, pyrimidinyl group, thiazolyl group, pyridyl group, furyl group, pyranone, pyridone, etc.

[0051] A "heterocycloalkyl group" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle that generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, the heterocycloalkyl group further comprises 1 to 3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include azetidinyl groups, morpholino groups, piperazinyl groups, piperidinyl groups, tetrahydropyranyl groups, oxetanyl groups, and the like.

[0052] "Alkyl NH2" or "alkyl NH2" refers to NH2 substituted with one or two alkyl groups, and is also written as -N-(alkyl)2 or -NH-alkyl, the latter of which is also written as monoalkyl NH2. Non-limiting examples include dimethyl NH2, monomethyl NH2, dimethyl NH2, monoethyl NH2, etc.

[0053] [ka] represents a vinyl group (-CH=CH-) and includes cis, trans, or mixed forms of cis and trans.

[0054] "Optionally" or "optionally" means that the event or environment described thereafter may occur, but does not necessarily occur, and the description includes both cases where the event or environment occurs and cases where it does not. For example, "an alkyl group that is optionally substituted with F" means that the alkyl group may be substituted with F, but does not necessarily have to be substituted with F, and indicates that this includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0055] "Pharmacologically acceptable salt" refers to a salt obtained by a reaction in which the compound of the present invention maintains the biological efficacy and properties of the free acid or free base, and by a reaction in which the free acid is reacted with a non-toxic inorganic base or organic base, or with a non-toxic inorganic acid or organic acid.

[0056] "Pharmaceutical composition" means one or more of the compounds herein or their stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, or mixtures with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0057] A "carrier" refers to a system that does not cause significant irritation to the living body, does not cause the loss of the biological activity and properties of the administered compound, alters the method of drug administration to the human body and its distribution within the body, controls the rate of drug release, and delivers the drug to the target organ. Non-limited examples include microcapsules and microspheres, nanoparticles, and liposomes.

[0058] "Excipients" are substances that are not therapeutic agents themselves, but are added to pharmaceutical compositions as diluents, excipients, adhesives and / or mediators to improve their treatment and preservation properties, or to allow or facilitate the formation of a dosage form for administration. As is known to those skilled in the art, medicinal excipients can provide a variety of functions and may be described as wetting agents, buffers, suspension aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of medicinal excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa (9) Fat, suppository wax, (10) Oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, olive oil, corn oil and soybean oil, (11) Glycols, such as propylene glycol, (12) Polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (13) Esters, such as ethyl oleate and ethyl laurate, (14) Agar, (15) Buffers, such as magnesium hydroxide and aluminum hydroxide, (16) Alginic acid, (17) Water for endotoxin testing, (18) Isotonic saline solution, (19) Ringer's solution, (20) Ethanol, (21) pH buffer solution, (22) Polyesters, polycarbonates and / or polyanhydrides, and (23) Other non-toxic and suitable substances used in pharmaceutical formulations, but not limited to these.

[0059] The term "isomer" includes "stereoisomers" and "tautomers." "Stereoisomers" refer to isomers that arise from having the same order of interconnected atoms or groups of atoms within a molecule, but with different stereochemical configurations. Stereoiomers include cis-trans isomers, optical isomers, and conformational isomers. "Tautomers" are compounds that can interconvert through a reversible chemical reaction called tautomerization, which typically involves the simultaneous movement of hydrogen atoms and π bonds (double or triple bonds), resulting in the conversion of one functional group to the other. Examples include the following pairs of compounds: aldehydes / ketones / enols and imines / enamines.

[0060] A "solvate" refers to a substance formed when the compound or salt thereof of the present invention forms intermolecular non-covalent bonds with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0061] A "cocrystal" refers to a crystalline body formed when an active pharmaceutical ingredient (API) and a cocrystal compound (CCF) are bonded together by hydrogen bonds or other non-covalent bonds, where the pure states of the API and CCF are both solids at room temperature, and a fixed stoichiometric ratio exists between each component. Cocrystals are multi-component crystalline bodies, including not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate. [Modes for carrying out the invention]

[0062] The present invention will be described in detail below with reference to examples. Unless specific conditions are specified in the examples, the experiments were carried out according to general experimental conditions. The examples given are for the purpose of better illustrating the present invention, and it should be understood that the present invention is not limited to the examples given. Non-essential improvements and adjustments made 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.

[0063] Dess-Martin reagent: 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one DIPEA: N,N-diisopropylethylamine NMP: N-methylpyrrolidone TBDMSCl:tert-butyldimethylchlorosilane DMAP: 4-dimethylaminopyridine HATU:2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate T3P: Tricyclopropyl Phosphate Anhydride Intermediate 1: [ka]

[0064] Kojic acid (20.0 g, 140.7 mmol) was dissolved in 40 ml of thionyl chloride and reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake was beaten with 100 ml of petroleum ether, filtered, and the filter cake was dried to obtain intermediate 1 (29.8 g, yield: 90%).

[0065] LCMS(ESI): m / z = 161.2[M+H] 1 H NMR (400MHz,DMSO) δ 8.12 (s,1H),6.57(s,1H),4.66 (s,2H). Intermediate 2: [ka]

[0066] Step 1: Compound 2a (2g, 9.30 mmol) and triethylamine (2.82g, 27.9 mmol) were dissolved in dichloromethane (8 mL), and methanesulfonyl chloride (1.28, 11.16 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the mixture was allowed to rise naturally to room temperature. After 3 hours, the end of the reaction was detected by TLC, 50 mL of water was added to the reaction mixture, and it 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 obtain the target compound intermediate 2 (2.74 g). LC-MS (ESI): m / z = 294.1 [M+H] + . Example 1: [ka]

[0067] Step 1: 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 reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated, 25 mL of water was added to the residue, and it was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 1B (1.08 g, yield: 58%). LC-MS (ESI): m / z = 262.2[M+H] + .

[0068] Step 2: 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 for 3 hours under a nitrogen gas atmosphere. After complete reaction, the mixture was cooled to room temperature, 40 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, 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, yield: 78%). LC-MS (ESI): m / z = 459.6 [M + H] + .

[0069] Step 3: 1C (1.47 g, 3.21 mmol) was dissolved in a 10 mL solution of 1,4-dioxane in 4 M hydrogen chloride and reacted at room temperature for 3 hours. After complete reaction, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 1D (1.01 g, yield: 88%). LC-MS (ESI): m / z = 359.4 [M + H] + .

[0070] Step 4: Compound 1D (200 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), triethylamine (227 mg, 2.24 mmol) was added, and then cyclopropylmethanesulfonyl chloride (130 mg, 0.84 mmol) was added dropwise under an ice bath in a nitrogen atmosphere, and the mixture was reacted overnight at room temperature. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (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 obtain compound 1 (58 mg, yield: 22%).

[0071] 1 H NMR (400MHz,CDCl3) δ 7.53 (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). LC-MS (ESI): m / z = 477.5 [M + H] + . Example 2: [ka]

[0072] Step 1: 1D (200 g, 0.56 mmol) and triethylamine (227 mg, 2.24 mmol) were dissolved in dichloromethane (1 mL), and p-nitrophenyl chloroformate (124 mg, 0.62 mmol) was added dropwise under an ice bath in a nitrogen atmosphere. The mixture was allowed to react overnight at room temperature. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 2A (178 mg, yield: 61%). LC-MS (ESI): m / z = 524.6 [M + H] + .

[0073] Step 2: Oxetan-3-ol (101 mg, 1.36 mmol) was dissolved in tetrahydrofuran (4 mL), and under a nitrogen gas atmosphere and an ice bath, 60% sodium hydride (27 mg, 0.68 mmol) was added and the mixture was stirred for 15 minutes. Then, a solution of 2A (178 mg, 0.34 mmol) in DMF (3 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. After complete reaction, 15 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, 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 obtain compound 2 (47 mg, yield: 30%).

[0074] 1 H NMR (400MHz,CDCl3) δ 7.53 (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). LC-MS (ESI): m / z = 459.1[M+H] + . Example 3: [ka]

[0075] Step 1: 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 bath conditions, and after the addition was complete, p-nitrophenyl chloroformate (39.18 g, 194.39 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed twice with saturated sodium carbonate aqueous solution (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, yield: 46%).

[0076] Step 2: In a 500 mL single-necked flask, compound 3B (18 g, 75.26 mmol) was dissolved in dry dichloromethane (360 mL). Under an ice bath, triethylamine (26.65 g, 263.41 mmol) was added, and after the addition was complete, 4-hydroxymethylpiperidine (13.00 g, 122.89 mmol) was slowly added under an ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (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).

[0077] Step 3: In a 500 mL single-necked flask, compound 3C (14.4 g, 66.90 mmol) was dissolved in dry dichloromethane (250 mL). Under ice bath, triethylamine (23.70 g, 234.17 mmol) was added, and after the addition was complete, p-toluenesulfonyl chloride (14.03 g, 73.59 mmol) was slowly added under ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (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, yield: 81%).

[0078] Step 4: 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), DIPEA (1 mL) was added, and the mixture was reacted at room temperature for 3 hours. Complete reaction of the starting materials was detected by LC-MS, and after concentrating the system, it was separated by column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:1) to obtain the target compound 4D (0.3 g, yield: 91%). LC-MS (ESI): m / z = 264.1 [M+H] + .

[0079] Step 5: 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 overnight at 80°C, and completion of the reaction was detected by TLC. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography (DCM:MeOH(v / v)=10:1) to obtain compound 3 (48 mg, yield 18.3%).

[0080] 1 H NMR (400MHz,CDCl3) δ 7.59 (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). LC-MS (ESI): m / z = 461.2[M+H] +. Example 4: [ka]

[0081] Step 1: 4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.15 g, 1.1 mmol) and intermediate 1 (0.2 g, 1.25 mmol) were dissolved in acetonitrile (20 mL), DIPEA (1 mL) was added, and the mixture was reacted at room temperature for 3 hours. Complete reaction of the starting materials was detected by LC-MS, and after concentrating the system, it was separated by column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:1) to obtain the target compound 4A (0.3 g, yield: 91%). LC-MS (ESI): m / z = 264.1 [M+H] + .

[0082] Step 2: Compound 4A (150 mg, 0.57 mmol) was dissolved in DMF (10 mL), 3D (211 mg, 0.57 mmol) and potassium carbonate (158 mg, 1.14 mmol) were added, and the mixture was stirred overnight at 80°C. Completion of the reaction was detected by TLC, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 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%).

[0083] 1H NMR (400MHz,CDCl3) δ 7.59 (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). LC-MS (ESI): m / z = 461.60 [M+H] + . Example 5: [ka]

[0084] Step 1: In a 500 mL single-necked flask, 5A (20 g, 169.21 mmol) was dissolved in glacial acetic acid (200 mL), and paraformaldehyde (5.08 g, 169.21 mmol) was added under an ice bath. After the addition was complete, 40% hydrobromide-glacial acetic acid solution (100 mL, 169.21 mmol) was slowly added dropwise under an ice bath, and the mixture was stirred at room temperature for 30 minutes. Then, it was slowly heated to 80°C and allowed to react overnight. After the reaction was complete, 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), once with saturated brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:0) to obtain compound 5B (28 g, yield: 54%).

[0085] Step 2: Compound 5B (28 g, 92.10 mmol) was dissolved in ethanol (280 ml), potassium carbonate (44.55 g, 322.82 mmol) was added, and benzylamine (24.67 g, 230.25 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the mixture was reacted at 80°C for 4 hours. After the reaction was complete, the reaction solution was filtered over diatomaceous earth, the filtrate was concentrated, and then purified by column chromatography (PE:EA = 40:1) to obtain compound 5C (9.4 g, yield: 40%).

[0086] Step 3: Compound 5C (9.40 g, 92.10 mmol) was dissolved in methanol (940 ml), palladium-carbon (0.8 g, 7.52 mmol) was added, the mixture was substituted three times with hydrogen gas, and the reaction was carried out overnight at 40°C. After the reaction was complete, diatomaceous earth was placed over the reaction solution, and the solution was filtered. The filtrate was concentrated to obtain compound 5D (4.6 g).

[0087] Step 4: 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 bath conditions, and after the addition was complete, p-nitrophenyl chloroformate (39.18 g, 194.39 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed twice with saturated sodium carbonate aqueous solution (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 5F (18 g, yield: 46%).

[0088] Step 5: In a 500 mL single-necked flask, compound 5F (18 g, 75.26 mmol) was dissolved in dry dichloromethane (360 mL). Under an ice bath, triethylamine (26.65 g, 263.41 mmol) was added, and after the addition was complete, 4-hydroxymethylpiperidine (5 G) (13.00 g, 122.89 mmol) was slowly added under an ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (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).

[0089] Step 6: In a 500 mL single-necked flask, compound 5H (14.4 g, 66.90 mmol) was dissolved in dry dichloromethane (250 mL). Under ice bath, triethylamine (23.70 g, 234.17 mmol) was added, and after the addition was complete, p-toluenesulfonyl chloride (14.03 g, 73.59 mmol) was slowly added under ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (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 5I (20 g, yield: 81%).

[0090] Step 7: 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) was added, and kojic acid (14.03 g, 73.59 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was slowly heated to 100 °C and allowed to react overnight. After complete reaction, the reaction solution was diluted with ethyl acetate (500 mL), the organic phase was washed three times with water (375 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:1) to obtain compound 5J (8.4 g, yield: 96%).

[0091] Step 8: 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 bath conditions, and after the addition was complete, methanesulfonyl chloride (127 mg, 1.11 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (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).

[0092] Step 9: 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 bath, and after the addition was complete, compound 5D (140 mg, 0.89 mmol) was slowly added under ice bath, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (100 mL), the organic phase was washed twice with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then separated and purified using a preparative solution (instrument: waters 2767 preparative solution, chromatography column: SunFire@Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 1 / 1000 trifluoroacetic acid), gradient: 30%~80% acetonitrile, isocratic elution, cycle time: 15 minutes) to obtain compound 5.

[0093] LCMS m / z = 481.2[M+H] + . Example 6: [ka]

[0094] Step 1: Compound 6A (4.0 g, 13.4 mmol) and trimethylsilylacetylene (13.2 g, 134 mmol) were dissolved in 50 mL of tetrahydrofuran. Palladium bis(triphenylphosphine)dichloride (941 mg, 1.34 mmol) and triethylamine (5.5 g, 53.6 mmol) were added, and the mixture was reacted in a sealed tube at 50 °C for 4 hours. After monitoring the completion of the reaction by TLC, the reaction mixture 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, yield: 85%). LCMS(ESI): m / z = 260.1[M+H-tBu]

[0095] Step 2: Compound 6B (3.60 g, 11.4 mmol) was dissolved in 10 mL of anhydrous dioxane solution, and 10 mL of 4 M dioxane hydrochloride was added. The reaction was allowed to proceed at room temperature for 8 hours. LC-MS was used to monitor the completion of the reaction and the absence of hydrochloric acid addition products. Excess solvent was removed by spin, and the residue 6C (in which the TMS protecting group was partially removed) was used directly in the next step (2.38 g). LCMS(ESI): m / z = 216.2[M+H]

[0096] Step 3: Crude compound 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 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the target compound 6D (1.39 g, 2-step total yield 83%) was obtained by silica gel column chromatography (PE:EA = 1:1). LCMS(ESI): m / z = 144.2[M+H]

[0097] Step 4: 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. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was added dropwise to 20 mL of ice water and extracted with dichloromethane (50 mL x 3). The organic phases were combined, concentrated, and separated by silica gel column chromatography to obtain the target compound 6E (DCM:MeOH = 15:1) (620 mg, yield: 24%). LCMS(ESI): m / z = 268.3[M+H]

[0098] Step 5: Using 6E and 5I as raw materials, compound 6 was obtained by referring to the synthesis step in step 7 of Example 5.

[0099] LC-MS (ESI): m / z = 465.3 [M + H] + . 1 H NMR(400MHz,CDCl3):δ 7.60 (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). Example 7: [ka]

[0100] Step 1: 5-(trifluoromethyl)isoindole (0.45 g, 2.42 mmol) and intermediate 1 (0.47 g, 2.93 mmol) were dissolved in acetonitrile (20 mL), DIPEA (0.47 g, 3.63 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-8% MeOH / DCM) to obtain compound 7B (0.38 g, yield 50.4%). LC-MS (ESI): m / z = 312.3[M+H] + .

[0101] Step 2: 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 mixture was reacted overnight at 80°C. Complete reaction of the starting materials was detected by LC-MS, the reaction mixture was quenched by pouring it into ice water, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 7C (0.26 g, yield 42.9%). LC-MS (ESI): m / z=409.2[M+H-100] + .

[0102] Step 3: Compound 7C (0.26 g, 0.51 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 hour. Complete reaction of the starting materials was detected by LC-MS, and the reaction mixture was concentrated to obtain compound 7D, which was used directly in the next step without purification (0.20 g). LC-MS (ESI): m / z = 409.1[M+H]+.

[0103] Step 4: In a 50 mL single-necked flask, at 0°C, sodium hydride (0.02 g, 0.48 mmol), dried tetrahydrofuran (10 mL), and 3,3-difluorocyclobutanol (0.078 g, 0.72 mmol) were added and stirred for 15 minutes. Carbonyl diimidazole (0.078 g, 0.48 mmol) was added and the mixture was stirred for 1 hour. Then, a tetrahydrofuran solution of compound 7D (0.13 g, 0.24 mmol) and triethylamine (0.025 g, 0.24 mmol) was added, and the mixture was heated to room temperature and reacted with stirring for 2 hours. The reaction mixture was injected into water, extracted with ethyl acetate (20 mL x 3), washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 7 (40 mg, yield 30.7%).

[0104] LC-MS (ESI): m / z = 543.2 [M + H] + . 1 H NMR(400MHz,CDCl3):δ 7.59 (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). Example 8: [ka]

[0105] Step 1: 6A (1 g, 3.36 mmol), cyclopropylboronic acid (576 mg, 6.72 mmol), bis(triphenylphosphine)dichloride palladium (236 mg, 0.34 mmol), and potassium phosphate (2.14 g, 10.08 mmol) were dissolved in a mixed solvent of toluene (20 mL) and water (2 mL), and reacted overnight at 100 °C under a nitrogen gas atmosphere. After complete reaction, the mixture was cooled to room temperature, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated sodium bicarbonate solution (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to obtain 8B (570 mg, yield: 66%). LC-MS (ESI): m / z=204.1[M+H-56] + .

[0106] Step 2: 8B (570 mg, 2.20 mmol) was dissolved in 1,4-dioxane solution in 4 M hydrogen chloride (8 mL) and reacted overnight at room temperature. After 16 hours, the solvent was removed by rotary evaporation under reduced pressure, and 25 mL of saturated sodium bicarbonate solution was added to the residue. Extraction was performed with ethyl acetate (20 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 8C (335 mg, yield: 96%). LC-MS (ESI): m / z = 160.1 [M+H] + .

[0107] Step 3: 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 reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 8D (382 mg, yield: 64%). LC-MS (ESI): m / z = 283.3[M+H]+.

[0108] Step 4: 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 for 3 hours under a nitrogen gas environment. After complete 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 then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 8E (268 mg, yield: 79%). LC-MS (ESI): m / z = 481.3[M+H]+.

[0109] Step 5: 8E (268 mg, 0.56 mmol) was dissolved in a 1,4-dioxane solution in 4 M hydrogen chloride (5 mL) and reacted at room temperature for 1 hour. After complete reaction, the solvent was removed by reduced-pressure rotational evaporation, and the solution was concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 8F (200 mg, yield: 94%).

[0110] Step 6: 8F (200 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (210 mg, 1.59 mmol) and HATU (264 mg, 0.69 mmol) were added. The mixture was stirred at room temperature for 10 minutes, then cyclopropylacetic acid (53 mg, 0.53 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), 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 8 (60 mg, yield: 25%).

[0111] 1 H NMR (400MHz,CD3Cl) δ 7.59 (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),1.28-1.18 (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). LC-MS (ESI): m / z = 463.2[M+H]+. Example 9: [ka]

[0112] Step 1: 9A (500 mg, 2.18 mmol) and N,N-diisopropylethylamine (845 mg, 6.54 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (374 mg, 3.27 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was allowed to react overnight at room temperature. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with 1 M dilute hydrochloric acid aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 9B (580 mg).

[0113] 1 H NMR (400MHz,CD3Cl) δ 4.61 (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). LC-MS (ESI): m / z=252.2[M+H-56] + .

[0114] Step 2: 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 overnight at 60°C in a nitrogen gas environment. After complete 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 organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 9C (470 mg, yield: 70%). LC-MS (ESI): m / z=423.1[M+H-100] + .

[0115] Step 3: 9C (470 mg, 0.90 mmol) was dissolved in a 1,4-dioxane solution of 4 M hydrogen chloride (8 mL) and reacted at room temperature for 1 hour. After complete reaction, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was concentrated to obtain crude 9D (350 mg, 92%), which was used directly in the next step without further purification. LC-MS (ESI): m / z = 423.4[M+H] + .

[0116] Step 4: Cyclopropanecarboxylic acid (48 mg, 0.56 mmol) was dissolved in DMF (6 mL), N-methylimidazole (69 mg, 0.84 mmol) and TCFH (86 mg, 0.31 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then 9D (120 mg, 0.28 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), 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 9 (33 mg, yield: 24%).

[0117] 1 H NMR (400MHz,CD3Cl) δ 7.61 (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). LC-MS (ESI): m / z = 491.3[M+H] + . Example 10: [ka]

[0118] Step 1: 9D (100 mg, 0.24 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol) were dissolved in dichloromethane (8 mL), and cyclopropylmethanesulfonyl chloride (56 mg, 0.36 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was allowed to react overnight at room temperature. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain compound 10 (25 mg, yield: 19%).

[0119] 1 H NMR (400MHz,CD3Cl) δ 7.55-7.52 (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),2.89-2.86 (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). LC-MS (ESI): m / z = 541.3 [M+H] + . Example 11: [ka]

[0120] Step 1: 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, and N-methylpyrrolidone (150 mL) was added. The mixture was heated to 130 °C and reacted overnight. After cooling to room temperature, the reaction mixture was poured into water (600 mL), extracted with ethyl acetate (100 mL x 5), and the organic phases were combined. The mixture was washed three times with water (150 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0~50 / 50) to obtain the target compound 11B (21.3 g, yield: 52.9%). LC-MS (ESI): m / z = 390.1 [M+H] +

[0121] Step 2: Compound 11B (21.3 g, 54.6 mmol) and potassium tert-butoxide (12.2 g, 109 mmol) were dissolved in tert-butanol (150 mL), heated to 80°C, and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, water (400 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 5). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the reaction mixture was concentrated under reduced pressure. Separation and purification were performed by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0~70 / 30) to obtain the target compound 11C (19.4 g, yield: 96.0%). LC-MS (ESI): m / z = 370.1 [M+H] +

[0122] Step 3: At room temperature, compound 11C (1.80 g, 4.86 mmol) was dissolved in dichloromethane (24 mL), trifluoroacetic acid (8 mL) was added, and stirring was continued at room temperature for 1 hour. After monitoring the disappearance of the starting material by LC-MS, the mixture was directly concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 11D (2.45 g), which was then directly proceeded to the next step without purification. LC-MS (ESI): m / z = 270.1 [M+H] + .

[0123] Step 4: Under ice water bath, the crude trifluoroacetate salt of compound 11D obtained in the previous step (2.45 g) was dissolved in dichloromethane (60 mL), and triethylamine (2.95 g, 29.2 mmol) and methanesulfonyl chloride (836 mg, 7.30 mmol) were added in sequence. The reaction was maintained at 0°C for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL), extracted with dichloromethane (50 mL x 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 90 / 10) to obtain compound 11E (1.58 g, 2-step yield 93.5%). LC-MS (ESI): m / z = 348.1[M+H] + .

[0124] Step 5: Under the protection of nitrogen gas, compounds 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 all dissolved in 1,4-dioxane (30 mL), and the mixture was heated to 100°C and reacted overnight. After monitoring the completion of the reaction by LC-MS, the mixture was directly concentrated under reduced pressure, and the crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0~85 / 15), and further separated and purified by preparative HPLC to obtain racemic compound 11 (24 mg, yield: 3.6%).

[0125] Separation and purification method by preparative HPLC: 1. Instrument: waters2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate), b. Gradient elution, with mobile phase A content of 5% to 50%, c. Flow rate: 12 mL / min, d. Elution time: 30 min.

[0126] 1 H NMR (400MHz,DMSO-d6) δ 9.68 - 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,1H),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). LC-MS (ESI): m / z = 579.3 [M+H] + . Example 12: [ka]

[0127] Step 1 7D (300 mg, 0.67 mmol) and triethylamine (203 mg, 2.01 mmol) were dissolved in 5 ml of dichloromethane, and 3-butyne-1-sulfonyl chloride (152 mg, 1.00 mmol) was added under ice bath, and the reaction was allowed to proceed for 1 hour. After the reaction was complete, excess solvent was removed from the reaction solution using a rotary evaporator, and the mixture was purified by silica gel column chromatography (DCM:MeOH(v / v)=20:1) to obtain the target compound 12 (142 mg, yield: 39%).

[0128] LCMS(ESI): m / z=525.3[M+H] + 1 H NMR (400MHz,DMSO) δ 8.14 (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). Example 13: [ka]

[0129] Step 1: 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) were added sequentially to a 250 mL single-necked flask. After reacting at room temperature for 6 hours, the temperature was raised to 60 °C and the reaction was continued for 24 hours. After filtration, ethyl acetate (500 mL) was added to the filtrate, and the mixture was 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. Separation and purification were performed by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 13B (10.0 g, yield: 64.5%). LC-MS (ESI): m / z = 336.2[M+H] + .

[0130] Step 2: 10.0 g (29.9 mmol) of 13B, 100 mL of ethyl acetate, and 2 g of palladium carbon were added sequentially to a 250 mL single-necked flask. The mixture was hydrogenated and reacted at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product of 13C (7.0 g). LC-MS (ESI): m / z = 306.2[M+H] + .

[0131] Step 3: In a 100 mL single-necked flask, acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous iodide (2.24 g, 11.8 mmol) were added 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. After the dropwise addition was complete, the mixture was reacted at 65 °C for 4 hours. After turning off the heat, the mixture was continued to react for 12 hours. The mixture was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 13D (0.4 g, yield: 12.6%). LC-MS (ESI): m / z=361.2[M-56+H] + .

[0132] Step 4: At room temperature, compound 13D (2.0 g, 4.80 mmol) was dissolved in dichloromethane (40 mL), trifluoroacetic acid (10 mL) was added, and stirring was continued at room temperature for 1 hour. After monitoring the disappearance of the starting material by LC-MS, the mixture was directly concentrated under reduced pressure at 30°C to obtain the crude trifluoroacetate salt of compound 13E (2.98 g), which was then proceeded directly to the next step without purification. LC-MS (ESI): m / z = 317.1 [M + H] + .

[0133] Step 5: Under ice water bath, the crude trifluoroacetate salt of compound 13E obtained in the previous step (2.98 g) was dissolved in dichloromethane (80 mL), and triethylamine (2.92 g, 28.8 mmol) and methanesulfonyl chloride (1.10 g, 9.61 mmol) were added in sequence. The mixture was heated to room temperature and reacted for 4 hours. After monitoring the completion of the reaction by LC-MS, the reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), extracted with dichloromethane (50 mL x 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0~65 / 35) to obtain compound 13F (1.46 g, yield: 77.1%). LC-MS (ESI): m / z = 395.1 [M + H] + .

[0134] Step 5: Under the protection of nitrogen gas, compounds 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 all dissolved in 1,4-dioxane (30 mL), and the mixture was heated to 100°C and reacted overnight. After monitoring the completion of the reaction by LC-MS, the mixture was directly concentrated under reduced pressure, and the crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0~85 / 15), and further separated and purified by preparative HPLC to obtain racemic compound 13 (27 mg, yield: 6.1%).

[0135] Separation and purification method by preparative HPLC: 1. Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.1% trifluoroacetic acid), b. Gradient elution, with mobile phase A content of 5% to 50%, c. Flow rate: 12 mL / min, d. Elution time: 30 min. After preparative elution was complete, the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate.

[0136] 1 H NMR (400MHz,DMSO-d6) δ 9.58 - 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),4.07 (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). LC-MS (ESI): m / z = 578.2[M+H] + .

[0137] Chromatography analysis conditions: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6×50mm, 3μm, 3. Mobile phase system: 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. Example 14: [ka]

[0138] Step 1: 14A (1.02 g, 4.45 mmol) and N-methylmorpholine (900 mg, 8.90 mmol) were dissolved in dichloromethane (20 mL), and methanesulfonyl chloride (610 mg, 5.34 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was allowed to react overnight at room temperature. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with 1 M dilute hydrochloric acid aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 14B (1.05 mg, yield: 76.7%).

[0139] 1 H NMR (400MHz,CDCl3) δ 4.38 (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). LC-MS (ESI): m / z=252.2[M+H-56] + .

[0140] Step 2: Compound 14C (400 mg, yield: 50%) was obtained using 14B (470 mg, 1.53 mmol) as a starting material, following the procedure (step 2) in Example 9. LC-MS (ESI): m / z=467.50[M+H-56] + .

[0141] Step 3: Using 14C (400 mg, 0.77 mmol) as a starting material, the crude product of compound 14D hydrochloride (472 mg) was obtained by referring to the procedure in Example 9 (Step 3), and was used directly in the next step reaction without further purification. LC-MS (ESI): m / z = 423.2[M+H] + .

[0142] Step 4: 14D (220 mg, 0.52 mmol) and triethylamine (158 mg, 1.56 mmol) were dissolved in dichloromethane (10 mL), and cyclopropylmethanesulfonyl chloride (96 mg, 0.62 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was reacted overnight at room temperature. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), 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 14 (51 mg, yield: 18.1%).

[0143] LC-MS (ESI): m / z = 541.60 [M+H] + . 1H NMR (400MHz,CDCl3) δ 7.57 (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),3.35 - 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). Example 15: [ka]

[0144] Step 1: 14D (220 mg, 0.52 mmol) and triethylamine (158 mg, 1.56 mmol) were dissolved in dichloromethane (8 mL), and cyclopropane carbonyl chloride (65 mg, 0.62 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was allowed to react overnight at room temperature. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain compound 15 (72 mg, yield: 28.2%).

[0145] LC-MS (ESI): m / z = 491.50 [M+H] + . 1H NMR (400MHz,CDCl3) δ 7.57 (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). Example 16: [ka]

[0146] Step 1: Kojic acid (10.0 g, 70.3 mmol) was dissolved in DMF (120 mL), potassium carbonate (11.7 g, 84.4 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (30.2 g, 84.4 mmol) were added, and the mixture was allowed to react at room temperature for 14 hours until complete. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 16B (17.0 g, yield: 88.2%). 1 H NMR (400MHz,CDCl3) δ 8.08 (s,1H),6.69 (s,1H),4.53 (s,2H).

[0147] Step 2: 16B (8.13 g, 29.7 mmol) and (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate tert-butyl (10.0 g, 29.7 mmol) were dissolved in 1,4-dioxane (300 mL). Then, 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (2.2 g, 2.9 mmol), potassium carbonate (8.2 g, 59.3 mmol), and water (60 mL) were added. The mixture was purged three times with nitrogen gas, heated to 90°C for 3 hours, and then passed through a silica gel short column, rinsed with ethyl acetate, concentrated, and obtained compound 16C (5.2 g, yield: 52%) by column chromatography (petroleum ether / ethyl acetate = 1 / 1). LC-MS (ESI): m / z=280.2[M+H-56] + .

[0148] Step 3: 16C (1.5 g, 4.5 mmol) was dissolved in DCM (50 mL), and Dess-Martin oxidizing agent (2.28 g, 5.4 mmol) was gradually added at room temperature. After the addition was complete, the mixture was reacted at room temperature for two hours. The mixture was quenched with saturated sodium thiosulfate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotated to obtain 16D (1.4 g, yield: 94%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z=278.2[M+H-56] + .

[0149] Step 4: 16D (500 mg, 1.5 mmol) was dissolved in 1,2-dichloroethane (10 mL) and acetic acid (1 mL), and 5-cyclopropyl-2,3-dihydro-1H-isoindole (0.29 g, 1.8 mmol) was added. The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.41 g, 1.9 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotary evaporated to obtain 16E (490 mg, yield: 69%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z=421.3[M+H-56] + .

[0150] Step 5: 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 complete reaction, the reaction mixture was concentrated, and the crude product 16F was used directly in the next step without purification.

[0151] Step 6: The crude product 16F from the previous step was dissolved in DCM (20 mL), triethylamine (0.31 g, 3.1 mmol) was added, and the mixture was stirred at room temperature for five minutes. Then, 2-cyclopropylacetyl chloride (0.15 g, 1.3 mmol) was added, and the mixture was reacted at room temperature for one hour. The reaction mixture was quenched with water, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotary evaporated to obtain compound 16 (200 mg, yield: 38%) by silica gel column chromatography (rinsed with ethyl acetate).

[0152] LC-MS (ESI): m / z = 459.3 [M + H] + . 1H NMR (400MHz,DMSO-d6) δ 8.31 (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). Example 17: [ka]

[0153] Step 1: 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. After the addition was complete, the reaction was allowed to continue at this temperature for 3 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude 17B (1.2 g), which was then used to proceed directly to the next step in the reaction.

[0154] Step 2: Crude 17B (1.2 g) was added to 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 obtain the crude product. The crude product was purified using a medium-pressure preparative apparatus, Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain the target compound 17C (0.52 g), with a two-step yield of 41.8%.

[0155] Step 3: 17C (120 mg, 0.78 mmol) and CDI (84 mg, 0.6 mmol) were dissolved in THF (10 mL), stirred at room temperature for half an hour, then TEA (350 mg, 3.46 mmol) and 7D (160 mg, 0.4 mmol) were added, the temperature was raised to 60°C, and the reaction was allowed to proceed overnight. After the reaction was complete, 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 the crude product. The crude product was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain the target compound 17 (80 mg, yield 34.4%).

[0156] LC-MS (ESI): m / z = 586.1[M+H] + . 1 H NMR(400MHz,CDCl3):δ 7.60 (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). Example 18: [ka]

[0157] Step 1: 18A (1.2g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), and N,N-diisopropylethylamine (3.9g, 30 mmol) and tert-butyl bromoacetate (2.3g, 12 mmol) were added. The mixture was allowed to react at room temperature for 18 hours. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 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 then separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 18B (1.0 g, yield: 50%). 1 H NMR (400MHz,CDCl3) δ 4.11 - 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).

[0158] Step 2: Dilute hydrochloric acid (10 mL, 6 M) was added to 18B (1.0 g, 5 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was then removed at 60°C using a rotary evaporator to obtain product 18C (400 mg). LC-MS (ESI): m / z = 145.2 [M+H] + .

[0159] Step 3: 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 borohydride acetate (1.4 g, 6.8 mmol) were added. The mixture was allowed to react at room temperature for 2 hours until complete. After complete reaction, 10 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL x 2). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 18D (1.8 g, yield: 79.3%). LC-MS (ESI): m / z = 505.5[M+H] +.

[0160] Step 4: Compound 18D (1.5 g, 3.0 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (6 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 18E (1.3 g), which was used directly in the next step.

[0161] Step 5: 18E (202 mg, 0.50 mmol) was dissolved in DMF (10 mL), 18C (86.4 mg, 0.6 mmol) and N-methylimidazole (164 mg, 2 mmol) were added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (168 mg, 0.6 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. After complete reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 18 (40 mg, yield: 15%).

[0162] 1 H NMR (400MHz,CD3OD) δ 8.23 ​​(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). LC-MS (ESI): m / z = 531.2[M+H] + . Example 19: [ka]

[0163] Step 1: 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 hours. After the reaction was complete, the reaction solution was used directly in the next step without further processing.

[0164] Step 2: Compound 5-pentafluoride thioisoindoline hydrochloride (470 mg, 1.68 mmol) was added to the reaction solution from the previous step, dissolved in dichloromethane (15 mL), and then triethylamine (0.51 mg, 5.04 mmol) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated, and the resulting crude product was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 19C (550 mg, 2-step yield 57.7%). LC-MS(ESI): m / z = 467.5[M+H-100] + .

[0165] Step 3: Compound 19C (0.55 g, 0.98 mmol) was dissolved in DCM (10 mL), and a 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 spin-dried to obtain compound 19D (530 mg). LC-MS (ESI): m / z = 467.1[M+H] + .

[0166] Step 4: 17C (0.14 g, 0.93 mmol) was dissolved in tetrahydrofuran (15 mL), N,N'-Carbonyldiimidazole (0.15 g, 0.93 mmol) was added at room temperature, and the mixture was stirred for 0.5 hours at room temperature. Then triethylamine (0.25 g, 2.47 mmol) was added, and the mixture was stirred for another 0.5 hours. Finally, 19D (330 mg, 0.61 mmol) was added to the reaction system, the temperature was raised to 60°C, and the reaction was continued for 16 hours. The reaction mixture was directly spin-dried, and the resulting crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 19 (180 mg, yield: 48.4%).

[0167] LC-MS (ESI): m / z = 644.9 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.63 (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). Example 20: [ka]

[0168] Step 1: Intermediate 1 (15.0 g, 93.43 mmol) and imidazole (12.7 g, 187 mmol) were dissolved in DCM (100 mL), and tert-butyldimethylchlorosilane (15.49 g, 102.77 mmol) was added dropwise under ice bath. The mixture was allowed to react at room temperature for 1 hour. After complete reaction, 100 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (50 mL x 2). The organic layers were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to obtain 20A (20.0 g, yield: 77.9%). LC-MS (ESI): m / z = 275.1 [M+H] + .

[0169] Step 2: 20A (20.0 g, 72.78 mmol) was dissolved in DMF (30 mL), then sodium azide (5.2 g, 80.06 mmol) was added, and the mixture was reacted overnight at room temperature. After 16 hours, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1) to obtain 20B (19.0 g, yield: 92.7%). LC-MS (ESI): m / z = 282.3 [M + H] + .

[0170] Step 3: 20B (19.0 g, 67.52 mmol) was dissolved in tetrahydrofuran (100 mL), and triphenylphosphine (26.61 g, 101.47 mmol) was gradually added under ice bath. After stirring for 10 minutes, 2.5 mL of pure water was slowly added dropwise, and the mixture was reacted overnight at 50°C. After complete reaction, the mixture was cooled to room temperature, 50 mL of water was added to the reaction solution, and 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 obtain 20C (12 g, yield: 69.6%). LC-MS (ESI): m / z = 256.3 [M + H] + .

[0171] Step 4: 20C (1.2g, 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 gas atmosphere. After complete reaction, the mixture was cooled to room temperature, 40 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 20D (300 mg, yield: 17.5%). LC-MS (ESI): m / z = 364.2[M+H] + .

[0172] Step 5: 20D (300 mg, 0.83 mmol) was dissolved in methanol (10 mL), potassium carbonate (343 mg, 2.49 mmol) was added, and the mixture was reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated, the residue was dissolved in EA (20 mL), the organic phase was washed with water (15 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and 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%). LC-MS (ESI): m / z = 250.2[M+H] + .

[0173] Step 6: 20E (200 mg, 0.80 mmol) was dissolved in dry DMF (10 mL), 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate tert-butyl (259 mg, 0.88 mmol) was added, and the mixture was stirred homogeneously. Potassium carbonate (331 mg, 2.4 mmol) was added, and the reaction was carried out at 80°C for 16 hours. The reaction was stopped by monitoring the disappearance of the starting material by TLC. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and it 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%). LC-MS (ESI): m / z = 447.2[M+H] + .

[0174] Step 7: At room temperature, 20F (100 mg, 0.22 mmol) was dissolved in DCM (10 mL), and a solution of dioxane in hydrochloric acid (0.5 mL, 2 mmol, 4 M) was added. The reaction was allowed to proceed at room temperature for 1 hour, and the disappearance of the starting material was monitored by TLC, at which point the reaction was stopped. The reaction mixture was concentrated, and 20 G (70 mg) was obtained without purification. LC-MS (ESI): m / z = 347.2 [M + H] +.

[0175] Step 8: At room temperature, 1-(methylsulfonyl)azetidine-3-ol (61 mg, 0.40 mmol) was dissolved in dry THF (10 mL), CDI (64.8 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (0.5 mL) was added, followed by 20 G (70 mg, 0.20 mmol), and the reaction was carried out at 80°C for 16 hours. The reaction was stopped by monitoring the disappearance of the starting materials by TLC. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and 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%).

[0176] 1 H NMR (400MHz,CDCl3) δ 7.59-7.58 (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). LC-MS (ESI): m / z = 524.1 [M+H] + . Example 21: [ka]

[0177] Step 1: Compound 19D (200 mg, 0.37 mmol) and triethylamine (150 mg, 1.48 mmol) were dissolved in dichloromethane (15 mL), and cyclopropylacetyl chloride (0.066 mg, 0.55 mmol) was added dropwise under an ice bath. After the addition was complete, the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and purified by passing it through a silica gel column (dichloromethane:methanol (v / v) = 20:1) to obtain compound 21 (62 mg, yield: 30.5%).

[0178] LC-MS (ESI): m / z = 549.9 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.63 (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). Example 22: [ka]

[0179] Step 1: At room temperature, 20 G (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), stirred at room temperature for 30 minutes, then TCFH (67.2 mg, 0.24 mmol) was added and the reaction was continued for 1 hour. The disappearance of the starting materials was monitored by TLC, and the reaction was stopped. 20 mL of water was added to the reaction mixture, extracted with dichloromethane (15 mL x 3), the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH(v / v)=15:1) to obtain compound 22 (15 mg, yield: 17.3%).

[0180] 1 H NMR (400MHz,CDCl3) δ 7.63-7.62 (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). LC-MS (ESI): m / z = 429.2[M+H] + . Example 23: [ka]

[0181] Step 1: Compound 13F (600 mg, 1.52 mmol), bis(pinacolato)diborone (1.16 g, 4.56 mmol), bistriphenylphosphine palladium chloride (214 mg, 0.304 mmol), and potassium acetate (298 mg, 3.04 mmol) were added sequentially to a 50 mL single-necked flask. After purging with nitrogen gas, N,N-dimethylformamide (30 mL) was injected and added. The mixture was heated to 100°C and reacted overnight. After monitoring the disappearance of the starting materials by TLC, the mixture was cooled to room temperature and directly concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 93 / 7~75 / 25) to obtain 23A (309 mg, yield: 51.5%). LC-MS (ESI): m / z = 395.2[M+H] + .

[0182] Step 2: 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 while stirring, and the mixture was reacted at room temperature for approximately 4 hours. After monitoring the disappearance of the starting materials by TLC, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0~65 / 35) to obtain compound 23B (908 mg, yield: 98.1%). LC-MS (ESI): m / z = 444.1[M+H] + .

[0183] Step 3: Under the protection of nitrogen gas, compounds 23A (270 mg, 0.685 mmol), 23B (364 mg, 0.822 mmol), bistriphenylphosphine palladium chloride (96.1 mg, 0.137 mmol), and potassium carbonate (189 mg, 1.37 mmol) were all dissolved in 1,4-dioxane (20 mL), water (10 drops) was added, and the mixture was heated to 100°C and reacted overnight. After monitoring the completion of the reaction by LC-MS, the mixture was cooled to room temperature and directly concentrated under reduced pressure. The crude product was initially separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0~85 / 15), and further separated and purified by SFC to obtain racemic compound 23 (65.2 mg, yield: 17.0%).

[0184] SFC purification method: 1. Instrument: Waters 150 Prep-SFC F, 2. Chromatography 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.

[0185] 1 H NMR (400MHz,DMSO-d6) δ 8.34 (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 (dd,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). LC-MS (ESI): m / z = 562.3 [M+H] + .

[0186] Chromatography analysis conditions: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6×50mm, 3μm, 3. Mobile phase system: 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. Example 24: [ka]

[0187] Step 1: 24A (1 g, 5.36 mmol) and triethylamine (1.63 g, 16.08 mmol) were dissolved in dichloromethane (20 mL), and methanesulfonyl chloride (798 mg, 6.97 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was allowed to react at room temperature for 1 hour. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (25 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 (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain 24B (1.18 g, yield: 83%). LC-MS (ESI): m / z=165.2[M+H-100] + .

[0188] Step 2: 24B (1.18 g, 4.46 mmol) was dissolved in dichloromethane, and a 4 mL solution of 1,4-dioxane in 4 M hydrogen chloride was added under ice bath. The reaction was carried out at room temperature for 30 minutes. After complete reaction, the solvent was removed by rotary evaporation under reduced pressure, and after drying, 24C (705 mg) was obtained and used directly in the next step without further purification.

[0189] Step 3: 7B (1 g, 3.21 mmol) and triethylamine (0.97 g, 9.67 mmol) were dissolved in tetrahydrofuran (15 mL), and trifluoromethanesulfonic anhydride (1.09 g, 3.86 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was reacted at room temperature for 4 hours. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (20 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 (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 24D (850 mg, yield: 60%). LC-MS (ESI): m / z = 444.0 [M+H] + .

[0190] Step 4: 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 gas environment, allyl tributyltin (338 mg, 1.02 mmol) was added dropwise at room temperature, and the mixture was reacted overnight at 100 °C. After complete 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 then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 24E (188 mg, yield: 82%). LC-MS (ESI): m / z = 336.2[M+H] + .

[0191] Step 5: 24E (188 mg, 0.56 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL). Then, potassium osmate dihydrate (21 mg, 0.056 mmol) and sodium periodate (300 mg, 1.40 mmol) were added, and the mixture was reacted at room temperature for 5 hours. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 5). The organic layers were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 24F (140 mg, yield: 74%). LC-MS (ESI): m / z = 338.1[M+H] + .

[0192] Step 6: 24F (140 mg, 0.42 mmol) and 24C (69 mg, 0.42 mmol) were dissolved in methanol (8 mL), and sodium triacetoxyborohydride (356 mg, 1.68 mmol) was added little by little. The mixture was reacted overnight at room temperature. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 4). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain compound 24 (35 mg, yield: 17%).

[0193] 1 H NMR (400MHz,DMSO-d6) δ 8.14 (s,1H),7.10-7.07 (m,1H),6.93-6.91 (m,2H),6.37 (s,1H),3.89 (s,4H),3.78-3.69 (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). LC-MS (ESI): m / z = 486.1[M+H] + . Example 25: [ka]

[0194] Step 1: Compound 25a (1.8 g, 7.6 mmol) was added to a 100 mL single-necked flask, dissolved with N-methylpyrrolidone (10 mL), and then cesium carbonate (5.4 g, 16.7 mmol) was added. The mixture was heated to 130 °C and reacted overnight. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried, concentrated, and obtained compound 25b (0.89 g, 40%) by column chromatography (petroleum ether / ethyl acetate = 10 / 1). LC-MS (ESI): m / z=220.1[M+H-56] + .

[0195] Step 2: Compound 25b (0.89 g, 3.2 mmol) was added to a 100 mL single-necked flask, dissolved with dichloromethane (15 mL), and then trifluoroacetic acid (3.0 mL) was added. The mixture was reacted at room temperature for 2 hours, and then concentrated to obtain compound 25c (1.0 g, 100%). LC-MS (ESI): m / z = 176.1[M+H] + .

[0196] Step 3: 25A (173 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), DIEPA (154 mg, 1.2 mmol) and bis(4-nitrophenyl) carbonate (365 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature for 30 minutes to obtain a dichloromethane solution of 25B, which was prepared for use.

[0197] Step 4: 25C (396 mg, 1.0 mmol, obtained by referring to the synthesis route of 8F using 25C as a starting material) was dissolved in dichloromethane (10 mL), DIEPA (258 mg, 2.0 mmol) and 25B solution were added, and the mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 25D (350 mg, yield: 59%). LC-MS (ESI): m / z = 596.7[M+H] + .

[0198] Step 5: Compound 25D (350 mg, 0.6 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for half an hour, after which it was concentrated to obtain compound 25E (295 mg, yield: 98%), which was used directly in the next step.

[0199] Step 6: Compound 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 minutes. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 25 (100 mg, yield: 29%).

[0200] LC-MS (ESI): m / z = 574.6 [M+H] + . 1H NMR (400MHz,CDCl3) δ 7.60 (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). Example 26: [ka]

[0201] Step 1: 18E (808 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (387 mg, 3.0 mmol) and 25B (1.0 g, 3.0 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain 26A (920 mg, yield: 77%). LC-MS (ESI): m / z = 603.6[M+H] + .

[0202] Step 2: Compound 26A (920 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 26B (890 mg), which was used directly in the next step.

[0203] Step 3: Compound 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 minutes. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 25 (300 mg, yield: 37%).

[0204] LC-MS (ESI): m / z = 581.6 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.80 (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). 19 F NMR (377MHz,CDCl3) δ -60.07 (s). Example 27: [ka]

[0205] Step 1: Cyclopropanol (116 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), DIEPA (308 mg, 2.4 mmol) and bis(4-nitrophenyl) carbonate (730 mg, 2.4 mmol) were added, and the mixture was stirred at room temperature for 30 minutes to obtain the dichloromethane solution 27B, which was prepared for use.

[0206] Step 2: 25C (792 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (516 mg, 4.0 mmol) and 27B (446 mg, 2.0 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 27 (400 mg, yield: 42%).

[0207] LC-MS (ESI): m / z = 480.6 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.59 (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). Example 28: [ka]

[0208] Step 1: Compound 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 bath conditions, and the reaction was continued with stirring for 2 hours. The reaction mixture was extracted with dichloromethane, the organic phase was concentrated under reduced pressure, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-30% EA / PE) to obtain compound 28B (0.41 g, yield 66.8%). LC-MS (ESI): m / z = 150.2 [M + H] + . 1H NMR (400MHz,CD3OD-d4):δ 4.63 - 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).

[0209] Step 2: Compound 28B (0.054 g, 0.36 mmol) and Compound 7D (0.1 g, 0.24 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.049 g, 0.35 mmol) was added, and the mixture was reacted overnight at 70°C. After detecting the complete reaction of the starting materials by LC-MS, the reaction mixture was quenched by pouring it into ice water, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain Compound 28 (0.050 g, yield 39.9%).

[0210] LC-MS (ESI): m / z = 522.2[M+H] + . 1 H NMR(400MHz,CDCl3):δ 7.58 (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). Example 29: [ka]

[0211] Step 1: Cyclopropanol (0.045 g, 0.78 mmol) was dissolved in tetrahydrofuran (15 mL), CDI (0.13 g, 0.78 mmol) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hours. Then triethylamine (0.21 g, 2.08 mmol) was added, and the mixture was stirred for another 0.5 hours. Finally, 19D (280 mg, 0.52 mmol) was added to the reaction system, the temperature was raised to 60°C, and the reaction was continued for 16 hours. The reaction mixture was directly spin-dried, and the resulting crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 19 (60 mg, yield: 20.9%).

[0212] LC-MS (ESI): m / z = 551.2[M+H] + . Example 30: [ka]

[0213] Step 1: 16D (750 mg, 2.25 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 5-cyclopropoxyisoindlytrifluoroacetate (780 mg, 2.70 mmol) was added. The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (572 mg, 2.7 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotary evaporated to obtain 30A (482 mg, yield: 43%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z=437.3[M+H-56] + .

[0214] Step 2: 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 complete reaction, the reaction mixture was concentrated, and the crude product 30B was used directly in the next step without purification.

[0215] Step 3: The crude product 30B from the previous step was dissolved in DCM (20 mL), N,N-diisopropylethylamine (379 mg, 2.94 mmol) was added, and the mixture was stirred at room temperature for five minutes. Then 27B (328 mg, 1.47 mmol) was added, and the mixture was reacted at room temperature for one hour. The reaction mixture was quenched with water, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotated to obtain compound 30 (200 mg, yield: 43%) by silica gel column chromatography (rinsed with ethyl acetate).

[0216] LC-MS (ESI): m / z = 477.7 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.79 (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). Example 31: [ka]

[0217] Step 1 Compound 18E (808 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (516 mg, 4.0 mmol) and 27B (446 mg, 2.0 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain compound 31 (360 mg, yield: 37%).

[0218] LC-MS (ESI): m / z = 488.5 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.79 (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). 19 F NMR (376MHz,CDCl3) δ -60.07 (s). Example 32: [ka]

[0219] Step 1: Cyclopropanol (57 mg, 0.98 mmol) and N,N'-carbonyldiimidazole (119 mg, 0.73 mmol) were dissolved in tetrahydrofuran (10 mL), stirred at room temperature for 30 minutes, then 7D (200 mg, 0.49 mmol) and triethylamine (198 mg, 1.96 mmol) were added, and the mixture was reacted overnight at 70°C under a nitrogen atmosphere. After complete reaction, the mixture was cooled to room temperature, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (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 32 (68 mg, yield: 28%).

[0220] 1 H NMR (400MHz,CDCl3) δ 7.59 (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). LC-MS (ESI): m / z = 493.2 [M + H] + . Example 33: [ka]

[0221] Step 1: 14D (550 mg, 1.30 mmol) and triethylamine (526 mg, 5.20 mmol) were dissolved in dichloromethane (10 mL), and deuteroacetyl chloride (117 mg, 1.43 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was reacted at room temperature for 1 hour. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), 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 33 (287 mg, yield: 47.2%).

[0222] LC-MS (ESI): m / z = 467.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.12 (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). Example 34: [ka]

[0223] Step 1: 34A (460 mg, 1.54 mmol, synthesized using 25c as a starting material and referring to the method of intermediate 8D) and 14B (520 mg, 1.69 mmol) were synthesized referring to the synthesis step of step 2 of Example 9 to obtain 34B (573 mg, yield: 73%). LC-MS (ESI): m / z = 511.2[M+H] + .

[0224] Step 2: Using 34B (570 mg) as a raw material, 34C (420 mg, yield: 91%) was synthesized by referring to the synthesis step in step 3 of Example 9. LC-MS (ESI): m / z = 411.8 [M + H] + .

[0225] Step 3: Compound 34 (340 mg, yield: 70%) was synthesized using 34C (420 mg, 1.02 mmol) as a starting material, following the synthesis steps in Step 4 of Example 9.

[0226] 1 H NMR (400MHz,CDCl3) δ 7.56 (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). LC-MS (ESI): m / z = 479.2[M+H] + . Example 35: [ka]

[0227] Step 1: 1-Methylpyrazole-4-carboxylic acid (179 mg, 1.42 mmol) and triethylamine (478 mg, 4.72 mmol) were dissolved in dichloromethane (20 mL). Under a nitrogen gas environment and an ice bath, HATU (673 mg, 1.77 mmol) was added and the mixture was stirred for 5 minutes. Compound 14D (500 mg, 1.18 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After complete reaction, 25 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine (25 mL), 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%).

[0228] LC-MS (ESI): m / z = 531.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.13 (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). Examples 36 and 37: [ka]

[0229] Step 1: 36A (400 mg, 1.66 mmol) was dissolved in tetrahydrofuran (10 mL), and boranetetrahydrofuran complex (5 mL, 1 M in THF) was slowly added dropwise under ice bath conditions. The reaction was continued under ice bath conditions for 2 hours. After the reaction was complete, 2 mL of 1 M aqueous solution of hydrogen chloride was added to the reaction mixture to quench the reaction, then 20 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain 36B (310 mg, yield: 82%). LC-MS (ESI): m / z=172.1[M+H-56] + .

[0230] Step 2: 36B (310 mg, 1.36 mmol) and triethylamine (410 mg, 4.08 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (187 mg, 1.63 mmol) was added dropwise under an ice bath in a nitrogen gas environment. The mixture was reacted at room temperature for 1 hour. After complete reaction, 30 mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 25:1) to obtain 36C (295 mg, yield: 71%). LC-MS (ESI): m / z=250.1[M+H-56] + .

[0231] Step 3: 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 overnight at 70°C in a nitrogen gas environment. After complete 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 organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 40:1) to obtain 36D (380 mg, yield: 75%). LC-MS (ESI): m / z=465.5[M+H-56] + .

[0232] Step 4: 36D (380 mg, 0.73 mmol) was dissolved in dichloromethane (10 mL), and a 1,4-dioxane solution in 4 M hydrogen chloride (2 mL) was added dropwise under ice bath. The mixture was reacted at room temperature for 2 hours. After complete reaction, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was concentrated to obtain crude 36E (300 mg, yield: 97%), which was used directly in the next step without further purification. LC-MS (ESI): m / z = 421.1 [M + H] + .

[0233] Step 5: 1-(methylsulfonyl)azetidine-3-ol (73 mg, 0.48 mmol) and N,N'-carbonyldiimidazole (117 mg, 0.72 mmol) were dissolved in tetrahydrofuran (6 mL), stirred at room temperature for 30 minutes, then 36E (200 mg, 0.48 mmol) and triethylamine (194 mg, 1.92 mmol) were added, and the mixture was reacted overnight at 70°C under a nitrogen atmosphere. After complete reaction, the mixture was cooled to room temperature, 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 36F (121 mg, yield: 43%).

[0234] Compound 36F was separated and purified by preparative HPLC to obtain compound 36 (41 mg) and compound 37 (21 mg).

[0235] Separation and purification method by preparative HPLC: 1. Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate), b. Gradient elution, with mobile phase A content of 5% to 50%, c. Flow rate: 12 mL / min, d. Elution time: 30 min.

[0236] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6×50mm, 3μm, 3. Mobile phase system: A for 0.05% TFA in H2O; B for ACN, 4. Gradient: B 5~95%, 5. Sampling time: 10 min, 6. Flow rate: 1.0 mL / min. Retention time: Compound 36: tR = 3.327 min, Compound 37: tR = 3.318 min.

[0237] Compound 36: 1H NMR (400MHz, CDCl3) δ 7.68-7.62 (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). LC-MS (ESI): m / z=598.9[M+H] + . Compound 37: 1 H NMR (400MHz, CDCl3) δ 7.63 (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). LC-MS (ESI): m / z=598.9[M+H] + . Example 38:

change

[0238] ステップ1: Using intermediate 1 (1 g, 6.28 mmol) and intermediate 3 (synthesized according to reference WO2007087231A2) as starting materials, compound 38A (820 mg, yield: 49.4%) was obtained by following the procedure in Example 1 (Step 1). LC-MS (ESI): m / z = 265.1[M+H] + .

[0239] Step 2: Compound 38B (544 mg, yield: 38.0%) was obtained using 38A (820 mg, 3.10 mmol) as a starting material, following the procedure (step 2) of Example 1. LC-MS (ESI): m / z = 462.2[M+H] + .

[0240] Step 3: Using 38B (544 mg, 1.18 mmol) as a starting material, the crude hydrochloride of compound 38C (873 mg) was obtained by referring to the procedure (step 3) of Example 1, and the next step was carried out directly without further purification.

[0241] Step 4: Using 38C (450 mg) as a starting material, compound 38 (65 mg, yield: 11.8%) was obtained by referring to the procedure (step 8) of Example 20.

[0242] LC-MS (ESI): m / z = 446.40 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.58 (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). Example 39: [ka]

[0243] Step 1: At room temperature, cyclopropanol (17 mg, 0.28 mmol) and triphosgene (83 mg, 0.28 mmol) were dissolved in dry DCM (10 mL). Under an ice bath, triethylamine (85 mg, 0.84 mmol) was added dropwise, and the mixture was stirred at 0°C for 30 minutes. Then, 20 G (50 mg, 0.14 mmol) was added, and the mixture was stirred uniformly. The reaction was then allowed to proceed at room temperature for 1 hour, and the disappearance of the starting materials was monitored by TLC to stop the reaction. 20 mL of water was added to the reaction mixture, 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 separated and purified by silica gel column chromatography (DCM:MeOH(v / v)=15:1) to obtain compound 39 (10 mg, yield: 16.1%).

[0244] 1 H NMR (400MHz,CDCl3) δ 7.59 (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). LC-MS (ESI): m / z = 431.1[M+H] + . Example 40: [ka]

[0245] Step 1: Compound 34 (200 mg, 0.42 mmol) was dissolved in tetrahydrofuran (6 mL), and under a nitrogen atmosphere and an ice bath, 60% sodium hydride (34 mg, 0.63 mmol) was gradually added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl iodide (118 mg, 0.63 mmol) was slowly added dropwise, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was slowly added dropwise to an aqueous solution of 1 M hydrogen chloride (10 mL) to quench the reaction, and after adding another 10 mL of water, 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, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 25:1) to obtain compound 40 (55 mg, yield: 27%).

[0246] 1 H NMR (400MHz,CDCl3) δ 7.56 (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). LC-MS (ESI): m / z = 493.4[M+H] + . Example 41: [ka]

[0247] Step 1: (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, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (0.16 g, 1.58 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 18E (160 mg, 0.40 mmol) was added dropwise at 0-5°C, and after the addition, the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 41 (85 mg, yield: 40%).

[0248] LC-MS (ESI): m / z = 519.7[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.32 (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). Example 42: [ka]

[0249] Step 1: (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, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (0.16 g, 1.58 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 18E (160 mg, 0.40 mmol) was added dropwise at 0-5°C, and after the addition, the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 42 (90 mg, yield: 40%).

[0250] LC-MS (ESI): m / z = 519.7[M+H] + . 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). Example 43: [ka]

[0251] Step 1 16D (333.0 mg, 2.25 mmol) was dissolved in 1,2-dichloroethane (20 mL), then 5D (174.9 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After stirring, sodium triacetoxyborohydride (466.0 mg, 2.2 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with dichloromethane, the organic layers were combined and washed with saturated NaCl solution, the organic layers were combined again, dried over Na2SO4, filtered, and rotary evaporated to obtain 43A (300.0 mg, yield: 63.0%) by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1). LC-MS (ESI): m / z = 477.2[M+H] + .

[0252] Step 2 Compound 43A (300.0 mg, 0.62 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (2.0 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 43B (310.0 mg), which was used directly in the next step. LC-MS (ESI): m / z = 377.2[M+H] + .

[0253] Step 3 Cyclopropanol (44.0 mg, 0.75 mmol) was dissolved in tetrahydrofuran (5.0 mL), and CDI (120.0 mg, 0.75 mmol) was added. The mixture was stirred and reacted at room temperature for 0.5 hours. Then, a solution of 43B (310.0 mg, 0.62 mmol) in tetrahydrofuran (5.0 mL) and triethylamine (191.0 mg, 1.9 mmol) were added. The mixture was heated to 60°C and reacted overnight. The complete reaction was monitored by TLC, and after concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain compound 43 (102.0 mg, yield: 35%).

[0254] LC-MS (ESI): m / z = 461.2[M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.79 (s,1H),7.04 (s,2H),6.55 - 6.49 (m,1H),6.42 (d,1H),6.17 (d,1H),4.45 - 3.86 (m,7H),3.78 (d,2H),2.94 - 2.71 (m,6H),2.32 - 2.15 (m,1H),2.11 - 2.04 (m,2H),1.74 (d,2H),1.36 (d,2H),0.69 - 0.67 (m,4H). Example 44: [ka]

[0255] Step 1: Kojic acid (1.00 g, 7.04 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 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. After all additions were made, the mixture was reacted overnight at 85 °C. After the reaction was complete, water (50 mL) was added to the reaction mixture to quench the reaction, and the mixture was 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, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4, (v / v)) to obtain 44B (256 mg, yield: 10%). LC-MS (ESI): m / z=298.4[M-56+H] + .

[0256] Step 2: 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. After adding the compounds, the mixture was reacted at room temperature for 30 minutes, then 5D (197 mg, 0.86 mmol) was added, and the mixture was reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain compound 44C (220 mg, yield: 61%). LC-MS (ESI): m / z = 495.3 [M + H] + .

[0257] Step 3: 44C (100 mg, 0.20 mmol) was dissolved in 1,4-dioxane (0.5 mL), and a 1,4-dioxane solution in 4N HCl (10 mL) was added at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 2.5 hours. After the reaction was complete, the reaction was concentrated to obtain the crude compound 44D, and the next step in the reaction was carried out directly.

[0258] Step 4: Crude product 44D was dissolved in dichloromethane (5 mL), and triethylamine (0.10 g, 1.00 mmol) and cyclopropane carbonyl chloride (0.31 g, 0.30 mmol) were added dropwise to the reaction system at room temperature. After the addition was complete, the mixture was allowed to react overnight at room temperature. After complete reaction, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 44 (15 mg, yield: 16%).

[0259] LC-MS (ESI): m / z = 463.5 [M + H] + . 1H NMR (400MHz,DMSO-d6) δ 8.11 (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),1.52-1.47 (m,1H),1.24 - 1.14 (m,2H),1.09-1.00 (m,2H),0.64 - 0.59 (m,4H). Example 45: [ka]

[0260] Step 1: At room temperature, compound 35 (281 mg, 0.53 mmol) was dissolved in dry DMF (5 mL). Under an ice bath, NaH (42 mg, 1.06 mmol) was added and the mixture was stirred for 10 minutes. Then, methyl iodide (113 mg, 0.79 mmol) was added to the reaction system, the temperature was raised to room temperature, and the reaction was allowed to continue for 6 hours until it was stopped. Water (10 mL) was added to quench the reaction, and the mixture was extracted with EA (15 mL). After liquid-liquid separation, the aqueous phase was washed twice with EA (10 mL), and the organic phase was combined. The organic phase was washed twice with saturated sodium chloride solution (20 mL), the organic phase was dried, concentrated, and compound 45 (17 mg, yield: 6.1%) was obtained by column chromatography (DCM:MeOH = 15:1).

[0261] LC-MS (ESI): m / z = 545.4 [M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.12 - 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). Example 46: [ka]

[0262] Step 1: Compound 46 (20 mg, yield: 10.4%) was obtained using compound 33 (187 mg, 0.40 mmol) as a starting material, following the procedure in Example 45 (Step 1).

[0263] LC-MS (ESI): m / z = 481.3 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.09 (s,1H),7.72 - 7.68 (m,1H),7.67 (s,1H),7.54 - 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 - 1.98 (m,1H),1.97 (s,2H),1.87 - 1.79 (m,4H),1.74 (s,1H),1.20 - 1.02 (m,4H). Example 47: [ka]

[0264] Step 1: At room temperature, 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), stirred at room temperature for 10 minutes, then TCFH (130 mg, 0.46 mmol) was added and the reaction was continued for 1 hour. The disappearance of the starting materials was monitored by TLC, and the reaction was stopped. 20 mL of water was added to the reaction mixture, 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 separated and purified by silica gel column chromatography (DCM:MeOH(v / v)=15:1) to obtain compound 47 (20 mg, yield: 9.6%).

[0265] 1 H NMR (400MHz,CDCl3) δ 7.92 (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). LC-MS (ESI): m / z = 536.3 [M+H] + . Example 48: [ka]

[0266] Step 1: (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. After adding the compounds, the reaction was allowed to proceed at room temperature for 4 hours. Triethylamine (120 mg, 1.23 mmol) was then added dropwise to the reaction system, and the reaction was allowed to proceed for 2 hours. Compound 41E (120 mg, 0.31 mmol) was then added dropwise under an ice bath. After adding the compounds, the reaction system was heated to 60°C and stirred overnight. Complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated and purified by preparative HPLC to obtain compound 48 (50 mg, yield: 32%).

[0267] LC-MS (ESI): m / z = 507.80 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.31 (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),1.94-1.84 (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). Example 49: [ka]

[0268] Step 1: Compound 49A (1.00 g, 4.25 mmol) was dissolved in DMF (20 mL), and bromocyclobutane (690 mg, 5.10 mmol) and cesium carbonate (3.46 g, 10.63 mmol) were added in sequence. The reaction mixture was stirred overnight at 90°C under the protection of nitrogen gas. After monitoring the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted twice with 30 mL of dichloromethane. The organic phases were combined, dried, and concentrated. The mixture was then separated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 49B (600 mg, yield: 48.8%). LC-MS (ESI): m / z=234.2[M-56+H] +

[0269] Step 2: 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 mixture was concentrated under reduced pressure to obtain the crude product compound 49C (800 mg), which was used directly in the next step of the reaction. LC-MS (ESI): m / z = 190.2[M+H] +

[0270] Step 3: 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 hours, then concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5) to obtain compound 49D (580 mg, yield: 77.4%). LC-MS (ESI): m / z = 314.1 [M + H] +

[0271] Step 4: Compound 49D (580 mg, 1.85 mmol) was dissolved in DMF (15 mL), and then 4-bromopiperidine-1-carboxylate tert-butyl (540 mg, 2.05 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were added. The reaction mixture was stirred at 85°C for 16 hours, 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, yield: 95.2%). LC-MS (ESI): m / z = 511.5 [M+H] +

[0272] Step 5: Compound 49E (900 mg, 1.76 mmol) was dissolved in dichloromethane (8 mL), and then dioxane hydrochloride solution (2 mL) was added. After reacting at room temperature for half an hour, the reaction mixture was concentrated under reduced pressure to obtain the crude product compound 49F (850 mg), which was used directly in the next step of the reaction. LC-MS (ESI): m / z = 411.2[M+H] +

[0273] Step 6: 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 minutes, and then 49F (850 mg, 1.76 mmol) was continuously added. The reaction mixture was transferred to 85°C and stirred for 16 hours under the protection of nitrogen gas. 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. Separation was then performed by silica gel column chromatography (dichloromethane / methanol (v / v) = 95 / 5), and compound 49 (80 mg, yield: 9.05%) was obtained by reverse phase preparative chromatography (acetonitrile / water (v / v) = 5 / 95~95 / 5).

[0274] 1 H NMR (400MHz,DMSO-d6) δ 8.12 (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 - 1.87 (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). LC-MS (ESI): m / z = 495.3 [M + H] + Example 50: [ka]

[0275] Step 1: 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), stirred for 10 minutes, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.23 g, 0.81 mmol) was added. The mixture was stirred at room temperature for 1 hour to allow it to react. The reaction mixture was injected into water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-50% EA / PE) to obtain compound 50A (0.215 g, yield 61.66%). LC-MS (ESI): m / z = 646.3 [M + H] + .

[0276] Step 2: Compound 50A (0.215 g, 0.33 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. Complete reaction of the starting materials was detected by LC-MS, the reaction mixture was quenched by pouring it into ice water, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 50B (0.15 g), which was used directly in the next step without purification. LC-MS (ESI): m / z = 546.1 [M+H] + .

[0277] Step 3: At 0°C, compound 50B (0.15 g, 0.27 mmol) and triethylamine (0.082 g, 0.81 mmol) were dissolved in dichloromethane (10 mL), stirred for 15 minutes, then methanesulfonyl chloride (0.037 g, 0.32 mmol) was added dropwise, and stirring was continued for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified using a Biotage Isolera One medium-pressure preparative apparatus (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 50 (40 mg, yield 23.7%).

[0278] LC-MS (ESI): m / z = 624.7 [M+H] + . 1H NMR(400MHz,CDCl3):δ 7.61 (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). Example 51: [ka]

[0279] Step 1: 51A (3.4g, 10 mmol) was dissolved in ethyl acetate (20 mL), IBX (5.6g, 20 mmol) was added, and the mixture was reacted at 80°C for 12 hours. After complete reaction, the mixture was filtered and concentrated to obtain 51B (2.1 g). LC-MS (ESI): m / z = 337.1 [M + H] + .

[0280] Step 2: Compound 51C (540 mg, 2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.0 mL) was added. The mixture was reacted at room temperature for 15 minutes, then concentrated to obtain compound 51D (520 mg), which was used directly in the next step. LC-MS (ESI): m / z = 169.2[M+H] + .

[0281] Step 3: 51B (606 mg, 1.8 mmol) was dissolved in DCE (20 mL), and 5-difluoromethylisoindoline hydrochloride (370 mg, 1.8 mmol), sodium borohydride acetate (763 mg, 3.6 mmol), and one drop of glacial acetic acid were added in sequence. The mixture was allowed to react at room temperature for 1 hour until completely reacted. After complete reaction, 10 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (20 mL x 2). The organic layers were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 51E (735 mg, yield: 83%). LC-MS (ESI): m / z = 169.2[M+H] + .

[0282] Step 4: 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 minutes, then concentrated to obtain compound 51F (710 g), which was used directly in the next step.

[0283] Step 5: 51F (710 mg, 1.4 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (254 mg, 2.0 mmol) and 25B (0.6 g, 2.0 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain 51G (589 mg, yield: 72%). LC-MS (ESI): m / z = 590.6 [M+H] + .

[0284] Step 6: Compound 51G (590 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for half an hour, then concentrated to obtain compound 51H (570 mg), which was used directly in the next step.

[0285] Step 7: 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 minutes. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 51 (120 mg, yield: 24%).

[0286] LC-MS (ESI): m / z = 568.6 [M + H] + . 1 H NMR (400MHz,CDCl3) δ 7.60 (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), 19 F NMR (400MHz,CDCl3) δ -107.63 (s). Example 52: [ka]

[0287] Step 1: 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 under an ice bath. After the addition was complete, the reaction was continued under an ice bath for 4 hours, and the complete reaction of the starting materials was detected by LC-MS. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 52 (40 mg, yield: 9%).

[0288] LC-MS (ESI): m / z = 487.30 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.32 (s,1H),7.62 (s,1H),7.57 (d,1H),7.46 (d,1H),6.76-6.60 (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,2H),1.31-1.09 (m,2H),1.00-0.87 (m,1H),0.48-0.38 (m,2H),0.15-0.06 (m,2H). Example 53: [ka]

[0289] Step 1: Compound 53A (5.4 g, 30 mmol) was dissolved in toluene (50 mL), and bis(cyclopentadienyl)dichlorohydride zirconium (397 mg, 1.5 mmol) and pinacolborane (5.0 g, 39 mmol) were added in sequence. The mixture was reacted at 60°C for 18 hours until complete. After complete reaction, the mixture was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 53B (7.7 g, yield: 83%). LC-MS (ESI): m / z = 310.2[M+H] + .

[0290] Step 2: 53B (7.7g, 25 mmol) was dissolved in 1,4-dioxane (40 mL), and then 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (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 mixture was purged three times with nitrogen gas, heated to 90°C for 3 hours, and then passed through a silica gel short column, rinsed with ethyl acetate, concentrated, and obtained compound 53C (4.6 g, yield: 60%) by column chromatography (petroleum ether / ethyl acetate = 9 / 1). LC-MS (ESI): m / z = 308.4[M+H] + .

[0291] Step 3: 53C (4.6 g, 15 mmol) was dissolved in ethyl acetate (50 mL), IBX (8.4 g, 30 mmol) was added, and the mixture was reacted at 80°C for 12 hours. After complete reaction, the mixture was filtered and concentrated to obtain 53D (4.3 g).

[0292] Step 4: 53D (1.5 g, 5 mmol) was dissolved in DCE (20 mL), and 5-trifluoromethylisoindoline hydrochloride (1.1 g, 5.0 mmol), sodium borohydride acetate (1.4 g, 6.8 mmol), and 5 drops of glacial acetic acid were added in sequence. The mixture was allowed to react at room temperature for 1 hour until completely reacted. After this time, 10 mL of water was added to the reaction mixture, and the mixture was extracted using DCM (20 mL x 2). The organic layers were combined, washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 53F (1.8 g, yield: 78%).

[0293] Step 5: Compound 53F (1.8 g, 3.8 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (8.0 mL) was added. The mixture was reacted at room temperature for 10 minutes, then concentrated to obtain compound 53G (1.6 g), which was used directly in the next step. LC-MS (ESI): m / z = 377.2[M+H] + .

[0294] Step 6: 53G (1.1g, 3.0 mmol) was dissolved in dichloromethane (20 mL), and DIEPA (1.1g, 8.0 mmol) and 27B (1.4g, 6 mmol) solutions were added. The mixture was stirred at room temperature for 30 minutes. After complete reaction, the solvent was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 53 (320 mg, yield: 30%).

[0295] LC-MS (ESI): m / z = 461.1[M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.81 (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). 19 F NMR (400MHz,CDCl3) δ -60.08 (s). Example 54: [ka]

[0296] Step 1: 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, following the synthesis steps in step 4 of Example 9.

[0297] 1H NMR (400MHz,CDCl3) δ 7.60 (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). LC-MS (ESI): m / z = 507.3 [M + H] + . Example 55: [ka]

[0298] Step 1: 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), stirred in an ice bath under nitrogen gas conditions for 10 minutes, 9D (250 mg, 0.59 mmol) was added, stirred in an ice bath for 5 minutes, returned to room temperature, and reacted for 1 hour. After complete reaction, the mixture was directly distilled under reduced pressure, concentrated, and 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%).

[0299] LC-MS (ESI): m / z = 527.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.18 (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). Examples 56 and 57: [ka]

[0300] Step 1: 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), stirred at room temperature for 30 minutes, then 7D (400 mg, 0.98 mmol) and triethylamine (397 mg, 3.92 mmol) were added, and the mixture was reacted overnight at 70°C under a nitrogen atmosphere. After complete reaction, the mixture was cooled to room temperature, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (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 56A (120 mg, yield: 22%).

[0301] Compound 56A was separated and purified by preparative HPLC to obtain compound 56 (36 mg, retention time: 3.940 min) and compound 57 (32 mg, retention time: 3.930 min).

[0302] Separation and purification method by preparative HPLC: 1. Instrument: Waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 0.1% ammonium acetate), b. Gradient elution, with mobile phase A content of 5% to 50%, c. Flow rate: 12 mL / min, d. Elution time: 30 min.

[0303] HPLC analysis method: 1. Instrument: Shimadzu LC-20AT, 2. Chromatography column: Xtimate C18 4.6×50mm, 3μm, 3. Mobile phase system: A for 0.05% TFA in H2O; B for ACN, 4. Gradient: B 5~95%, 5. Sampling time: 10 min, 6. Flow rate: 1.0 mL / min.

[0304] Compound 56: 1 H NMR (400MHz,CDCl3) δ 7.60 (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). LC-MS (ESI): m / z = 549.3 [M + H] + . Compound 57: 1H NMR (400MHz,CDCl3) δ 7.60 (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). LC-MS (ESI): m / z = 549.3 [M + H] + . Example 58: [ka]

[0305] Step 1: Compound 58A (1.0 g, 4.97 mmol) and triethylamine (1.51 g, 14.91 mmol) were sequentially added to dichloromethane (30 mL). Under an ice bath, methanesulfonic anhydride (1.73 g, 9.94 mmol) was slowly added, and the mixture was slowly heated to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, extracted with dichloromethane, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 58B (1.50 g). This crude product was used directly in the next step without purification. LC-MS (ESI): m / z = 280.1 [M+H] + .

[0306] Step 2: Compound 58B (0.5 g, 1.79 mmol) was dissolved in anhydrous methanol (2 mL), and methanol hydrochloric acid solution (5.0 mL, 4 M) was added. After the dropwise addition was complete, the mixture was reacted at room temperature for 3 hours. The reaction mixture was concentrated to obtain the crude compound 58C, which was used directly in the next step. LC-MS (ESI): m / z = 180.1[M+H] + .

[0307] Step 3: Compound 58C (0.45 g, 2.51 mmol) and triethylamine (0.76 g, 7.53 mmol) were sequentially added to dichloromethane (30 mL). Cyclopropane carbonyl chloride (0.34 g, 3.26 mmol) was slowly added under ice bath conditions, and the mixture was slowly heated to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, extracted with dichloromethane, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 58D (0.4 g). This crude product was used directly in the next step without purification. LC-MS (ESI): m / z = 248.1 [M+H] + .

[0308] Step 4: Compound 58D (0.4g, 1.62 mmol), intermediate 7B (0.50g, 1.62 mmol), and potassium carbonate (0.45g, 3.24 mmol) were successively added to DMF (20 ml), heated to 75°C, reacted overnight, filtered, diluted with water, extracted with ethyl acetate, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified the crude product using Biotage Isolera One (20 g silica gel column, eluent: 0-10% dichloromethane / anhydrous methanol) to obtain compound 58 (100 mg, yield: 13%).

[0309] LC-MS (ESI): m / z = 463.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.34(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). Example 59: [ka]

[0310] Step 1: Compound 59A (1.0 g, 4.97 mmol) and triethylamine (1.51 g, 14.91 mmol) were sequentially added to dichloromethane (30 mL). Under an ice bath, methanesulfonic anhydride (1.73 g, 9.94 mmol) was slowly added, and the mixture was slowly heated to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, extracted with dichloromethane, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 59B (1.50 g). This crude product was used directly in the next step without purification. LC-MS (ESI): m / z = 280.1 [M+H] + .

[0311] Step 2: Compound 59B (0.5 g, 1.79 mmol) was dissolved in anhydrous methanol (2 mL), and methanol hydrochloric acid solution (5.0 mL, 4 M) was added. After the dropwise addition was complete, the mixture was reacted at room temperature for 3 hours. The reaction mixture was concentrated to obtain the crude compound 59C, which was used directly in the next step. LC-MS (ESI): m / z = 180.1[M+H] + .

[0312] Step 3: Compound 59C (0.45 g, 2.51 mmol) and triethylamine (0.76 g, 7.53 mmol) were sequentially added to dichloromethane (30 mL). Cyclopropane carbonyl chloride (0.34 g, 3.26 mmol) was slowly added under ice bath conditions, and the mixture was slowly heated to room temperature and stirred overnight. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, extracted with dichloromethane, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 59D (0.5 g). This crude product was used directly in the next step without purification. LC-MS (ESI): m / z = 248.1 [M+H] + .

[0313] Step 4: 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 successively added to DMF (20 ml), heated to 75°C, reacted overnight, filtered, diluted with water, extracted with ethyl acetate, washed the combined organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and purified the crude product using Biotage Isolera One (20 g silica gel column, eluent: 0-10% dichloromethane / anhydrous methanol) to obtain compound 59 (130 mg, yield: 14%).

[0314] LC-MS (ESI): m / z = 463.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.29(d,1H),8.15 (s,1H),7.63 (s,1H),7.56-7.58 (m,1H),7.47 (d,1H),6.41 (s,1H),4.12-4.17 (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). Example 60: [ka]

[0315] Step 1: Compound 60A (1.0 g, 5.34 mmol) and triethylamine (1.62 g, 16.02 mmol) were weighed and placed in a 100 mL single-necked flask. They were dissolved in dichloromethane (20 mL), and methanesulfonic anhydride (1.12 g, 6.43 mmol) was added. After the addition was complete, the mixture was stirred at 25°C for 16 hours. The complete reaction was monitored using a TLC spot plate (petroleum ether:ethyl acetate = 3:1). Water (20 mL) was added, the mixture was stirred for 5 minutes, and the organic phase was separated by extraction with dichloromethane (20 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 60B (1.2 g, yield: 90%), which was used directly in the next step.

[0316] Step 2: Compounds 7B (0.5 g, 1.61 mmol) and 60B (0.48 g, 1.93 mmol) were added to a 100 mL single-necked flask, dissolved in DMF (20 mL), and potassium carbonate (0.66 g, 4.75 mmol) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 70 °C for 16 hours. Complete reaction of the starting materials was detected by LC-MS, water (20 mL) was added, and the mixture was stirred for 5 minutes. The mixture was extracted with ethyl acetate (20 mL) to separate the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the target compound 60C (0.5 g, yield: 64%). LCMS m / z=481.1[M+1] +

[0317] Step 3: Compound 60C (0.5 g, 1.04 mmol) was added to a 100 mL single-necked flask, dissolved with dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 20 °C for 2 hours. The complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain the target compound 60D (0.4 g, crude product). LCMS m / z=381.1[M+1] +

[0318] Step 4: The compounds carbonyldiimidazole (0.34 g, 2.1 mmol) and N-Boc-3-hydroxyazetidine (0.36 g, 2.1 mmol) were weighed and placed in a 100 mL single-neck flask. They were dissolved in tetrahydrofuran (10 mL) and stirred at 25 °C for 1 hour. Then, 60 D (0.4 g, 1.05 mmol) and triethylamine (0.32 g, 3.15 mmol) were added. After the addition was complete, the mixture was stirred at 70 °C for 16 hours. The complete reaction was monitored using a TLC spot plate (petroleum ether:ethyl acetate = 1:1). Water (20 mL) was added, the mixture was stirred for 5 minutes, and the organic phase was separated by extraction with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 60 E (0.40 g, yield: 66%). LCMS m / z=524.1[M -55] +

[0319] Step 5: Compound 60E (0.4 g, 0.69 mmol) was added to a 100 mL single-necked flask, dissolved with dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 20 °C for 4 hours. The complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain the target compound 60F (0.4 g, crude product). LCMS m / z=480.1[M+1] +

[0320] Step 6: Compound 60F (300 mg, 0.73 mmol) and triethylamine (0.16 g, 1.58 mmol) were weighed and placed in a 100 mL single-necked flask. They were dissolved in dichloromethane (6 mL), and methanesulfonyl chloride (89 mg, 0.77 mmol) was added at 0°C. After the addition was complete, the system was protected with nitrogen gas and stirred at 0°C for 2 hours. Complete reaction of the starting materials was detected by LC-MS. Water (20 mL) was added, stirred for 5 minutes, and extracted with dichloromethane (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the crude product of the target compound. Compound 60 (35 mg, yield: 12%) was obtained by preparative HPLC.

[0321] Preparative chromatography method: Instrument: Waters 2767 preparative liquid, chromatographic column: SunFire@ Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5 mM aqueous ammonia), b. Gradient elution, with mobile phase A content of 35% to 70%, c. Flow rate: 15 mL / min, d. Elution time: 20 min.

[0322] LCMS m / z=558.2[M+1] + 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). Example 61: [ka]

[0323] Step 1: 61A (2.00 g, 8.96 mmol) was dissolved in dry toluene (60 mL), pinacolborane (2.00 g, 15.61 mmol) was added dropwise, and bis(cyclopentadienyl)chlorohydridozirconium (0.46 g, 1.79 mmol) was added. After the addition was complete, the mixture was purged with nitrogen gas and stirred at 65°C for 18 hours to allow the reaction to proceed. The complete reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1 (v / v)), the reaction mixture was concentrated, and the crude product was used directly in the next step.

[0324] Step 2: Compounds 61B (3.14 g, 8.94 mmol) and 61a (3.96 g, 8.94 mmol, prepared using 7B as a starting material and referring to the synthesis method of 16B) were dissolved in 1,4-dioxane (60 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.65 g, 0.89 mmol), potassium carbonate (4.32 g, 31.29 mmol), and water (12 mL) were added in sequence. After all additions were made, the mixture was purged with nitrogen gas three times and stirred at 85°C for 18 hours to allow the reaction to proceed. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were then combined and washed with saturated brine (40 mL x 1). After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to obtain compound 61C (1.4 g, yield: 30%). LC-MS (ESI): m / z=463.10[M-56+H] + .

[0325] Step 3: Compound 61C (800 mg, 1.54 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The complete reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1 (v / v)), and after concentrating the reaction mixture, compound 61D (640 mg, crude product) was obtained and used directly in the next step without purification. LC-MS (ESI): m / z = 419.10[M+H] + .

[0326] Step 4: Compound 61D (640 mg, 1.53 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (542 mg, 5.35 mmol) and cyclopropane carbonyl chloride (240 mg, 2.30 mmol) were added sequentially under an ice bath. After the addition was complete, the reaction was continued under an ice bath for 2 hours, and the complete reaction was monitored by TLC (dichloromethane:methanol = 20:1 (v / v)). The reaction mixture 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%).

[0327] LCMS m / z=487.7[M+1] + 1 H NMR (400 MHZ,DMSO-d6) δ 8.30 (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). Example 62: [ka]

[0328] Step 1: Compound 61D (485 mg, 1.16 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (411 mg, 4.06 mmol) and cyclopropylmethanesulfonyl chloride (269 mg, 1.74 mmol) were added sequentially under an ice bath. After the addition was complete, the reaction was continued under an ice bath for 7 hours, and the complete reaction was monitored by TLC (dichloromethane:methanol = 20:1 (v / v)). 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%).

[0329] LCMS m / z=537.8[M+1] + 1 H NMR (400 MHZ,DMSO-d6) δ 8.30 (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,4H),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). Example 63 [ka]

[0330] Step 1: Compound 63 (46 mg, yield: 23%) was synthesized using 14D (200 mg, 0.47 mmol) and oxetane-3-carboxylic acid (58 mg, 0.56 mmol) as starting materials, following the synthesis steps in step 4 of Example 9.

[0331] 1H NMR (400MHz,CDCl3) δ 7.58 (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). LC-MS (ESI): m / z = 507.8 [M+H] + . Example 64 [ka]

[0332] Step 1: Compound 64 was synthesized using compound 14D and compound 17C as starting materials, following the procedure described in step 3 of Example 17 of the compound.

[0333] LC-MS (ESI): m / z = 600.6 [M + H] + . 1 H NMR(400MHz,CDCl3):δ 7.57 (s,1H),7.50 (d,1H),δ 7.46 (s,1H),7.31 (s,1H),6.48 (s,1H),5.17-5.11 (m,1H),δ 4.68 (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). Example 65: [ka]

[0334] Step 1: (1R)-2,2-difluorocyclopropane-1-carboxylic acid (86 mg, 0.71 mmol) and compound 14D (250 mg, 0.54 mmol) were used as starting materials, and compound 65 (61 mg, yield 19.6%) was obtained by referring to step 1 of Example 55.

[0335] LC-MS (ESI): m / z = 527.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.22 - 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). Example 66 [ka]

[0336] Step 1: (1S)-2,2-difluorocyclopropane-1-carboxylic acid (86 mg, 0.71 mmol) and compound 14D (250 mg, 0.54 mmol) were used as starting materials, and compound 66 (53 mg, yield 17.1%) was obtained by referring to step 1 of Example 55.

[0337] LC-MS (ESI): m / z = 527.2[M+H] + . 1H NMR (400MHz,DMSO-d6) δ 8.21 - 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). Example 67: [ka]

[0338] Step 1: Using cyclopropanol (83 mg, 1.42 mmol) and compound 14D (300 mg, 0.65 mmol) as starting materials, compound 67 (135 mg, yield 37.5%) was obtained by referring to step 4 of Example 19.

[0339] LC-MS (ESI): m / z = 507.1[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.11 (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). Example 68 [ka]

[0340] Step 1: Compound 68 (57 mg, yield: 25%) was obtained using 14D (170 mg, 0.37 mmol) and 3-thiophenesulfonyl chloride (88 mg, 0.48 mmol) as starting materials, following the procedure (step 4) of Example 14.

[0341] LC-MS (ESI): m / z = 569.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.14 - 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). Examples 69, 70: [ka]

[0342] Step 1: Isomer A and Isomer B were obtained from compound 50 as a starting material by SFC fractionation.

[0343] SFC preparative method: Instrument: Waters 150 Prep-SFC E preparative liquid, chromatography 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: Composition of mobile phases A and B: 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. Retention time for Isomer A: 1.247 min, compound 69. Retention time for Isomer B: 1.741 min, compound 70.

[0344] 'omer A: LC-MS (ESI): m / z = 624.3 [M + H] + . 1 H NMR(400MHz,CDCl3):δ 7.60 (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). Mayor B: LC-MS (ESI): m / z = 624.7 [M+H] + . 1H NMR(400MHz,CDCl3):δ 7.61 (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). Example 71 [ka]

[0345] Step 1: Compound 71 (140 mg, yield: 48.8%) was obtained using 14D (200 mg, 0.49 mmol) and 3-thiophenesulfonyl chloride (147 mg, 0.98 mmol) as starting materials, following the procedure (step 4) of Example 14.

[0346] LC-MS (ESI): m / z = 585.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.13 (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). Example 72 [ka]

[0347] Step 1: Using 7D (150 mg, 0.37 mmol) and 72A (80 mg, 0.37 mmol) as raw materials, 72B (161 mg, yield: 72%) was synthesized by referring to the synthesis step in Step 1 of Example 50.

[0348] Step 2: Using 72B (161 mg, 0.27 mmol) as a starting material, 72C (113 mg, yield: 83%) was synthesized by referring to the synthesis step in step 2 of Example 50. LC-MS (ESI): m / z = 506.2[M+H] + .

[0349] Step 3: Compound 72 (34 mg, yield: 26%) was synthesized using 72C (113 mg, 0.22 mmol) as a starting material, following the synthesis steps in step 3 of Example 50.

[0350] 1 H NMR (400MHz,CDCl3) δ 7.61 (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). LC-MS (ESI): m / z = 584.7 [M+H] + . Example 73 [ka]

[0351] Step 1: Compound 73 was obtained by synthesizing 73A and 7D using them as raw materials, following the synthesis steps of Step 1 of Example 50.

[0352] 1 H NMR (400MHz,CDCl3) δ 7.60 (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). LC-MS (ESI): m / z = 527.2[M+H] + . Example 74 [ka]

[0353] Step 1: Using 74A (3.5g, 24.93 mmol) as a starting material, 74B (5.1g, yield: 76.8%) was synthesized by referring to the literature (Journal of Materials Chemistry C: Materials for Optical and Electronic Devices, Volume: 10, Issue: 42, Pages: 15861-15871, 2022).

[0354] Step 2: At room temperature, 74B (5.1 g, 19.17 mmol) was dissolved in methanol (50 mL), and sodium borohydride (1.45 g, 38.34 mmol) was gradually added under an ice bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours, and the disappearance of the starting material was monitored by TLC to stop the reaction. The reaction mixture was concentrated, the residue was redissolved in EA (50 mL), the organic phase was washed with water (50 mL x 2), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 74C (4.5 g, yield: 86.9%).

[0355] Step 3: At room temperature, 74C (4.5 g, 16.66 mmol) was dissolved in dry DCM (50 mL), and thionyl chloride (3.96 g, 33.36 mmol) was added dropwise under an ice bath. After the addition was complete, the mixture was reacted at room temperature for 2 hours, and the disappearance of the starting material was monitored by TLC, at which point the reaction was stopped. The reaction mixture was concentrated, the residue was redissolved in DCM (50 mL), the organic phase was washed with water (50 mL x 2), then with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1) to obtain 74D (3.5 g, yield: 68.4%).

[0356] Step 4: At room temperature, 74D (3.5 g, 11.40 mmol) was dissolved in dry DMF (20 mL), sodium hydride (1.0 g, 24.97 mmol) was added under ice bath, and the mixture was stirred uniformly. p-toluenesulfonamide (1.95 g, 11.4 mmol) was added, and the reaction was carried out at 0°C for 30 minutes. After that, the temperature was raised to room temperature and the reaction was continued for 2 hours. The disappearance of the starting material was monitored by TLC, and the reaction was stopped. EA (40 mL) was added to the reaction solution, and the organic phase was washed with water (50 mL x 2), then with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA = 4:1) to obtain 74E (2.5 g, yield: 54.1%). LC-MS (ESI): m / z = 405.9 [M + H] + .

[0357] Step 5: At room temperature, 74E (2.5 g, 6.17 mmol) was dissolved in dry DMF (20 mL), cuprous iodide (1.53 g, 8.03 mmol) and HMPA (5.53 g, 30.85 mmol) were added, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Then, methyl fluorosulfonyl difluoroacetate (5.93 g, 30.81 mmol) was added, and the reaction was carried out at 100 °C for 3 hours under a nitrogen atmosphere. The reaction was stopped by monitoring the disappearance of the starting materials by TLC. After cooling to room temperature, EA (30 mL) was added to the reaction mixture, and the organic phase was washed with water (60 mL x 2), then with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (PE:EA = 4:1) to obtain 74F (1.7 g, yield: 79.3%). LC-MS (ESI): m / z = 348.3[M+H] + .

[0358] Step 6: At room temperature, 74F (1.7g, 4.89 mmol), phenol (0.92g, 9.78 mmol), and propionic acid (1.49g, 1.5mL, 20.05 mmol) were sequentially added to a round-bottom flask. 20mL of 48% hydrobromic acid aqueous solution was then added, and the reaction was carried out at 100°C for 16 hours under a nitrogen atmosphere. The reaction was stopped by monitoring the disappearance of the starting materials by TLC. After cooling to room temperature, water (10mL) was added to the reaction mixture, and the aqueous phase was washed with ether (30mL x 3). The aqueous layer was concentrated, and product 74G (1.2g, yield: 89.9%) was obtained without purification. LC-MS (ESI): m / z = 194.1[M+H] + .

[0359] Step 7: Compound 74H (100 mg, yield: 55.5%) was synthesized using 74G (74.38 mg, 0.39 mmol) as a starting material, referring to the synthesis method in Step 1 of Example 1. LC-MS (ESI): m / z=415.1[M+H-100] + .

[0360] Step 8: Compound 74I (75 mg, yield: 95.25%) was synthesized using 74H (100 mg, 0.19 mmol) as a starting material, referring to the synthesis method in step 3 of Example 1. LC-MS (ESI): m / z = 415.2[M+H] + .

[0361] Step 9: Using 74I (75 mg, 0.18 mmol) as a starting material, the target compound 74 (20 mg, yield: 18.8%) was synthesized by referring to the synthesis method in step 8 of Example 20.

[0362] LC-MS (ESI): m / z = 592.0 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.59 (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). Example 75 [ka]

[0363] Step 1: Compound 75A was synthesized using 7D and 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid as starting materials, referring to the synthesis step in step 1 of Example 50. LC-MS (ESI): m / z = 660.9 [M+H] + .

[0364] Step 2: Compound 75B was obtained by synthesizing compound 75B using 75A as a raw material, referring to the synthesis step in step 2 of Example 50. LC-MS (ESI): m / z = 560.7 [M+H] + .

[0365] Step 3: Compound 75 was synthesized using 75B as a raw material, referring to the synthesis step in step 3 of Example 50.

[0366] 1 H NMR (400MHz,CDCl3) δ 7.59 (s,1H),7.49 (d,J=8.0 Hz,1H),7.45 (s,1H),7.31 (d,J=8.0 Hz,1H),6.48 (s,1H),4.63 (d,J=13.6 Hz,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=13.2,2.4 Hz,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=12.8 Hz,1H),1.77 - 1.75 (m,2H),1.69 - 1.66 (m,2H),1.24 - 1.14 (m,2H). LC-MS (ESI): m / z = 638.3 [M + H] + . Example 76 [ka]

[0367] Step 1: Compound 76 was obtained by synthesizing 76A and 7D using them as raw materials, following the synthesis steps of Step 1 of Example 71.

[0368] LC-MS (ESI): m / z = 542.2[M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.59 (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). Example 77 [ka]

[0369] Step 1: Compound 77A (1.20 g, 5.63 mmol) and triethylamine (1.71 g, 16.89 mmol) were weighed and placed in a 100 mL single-neck flask. They were dissolved in dichloromethane (20 mL), and methanesulfonic anhydride (1.18 g, 6.76 mmol) was added. After the addition was complete, the mixture was stirred at 25°C for 16 hours. The complete reaction was monitored using a TLC spot plate (petroleum ether:ethyl acetate = 3:1). Water (20 mL) was added, the mixture was stirred for 5 minutes, and the organic phase was separated by extraction with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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.

[0370] Step 2: Compounds 7B (1.50 g, 4.81 mmol) and 77B (1.40 g, 4.81 mmol) were added to a 100 mL single-necked flask, dissolved in DMF (20 mL), and potassium carbonate (1.99 g, 14.43 mmol) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 70 °C for 16 hours. Complete reaction of the starting materials was detected by LC-MS, water (40 mL) was added, and the mixture was stirred for 5 minutes. The mixture was extracted with ethyl acetate (40 mL) to separate the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the target compound 77C (0.90 g, yield: 37%). LCMS m / z=451.2[M - 55] +

[0371] Step 3: Compound 77C (1.0 g, 1.97 mmol) was added to a 100 mL single-necked flask, dissolved with dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 20 °C for 2 hours. The complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain the target compound 77D (0.8 g, crude product). LCMS m / z=407.1[M+1] +

[0372] Step 4: The compounds carbonyldiimidazole (0.40 g, 2.47 mmol) and N-Boc-3-hydroxyazetidine (0.43 g, 2.47 mmol) were weighed and placed in a 100 mL single-neck flask. They were dissolved in tetrahydrofuran (20 mL) and stirred at 25 °C for 1 hour. Then, 77D (0.50 g, 1.23 mmol) and triethylamine (0.37 g, 3.65 mmol) were added. After the addition was complete, the mixture was stirred at 70 °C for 16 hours. The complete reaction was detected by TLC spot plate (petroleum ether:ethyl acetate = 1:1). Water (20 mL) was added, the mixture was stirred for 5 minutes, and the organic phase was extracted with ethyl acetate (20 mL) to separate it. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 77E (0.40 g, yield: 53%). LCMS m / z=550.1[M -55] +

[0373] Step 5: Compound 77E (0.4 g, 0.66 mmol) was added to a 100 mL single-necked flask, dissolved with dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. After the addition was complete, the system was protected with nitrogen gas and stirred at 20 °C for 4 hours. The complete reaction of the starting materials was detected by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain the target compound 77F (0.3 g, crude product). LCMS m / z=506.1[M+1] +

[0374] Step 6: Compound 77F (300 mg, 0.59 mmol) and triethylamine (0.18 g, 1.78 mmol) were weighed and placed in a 100 mL single-neck flask. They were dissolved in dichloromethane (6 mL), and methanesulfonyl chloride (81 mg, 0.71 mmol) was added at 0°C. After the addition was complete, the system was protected with nitrogen gas and stirred at 0°C for 2 hours. Complete reaction of the starting materials was detected by LC-MS. Water (20 mL) was added, and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane (20 mL) to separate the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the crude product of the target compound. Compound 77 (35 mg, yield: 12%) was obtained by preparative HPLC.

[0375] Preparative chromatography method: Instrument: Waters 2767 preparative liquid, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5 mM aqueous ammonia), b. Gradient elution, with mobile phase A content of 40% to 80%, c. Flow rate: 15 mL / min, d. Elution time: 20 min.

[0376] LCMS m / z=584.2[M+1] + 1 H NMR (400 MHZ,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),3.81-3.87 (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). Example 78: [ka]

[0377] Step 1: N-bromosuccinimide (4.67 g, 26.26 mmol) and silver fluoride (7.57 g, 59.68 mmol) were added to a mixed solution of acetonitrile (90 mL) and water (10 mL). 78A (5.00 g, 23.87 mmol) was added at room temperature, and the mixture was reacted overnight at 80°C. After complete reaction, the reaction was cooled to room temperature. The reaction solution was then filtered by suction, and 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 obtain 78B (5.50 g, yield: 74%). LC-MS (ESI): m / z=252.2[M-56] + .

[0378] Step 2: 78B (3.00 g, 9.73 mmol) was dissolved in 1,4-dioxane (30 mL), and bis(pinacolato)diborone (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. After adding these, the mixture was purged with nitrogen gas three times. Then, tris(dibenzylidene-BASE acetone)dipalladium (0.89 g, 0.97 mmol) was added, and after adding this, the mixture was purged with nitrogen gas three times. The mixture was reacted overnight at 80°C. After the reaction was complete, the reaction mixture was filtered by suction, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1, (v / v)) to obtain 78C (3.40 g, yield: 98%). LC-MS (ESI): m / z=255.4[M-100] + .

[0379] Step 3: 41B (1.70 g, 3.83 mmol) was dissolved in 1,4-dioxane (30 mL) and water (6 mL). At room temperature, 78C (1.70 g, 4.79 mmol), potassium carbonate (1.32 g, 9.55 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.35 g, 0.48 mmol) were added. After the addition was complete, the mixture was purged with nitrogen gas three times and reacted at 90°C for 3 hours. After the reaction was complete, the reaction was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain 78D (0.60 g, yield: 23%). LC-MS (ESI): m / z=467.6[M-55] + .

[0380] Step 4: 78D (300 mg, 0.57 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added at 0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2.5 hours. After the reaction was complete, the reaction was concentrated to obtain crude product 78E, and the next step in the reaction was carried out directly.

[0381] Step 5: 1-Methylsulfonylazetidine-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. After the addition, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (288.39 mg, 2.85 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 1 mL of tetrahydrofuran solution of 78E (240 mg, 0.57 mmol) was added dropwise at 0-5°C, and the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 78 (195 mg, yield: 57%).

[0382] LC-MS (ESI): m / z = 600.2 [M + H] + . 1H NMR (400MHz,DMSO-d6) δ 8.49 (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),4.17-4.13 (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). Example 79: [ka]

[0383] Step 1: 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 trihydrogen (3.59 g, 89.75 mmol) was added at 0-5°C, and the mixture was reacted at room temperature for 30 minutes. Then, p-toluenesulfonamide (6.15 g, 35.90 mmol) was added at 0-5°C, and the mixture was reacted at room temperature for 3 hours. After complete reaction, water (200 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 2). After concentrating the organic phase, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain 79B (4.80 g, yield: 47%). LC-MS (ESI): m / z = 280.2[M+H] + .

[0384] Step 2: 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. After the addition was complete, the mixture was reacted at room temperature for 1.5 hours. After the reaction was complete, the reaction was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, (v / v)) to obtain 79C (0.50 g, yield: 70%).

[0385] Step 3: 79C (0.50 g, 1.40 mmol) was dissolved in 1,4-dioxane (16 mL) and water (2 mL). Methylboronic acid (355.22 mg, 5.60 mmol) and potassium carbonate (967.47 mg, 7.00 mmol) were added at room temperature, and the mixture was purged with nitrogen gas three times after the additions were complete. Tetrakis(triphenylphosphine)palladium (161.78 mg, 0.14 mmol) was then added, and the mixture was purged with nitrogen gas three times after the additions were complete. The mixture was reacted overnight at 100 °C. After the reaction was complete, the reaction mixture was filtered by suction, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, (v / v)) to obtain 79D (0.25 g, yield: 60%). LC-MS (ESI): m / z = 294.1 [M+H] + .

[0386] Step 4: 79D (0.25 g, 0.85 mmol) was dissolved in an aqueous solution of hydrogen bromide (1 mL), and phenol (385.159.99 mg, 1.70 mmol) was added at room temperature. After the addition was complete, the mixture was reacted overnight at 100 °C. After the reaction was complete, the reaction solution was extracted with ether (15 mL x 2), and the aqueous phase was directly concentrated to obtain crude product 79E, from which the next step reaction was carried out directly. LC-MS (ESI): m / z = 140.1 [M+H] + .

[0387] Step 5: 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. After adding the compounds, the mixture was reacted at room temperature for 30 minutes, then 79E (90.21 mg, 0.65 mmol) was added, and the mixture was reacted overnight at room temperature. After complete reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain compound 79F (110 mg, yield: 44%). LC-MS (ESI): m / z=401.4[M-55] + .

[0388] Step 6: 79F (110 mg, 0.24 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added at 0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated to obtain the crude product 79G, and the next step in the reaction was carried out directly.

[0389] Step 7: 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, the reaction was allowed to proceed at room temperature for 4.5 hours, and then triethylamine (121.43 mg, 1.20 mmol) was added dropwise to the reaction system at room temperature. After the addition, the reaction was allowed to proceed at room temperature for 2 hours, and then 0.5 mL of a tetrahydrofuran solution of 79 G of the crude product was added dropwise at 0-5°C, and the reaction was allowed to proceed overnight at 60°C. After the reaction was complete, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 79 (5 mg, yield: 4%).

[0390] LC-MS (ESI): m / z = 411.8 [M + H] + . 1H NMR (400MHz,DMSO-d6) δ 8.29 (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). Example 80 [ka]

[0391] Step 1: 61D (320 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (153.81 mg, 1.52 mmol) and deuteroacetyl chloride (92.93 mg, 1.14 mmol) were added sequentially at 0-5°C. After the addition was complete, the mixture was allowed to react overnight at room temperature. After complete reaction, the reaction mixture was concentrated and purified by preparative HPLC to obtain compound 80 (160.00 mg, yield: 45%).

[0392] LC-MS (ESI): m / z = 464.5[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.30 (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),6.35 (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). Example 81 [ka]

[0393] Step 1: 81A (2.6g, 18.56 mmol) was dissolved in N,N-dimethylformamide (30 mL), and cesium carbonate (9.07g, 27.84 mmol) and deuterated methyl iodide (3.23g, 22.27 mmol) were added sequentially at 0-5°C. After all additions were made, the mixture was allowed to react overnight at room temperature. After complete reaction, water (200 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were then combined and washed once each with water (200 mL) and saturated brine (200 mL). After drying over anhydrous sodium sulfate, the mixture was concentrated to obtain 81B (2.7g, yield: 92%). LC-MS (ESI): m / z = 158.2[M+H] + .

[0394] Step 2: 81B...

Claims

1. A compound represented by formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts, 【Chemistry 1】 Ring A is selected from 4-8 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 6-12 membered bicyclic heterocycloalkyl groups, and 8-14 membered tricyclic heterocycloalkyl groups. Ring B is, 【Chemistry 2】 Selected from, the left side of ring B is L １ It is connected to, The C ring is selected from a phenyl group, a 5-6 membered heteroaryl group, a 6-12 membered bicyclic carbocyclic group, a 6-12 membered bicyclic heterocycloalkyl group, and an 8-14 membered tricyclic heterocycloalkyl group, and ring C is 【Transformation 3】 Instead, L １ is, W １ -R Ｌａ -W ２ Selected from, L １ The left side is connected to A, L ２ is selected from W ３ -R Ｌｂ -W ４ and the left side of L ２ is connected to B, and L １ and L ２ are not joined simultaneously R Ｌａ , R Ｌｂ Each is independent, combined, C １－４ Alkylene group, C ２－４ Alkenylene group, C ２－４ Selected from alkylene groups, the alkylene group and alkenylene group optionally have 1 to 4 R Ｌ１ It is further replaced by, R Ｌ１ These are, independently, halogen and C １－４ Alkyl alkyl group, C ２－４ Alkenyl group, C １－４ Selected from alkoxy groups and 3- to 6-membered cycloalkyl groups, the alkyl group, alkenyl group, alkoxy group, and cycloalkyl group may optionally be halogen, CN, OH, and NH. ２ Further substituted with 1 to 4 substituents selected from, or two R atoms on the same carbon atom or two adjacent carbon atoms. Ｌ１ And the atoms to which they are linked together form a 3-8 membered cycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group. W １ , W ２ , W ３ , W ４ These are, independently, bonded, -O-, -S-, and -NR Ｗ１ -, -Se-, -C(O)- are selected, R Ｗ１ H, halogen, C １－４ Selected from alkyl groups, R Ａ These are, independently, halogen, =O, CN, COOH, and C. １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -O-C １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ - (CH ２ ) １－３ -R ａ , -P(O)-(C １－４ Alkyl) ２ , -C(O)-O-(CH ２ ) ｐ -R ａ ,-(CH ２ ) １－２ -C(O)-R ａ , -C(O)-(CH ２ ) １－２ -R ａ , -C(O)-O-HaloC １－４ Alkyl alkyl group, -C(O)-(6-9 membered bicyclic heterocycloalkyl group), -NH-C(O)-(CH ２ ) ｐ -R ａ ,-NH-R ａ , -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-SO ２ - (CH ２ ) １－２ -R ａ , -NH-C(O)-OR ａ , -C(O)-(CH ２ ) ｐ - (4-6 member monocyclic heterocycloalkyl), -C(O)-(CH ２ ) ｐ -(4-6 member monocyclic cycloalkyl),-NH-C(O)-NH-R ａ , -C(O)-Deuterized C １－４ Alkyl alkyl groups, -C(O)-NH- (4-6 member monocyclic cycloalkyl groups), -C(O)-NH- (4-6 member monocyclic heterocycloalkyl groups), -C(O)-NH-S(O) ２ -C １－４ Alkyl alkyl, -NH-C(O) deuterated C １－２ Alkyl alkyl, -NH-C(O)-NH-C １－２ Alkyl alkyl group or -NH-C(O)-C １－２ Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be a halogen, OH, or NH ２ ,CN,-S(O) ２ -CH ３ ,-O-HaroC １－４ Alkyl group, -NH-S(O) ２ -CH ３ Further substitution with 1 to 4 groups selected from, R ａ is selected from a deuterated C １－４ alkyl group, a C ２－４ alkynyl group, a 3- to 5-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group are optionally further substituted with 1 to 4 groups selected from halogen, OH, =O, C １－４ alkyl group, deuterated C １－４ alkyl group, C １－４ alkoxy group, C ２－４ alkynyl group, -O-halo C １－４ alkyl group, -S(O) ２ -CH ３ or =CH ２ and are further substituted with 1 to 4 groups selected therefrom R Ｃ is, independently of each other, H, CN, halogen, OH, C １－４ alkyl group, halo C １－４ alkyl group, -O-halo C １－４ alkyl group, -Se-halo C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, =O, C ３－６ cycloalkyl group, -SCF ３ , -SF ５ , -(NH) ｑ -P(O)(C １－４ alkyl) ２ , -(CH ２ ) ｐ -O-C １－４ alkyl group, -O-(CH ２ ) ｐ -C ３－６ cycloalkyl group or -(CH ２ ) ｐ -O-C ３－６ cycloalkyl group, or any two Rs Ｃ and the atoms to which they are attached together form a 3- to 8-membered cycloalkyl group, q is selected from 0 or 1. p is 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 conditions are, (1) Ring A 【Chemistry 4】 If selected from, R Ａ is -S(O) ２ - (CH ２ ) ０－１ CH ３ Rather, and 【Transformation 5】 teeth, 【Transformation 6】 Instead, (2) R Ａ ga-S(O) ２ - (CH ２ ) ０－１ CH ３ If selected from, ring A is, 【Transformation 7】 Rather, and 【Transformation 8】 teeth, 【Chemistry 9】 Instead, (3) Ring C is 【Chemistry 10】 If selected from, R Ｃ It is not H, and 【Chemistry 11】 teeth, 【Chemistry 12】 Instead, (4) R Ｃ If H is selected only, then the C ring is 【Chemistry 13】 Rather, and 【Chemistry 14】 teeth, 【Chemistry 15】 Not the compound shown in formula (I), its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts.

2. Ring A is selected from 4-8 member cycloalkyl groups, 4-7 member monocyclic heterocycloalkyl groups, 5-6 member heterocycloalkyl condensed 5-6 member heterocycloalkyl groups, 4-6 member heterocycloalkyl spiro 5-6 member heterocycloalkyl groups, 5-6 member heterocycloalkyl spiro 4-6 member cycloalkyl groups, 5-6 member heterocycloalkyl spiro 5-6 member cycloalkyl groups, 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl groups, 10-14 member partially unsaturated tricyclic heterocycloalkyl groups, and 7-8 member bicyclic crosslinked heterocyclic groups. The C ring is selected from a phenyl group, a five-membered heteroaryl group, a six-membered heteroaryl group, a five- to seven-membered heterocycloalkyl condensed phenyl group, a five- to six-membered carbocyclic condensed phenyl group, a five- to six-membered heterocycloalkyl condensed five- to six-membered heteroaryl group, a five- to six-membered heterocycloalkyl condensed three- to six-membered cycloalkyl group, or a nine- to twelve-membered tricyclic heterocycloalkyl group. R Ｌａ , R Ｌｂ Each is independent, combined, C １－２ Alkylene group, C ２－４ Alkenylene group, C ２－４ Selected from alkylene groups, the alkylene group and alkenylene group optionally have 1 to 4 R Ｌ１ It is further replaced by, R Ｌ１ These are, independently, halogen and C １－２ Alkyl alkyl group, C ２－４ Alkenyl group, C １－２ Selected from alkoxy groups and 3- to 6-membered cycloalkyl groups, the alkyl group, alkoxy group, and cycloalkyl group can optionally be halogen, CN, OH, and NH. ２ Further substituted with 1 to 4 substituents selected from, or two R atoms on the same carbon atom or two adjacent carbon atoms. Ｌ１ And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. R Ｗ１ H, halogen, C １－２ Selected from alkyl groups, R Ａ These are, independently, halogen, =O, CN, COOH, and C. １－４ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, -OC １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ - (CH ２ ) １－３ -R ａ , -P(O)-(C １－４ Alkyl) ２ , -C(O)-O-(CH ２ ) ｐ -R ａ ,-(CH ２ ) １－２ -C(O)-R ａ , -C(O)-(CH ２ ) １－２ -R ａ ,-NH-R ａ , -C(O)-O-HaloC １－４ Alkyl alkyl group, -C(O)-(6-9 membered bicyclic heterocycloalkyl group), -NH-C(O)-(CH ２ ) ｐ -R ａ , -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-SO ２ - (CH ２ ) １－２ -R ａ , -NH-C(O)-OR ａ , -C(O)-(CH ２ ) ｐ - (4-6 member monocyclic heterocycloalkyl), -C(O)-(CH ２ ) ｐ -(4-6 member monocyclic cycloalkyl),-NH-C(O)-NH-R ａ , -C(O)-Deuterized C １－４ Alkyl alkyl groups, -C(O)-NH- (4-6 member monocyclic cycloalkyl groups), -C(O)-NH- (4-6 member monocyclic heterocycloalkyl groups), -C(O)-NH-S(O) ２ -C １－４ Alkyl alkyl, -NH-C(O) deuterated C １－２ Alkyl alkyl, -NH-C(O)-NH-C １－２ Alkyl alkyl group or -NH-C(O)-C １－２ Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be a halogen, OH, or NH ２ ,CN,-S(O) ２ -CH ３ ,-NH-S(O) ２ -CH ３ Further substitution with 1 to 4 groups selected from, R ａ is deuterated C １－２ Alkyl alkyl group, C ２－４ The group is selected from an alkynyl group, a 3- to 5-membered cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, or a 5-membered heteroaryl group, wherein the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally replaced with a halogen or C1. １－２ Alkyl alkyl group, OH, =O, -S(O) ２ -CH ３ , C １－２ Alkoxy group, deuterated C １－２ Alkyl alkyl group or =CH ２ Further substituted under the basis, R Ｃ These are H, CN, halogen, OH, and C, respectively, independently. １－４ Alkyl, Halo C １－４ Alkyl group, -O-halo C １－４ Alkyl alkyl group, -Se-halo C １－２ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, =O, C ３－６ Cycloalkyl groups, -SCF ３ , -SF ５ , - (NH) ｑ -P(O)(C １－４ Alkyl) ２ ,-(CH ２ ) ｐ -O-C １－４ Alkyl alkyl group, -O-(CH ２ ) ｐ -C ３－６ Cycloalkyl group or -(CH ２ ) ｐ -O-C ３－６ Selected from cycloalkyl groups, or any two R Ｃ And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. p is independently selected from 0, 1, 2, or 3. m is selected from 1, 2, or 3. n is selected from 1, 2, or 3 to be a compound of formula (I) according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, a solvate thereof, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

3. Ring A is selected from 4-6 membered cycloalkyl groups, 4-7 membered monocyclic heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 5-membered heterocycloalkyl groups, 5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered heterocycloalkyl spiro 6-membered heterocycloalkyl groups, 4-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered cycloalkyl spiro 6-membered heterocycloalkyl groups, 5-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, 6-membered heterocycloalkyl condensed 5-membered cycloalkyl groups, and 10-14 membered partially unsaturated tricyclic heterocycloalkyl groups. The C ring is selected from a 5-7 member heterocycloalkyl condensed phenyl group, a 5-6 member heterocycloalkyl condensed 5-6 member heteroaryl group, a 5-6 member heterocycloalkyl condensed 3-6 member cycloalkyl group, or a 9-12 member tricyclic heterocycloalkyl group. R Ａ These are, independently, halogen, =O, CN, COOH, and C. １－４ Alkyl alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, -OC １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ - (CH ２ ) １－３ -R ａ , -C(O)-O-(CH ２ ) ｐ -R ａ ,-(CH ２ ) １－２ -C(O)-R ａ , -C(O)-(CH ２ ) １－２ -R ａ , -C(O)-O-HaloC １－４ Alkyl alkyl, -NH-R ａ -C(O)-(6-9 membered bicyclic heterocycloalkyl), -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-C(O)-OR ａ , -C(O)-(CH ２ ) ｐ - (4-6 member monocyclic heterocycloalkyl), -C(O)-(CH ２ ) ｐ -(4-6 member monocyclic cycloalkyl),-NH-C(O)-NH-R ａ , -C(O)-Deuterized C １－４ Alkyl alkyl groups, -C(O)-NH- (4-6 member monocyclic cycloalkyl groups), -C(O)-NH- (4-6 member monocyclic heterocycloalkyl groups), -C(O)-NH-S(O) ２ -C １－４ Alkyl alkyl, -NH-C(O) deuterated C １－２ Alkyl alkyl, -NH-C(O)-NH-C １－２ Alkyl alkyl group or -NH-C(O)-C １－２ Selected from alkyl groups, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group may optionally be a halogen, OH, or NH ２ ,CN,-S(O) ２ -CH ３ ,-NH-S(O) ２ -CH ３ Further substitution with 1 to 4 groups selected from, R ａ is deuterated C １－２ Selected from alkyl groups, ethynyl groups, 3- to 5-membered cycloalkyl groups, 4- to 6-membered heterocycloalkyl groups, and 5-membered heteroaryl groups, wherein the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups can optionally be halogens, OH, =O, or C. １－２ Alkyl alkyl groups, deuterated C １－２ Alkyl alkyl group, C １－２ Alkoxy group, -S(O) ２ -CH ３ or = CH ２ Further substituted under the basis, p is independently selected from 0, 1, or 2. m is selected from 1, 2, or 3. n is selected from 1, 2, or 3 to be a compound of formula (I) according to claim 2, a stereoisomer thereof, a tautomer, a deuteride, a solvate thereof, a cocrystal, or a pharmaceutically acceptable salt thereof.

4. Ring A is, 【Chemistry 16】 One of these structures is selected, Ring C is, 【Chemistry 17】 One of these structures is selected, L １ is a bond, -(C １－２ Alkylene)-O-,-(C １－２ Alkilen)-Se-, C １－２ Alkylene group, -O-(C) １－２ Alkylene) -, C ２－４ Alkenylene group, -O-, C ２－４ Selected from alkylene groups, the alkylene group and alkenylene group optionally have 1 to 3 R Ｌ１ It is further replaced by, L ２ C １－２ The alkylene group, alkenylene group, and cycloalkyl group are selected from -NH- and -O-, and the alkylene group, alkenylene group, and cycloalkyl group are optionally selected to have 1 to 3 R groups. Ｌ１ It is further replaced by, R Ｌ１ These are, independently, halogen and C １－２ Alkyl, Halo C １－２ Alkyl alkyl group, C ２－４ Alkenyl group, C １－２ Alkoxy group, Halo C １－２ Selected from alkoxy groups, 3- to 6-membered cycloalkyl groups, or two R groups on the same carbon atom or two adjacent carbon atoms. Ｌ１ And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. R Ａ These are independent of each other: = O, C １－４ Alkyl alkyl group, -S(O) ２ -C １－４ Alkyl alkyl group, -S(O) ２ - (CH ２ ) １－３ -R ａ , -C(O)-O-(CH ２ ) ｐ -R ａ ,-(CH ２ ) １－２ -C(O)-R ａ , -C(O)-(CH ２ ) １－２ -R ａ , -C(O)-O-HaloC １－３ Alkyl alkyl group, -C(O)-(6-9 membered bicyclic heterocycloalkyl group), -NH-C(O)-(CH ２ ) ｐ -R ａ ,-NH-R ａ , -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-SO ２ - (CH ２ ) １－２ -R ａ , -NH-C(O)-OR ａ , -C(O)-(CH ２ ) ｐ - (4-6 member monocyclic heterocycloalkyl), -C(O)-(CH ２ ) ｐ -(4-6 member monocyclic cycloalkyl),-NH-C(O)-NH-R ａ , -C(O)-Deuterized C １－２ Alkyl alkyl groups, -C(O)-NH- (4-6 member monocyclic cycloalkyl groups), -C(O)-NH- (4-6 member monocyclic heterocycloalkyl groups), -C(O)-NH-S(O) ２ -C １－４ Alkyl alkyl, -NH-C(O) deuterated C １－２ Alkyl alkyl, -NH-C(O)-NH-C １－２ Alkyl alkyl group or -NH-C(O)-C １－２ Selected from alkyl groups, the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be halogen, OH, or NH ２ ,CN,-S(O) ２ -CH ３ ,-NH-S(O) ２ -CH ３ Further substitution with 1 to 4 groups selected from, R ａ is deuterated C １－２ Selected from alkyl groups, ethynyl groups, 3-5 membered cycloalkyl groups, 4-6 membered heterocycloalkyl groups, and 5-6 membered heteroaryl groups, wherein the cycloalkyl groups, heterocycloalkyl groups, and heteroaryl groups can be optionally replaced with halogens, methyl groups, deuterated methyl groups, methoxy groups, ethoxy groups, OH, =O, and -S(O). ２ -CH ３ or = CH ２ Further substituted under the basis, R Ｃ These are H, CN, F, Cl, Br, OH, -SF, each independently. ５ Methyl group, difluoromethyl group, trifluoromethyl group, ethyl group, ethynyl group, cyclopropyl group, -O-cyclopropyl group, -O-CH ２ -Cyclopropyl group, cyclobutyl group, -O-cyclobutyl group, -O-CH ２ - Selected from a cyclobutyl group, a -Se-trifluoromethyl group, or any two of the R groups. Ｃ And the atoms to which they are linked together form a 3-6 membered cycloalkyl group. p is independently selected from 0, 1, or 2. m is selected from 1 or 2. n is a compound of formula (I) according to claim 1, a stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt thereof, selected from 1 or 2. 【Request Item 5】 【Chemistry 18】 teeth, 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 One of these structures is selected, 【Chemistry 22】 teeth, 【Chemistry 23】 One of these structures is selected, L １ The bond is -CH ２ -O-, -CH ２ -Se-, -CH=CH-, -CF=CH-, -CH ２ -ien-CH ２ CH ２ - 【Chemistry 24】 -O-、-C(CH ３ )=CH-、-CH=C(CH ３ )-、 【Chemistry 25】 Selected from, L ２ is, -CH ２ A compound of formula (I) according to claim 1, a stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt thereof, selected from -.

6. The aforementioned compound has the structures of formulas (I-a) and (I-c), 【Chemistry 26】 Here, Xa is selected from CH or N, X ｂ It is selected from CH or N, C １ The compound according to claim 1, its stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof, wherein the ring is selected from a 5-6 membered heteroaryl group, a phenyl group, or a benzo-5-6 membered cycloalkyl group.

7. R Ａ is -S(O) ２ - (CH ２ ) １－３ -R ａ , -C(O)-O-(CH ２ ) ｐ -R ａ ,-(CH ２ ) １－２ -C(O)-R ａ , -C(O)-(CH ２ ) １－２ -R ａ , -C(O)-O-HaloC １－４ Alkyl alkyl group, -C(O)-(6-9 membered bicyclic heterocycloalkyl group), -NH-C(O)-(CH ２ ) ｐ -R ａ , -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-SO ２ - (CH ２ ) １－２ -R ａ , -NH-C(O)-OR ａ ,-NH-R ａ , -C(O)-(CH ２ ) ｐ - (4-6 member monocyclic heterocycloalkyl), -C(O)-(CH ２ ) ｐ -(4-6 member monocyclic cycloalkyl),-NH-C(O)-NH-R ａ , -C(O)-Deuterized C １－４ Alkyl alkyl groups, -C(O)-NH- (4-6 member monocyclic cycloalkyl groups), -C(O)-NH- (4-6 member monocyclic heterocycloalkyl groups), -C(O)-NH-S(O) ２ -C １－４ Alkyl alkyl, -NH-C(O) deuterated C １－２ Alkyl alkyl, -NH-C(O)-NH-C １－２ Alkyl alkyl group or -NH-C(O)-C １－２ Selected from alkyl groups, the alkyl group, cycloalkyl group, and heterocycloalkyl group may optionally be halogen, OH, or NH ２ ,CN,-S(O) ２ -CH ３ ,-O-HaroC １－４ Alkyl group, -NH-S(O) ２ -CH ３ Further substitution with 1 to 3 groups selected from, R ａ is deuterated C １－４ Alkyl alkyl group, C ２－４ The group is selected from an alkynyl group, a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the alkynyl group, cycloalkyl group, heterocycloalkyl group, and heteroaryl group can be optionally a halogen, OH, =O, or C １－４ Alkyl alkyl groups, deuterated C １－４ Alkyl alkyl group, C １－４ Alkoxy group, C ２－４ Alkynyl group, -O-halo C １－４ Alkyl alkyl group, -S(O) ２ -CH ３ or = CH ２ Further substitution with 1 to 4 groups selected from, R Ｃ is F, Cl, Halo C １－２ Alkyl alkyl group, C ２－４ Alkynyl group, 3-4 membered cycloalkyl group, -O-C ３－４ Selected from cycloalkyl groups, L １ is, -(C １－２ Alkylene)-O-, C １－２ Alkylene group, C ２－４ Selected from alkenylene group, -C(O)-NH-, n is selected from 1 or 2. p is selected from 0, 1, or 2, and is a compound according to claim 6, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, a solvate thereof, a cocrystal thereof, or a pharmaceutically acceptable salt thereof.

8. R Ａ is -C(O)-O-(CH ２ ) ｐ -R ａ , -C(O)-(CH ２ ) １－２ -R ａ , -NH-C(O)-(CH ２ ) ｐ -R ａ , -N(CH ３ )-C(O)-(CH ２ ) ｐ -R ａ , -NH-C(O)-OR ａ Selected from, R ａ The group is selected from a 3-5 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, or a 5-6 membered heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, or heteroaryl group can be optionally a halogen, C １－４ Alkyl alkyl groups, deuterated C １－４ Alkyl alkyl group, or -S(O) ２ -CH ３ Further substitution with 1 to 4 groups selected from, R Ｃ F, Cl, CHF ２ CF ３ A compound according to claim 6, selected from an ethynyl group, a cyclopropyl group, a cyclobutyl group, an -O-cyclopropyl group, or an -O-cyclobutyl group, stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof.

9. L １ The compound according to claim 1 or 6, selected from -CH=CH-, stereoisomers, tautomers, deuterides, solvates, cocrystals, or pharmaceutically acceptable salts thereof.

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

11. A pharmaceutical composition or pharmaceutical preparation comprising a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuteride, 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 to 1500 mg of the compound according to any one of claims 1 to 10 or its stereoisomer, tautomer, deuteride, solvate, cocrystal or pharmaceutically acceptable salt and carrier and / or excipient.

13. Uses of a compound according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer, a deuteride, a solvate thereof, a cocrystal or a pharmaceutically acceptable salt thereof, or a composition according to claim 11 or 12, in the manufacture of a pharmaceutical product for treating / preventing a CYP11A1-mediated disease.

14. The use according to claim 13, wherein the CYP11A1-mediated disease is selected from the treatment of steroid hormone-dependent cancers.

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