Phospho-SOS1 inhibitors

Abstract

The present application belongs to the field of pharmaceutical chemistry and relates to a phosphorus-containing SOS1 inhibitor, namely a compound of formula (I), and a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a drug for treating diseases and / or conditions associated with or regulated by SOS1.

Description

[0001] Citation of Related Applications

[0002] This application claims the priority and benefits of Chinese Patent Application No. 202010387620.0 filed with the State Intellectual Property Office of the People's Republic of China on May 9, 2020, and the priority and benefits of Chinese Patent Application No. 202110450032.1 filed with the State Intellectual Property Office of the People's Republic of China on April 25, 2021, the entire contents of which are hereby incorporated by reference into the text in their entirety. Technical Field

[0003] The present application relates to a phosphorus-containing SOS1 inhibitor, a method for preparing the same, a pharmaceutical composition containing the same, and use thereof in treating diseases and / or conditions associated with or regulated by SOS1. Background Art

[0004] RAS is the most frequently mutated oncogene in human cancer, and KRAS is the most common subtype in the RAS family, accounting for 86% of all RAS gene mutations.

[0005] The binding of the guanine nucleotide exchange factor (GEF) of Son of Sevenless 1 (SOS1) promotes the release of GDP from RAS family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112): 1338-43). When in the GTP-bound state, RAS family proteins are active and connect effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, PI3K / AKT / mammalian target of rapamycin (mTOR) pathway and RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3): 253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6). These pathways affect diverse cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth (Young et al., Adv. Cancer Res., 2009, 102: 1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6).

[0006] Selective inhibition of the binding of the catalytic site of SOS1 to RAS family proteins can prevent SOS1-mediated activation of RAS family proteins into the GTP-bound form. Therefore, SOS1 inhibitor compounds can inhibit signal transduction in cells downstream of RAS family proteins (e.g., ERK phosphorylation). Ideal SOS1 inhibitor compounds should be able to selectively and efficiently inhibit the binding of SOS1:RAS-family proteins and ERK phosphorylation in cells.

[0007] Recently, researchers at Bayer reported the discovery of a class of selective SOS1 inhibitors containing a quinazoline core structure (Proc Natl Acad Sci. 2019; 116(7): 2551-2560), represented by the compound BAY-293, which can block RAS activation by interfering with the RAS-SOS1 interaction.

[0008]

[0009] Herein, we provide novel SOS1 inhibitor compounds that inhibit ERK phosphorylation in cells by interfering with RAS-SOS1 interaction. DETAILED DESCRIPTION OF THE INVENTION

[0011] In one aspect, the present application provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0012]

[0013] in,

[0014] X and Y are independently selected from CR a , C(O), N or NR b ;

[0015] Depending on the difference between X and Y, they represent single bonds or double bonds;

[0016] R a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more deuterium or halogen;

[0017] R b Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0018] R 1 , R 2 are independently selected from C 1-6Alkyl, NH(R c )-C 1-6 Alkyl- or N(R c )(C 1-6 Alkyl)-C 1-6 Alkyl-, or R 1 , R 2 Together with the phosphorus atom connected thereto, a 5- to 10-membered heterocyclic group is formed, wherein the C 1-6 The alkyl group or the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c replace;

[0019] Each Rc is independently selected from hydrogen, O=, HN=, C 1-6 Alkyl-N=, C 1-6 Alkyl-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, 3-6 membered cycloalkyl-S(O)2-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl-OC 1-6 Alkyl-, C 1-6 Alkyl-OC 1-6 Alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C(O)-, amino-C 1-6 Alkyl-C(O)-, mono(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, amino-C(O)-C 1-6 Alkyl-, mono(C 1-6 alkyl)amino-C(O)-C 1-6 Alkyl-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 alkyl-, 3- to 6-membered heterocycloalkyl-, 3- to 6-membered heterocycloalkyl-C(O)-, 3- to 6-membered heterocycloalkyl-C 1-6 Alkyl-, C 6-10 Aryl-C 1-6 Alkyl- or C substituted with one or more hydroxyl or cyano groups 1-6 Alkyl-, wherein R c When not hydrogen and O=, it is optionally substituted by one or more halogens;

[0020] Ring A is selected from C 6-10Aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring or 8- to 12-membered fused heterocyclic ring;

[0021] n is 0, 1, 2 or 3;

[0022] Every R 3 are independently selected from amino, nitro, halogen, C 1-8 Alkyl-, 3-6-membered cycloalkyl- or phenyl, wherein the C 1-8 Alkyl-, 3-6-membered cycloalkyl- or phenyl- is optionally substituted with one or more R d replace;

[0023] R d Selected from hydroxyl, halogen or C 1-6 Alkyl-NH-C 1-6 alkyl-;

[0024] R 4 , R 5 are independently selected from hydrogen, deuterium or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens;

[0025] R 6 Selected from hydrogen, halogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens.

[0026] In some embodiments, X is selected from CR a or NR b , Y is selected from CR a , C(O), N or NR b In some embodiments, X is selected from CR a or NR b , Y is selected from CR a , C(O) or N.

[0027] In some embodiments, X is selected from CR a , Y is selected from CR a , C(O), N or NR b In some embodiments, X is selected from CR a , Y is selected from CR a , C(O) or N. In some embodiments, X is selected from CR a , Y is selected from N.

[0028] In some embodiments, X is selected from NR b , Y is selected from CR a , C(O), N or NR b In some embodiments, X is selected from NR b, Y is selected from CR a , C(O) or N. In some embodiments, X is selected from NR b , Y is selected from C(O).

[0029] In some embodiments, X and Y are both selected from CR a In some embodiments, X is selected from CH and Y is selected from CR a .

[0030] In some embodiments, R a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 Alkyl or C 1-4 The alkoxy groups are optionally substituted with one or more deuterium or halogen.

[0031] In some embodiments, R a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally substituted with one or more halogens, the C 1-4 Alkoxy is optionally substituted with one or more deuterium or halogen. a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 The alkyl group is optionally substituted with one or more halogens, the C 1-3 The alkoxy groups are optionally substituted with one or more deuterium or halogen.

[0032] In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-6 Alkoxy, wherein the C 1-6 The alkoxy groups are optionally substituted with one or more deuterium or halogen.

[0033] In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 Alkoxy, wherein the C 1-4 Alkoxy is optionally substituted with one or more deuterium or halogen. a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 Alkoxy, wherein the C 1-4 The alkoxy group is optionally substituted with 3 deuterium or one or more fluorine. a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 Alkoxy, wherein the C1-4 The alkoxy group is optionally substituted with 3 deuteriums, or 1 or 2 fluorines.

[0034] In some embodiments, R a is selected from hydrogen, hydroxy, fluorine, cyano, methoxy, monofluoromethoxy or difluoromethoxy, wherein the methoxy is optionally substituted with 3 deuteriums.

[0035] In some embodiments, R a Selected from hydrogen, hydroxyl, fluorine, cyano, CH3O-, CD3O-, CH2FO- or CHF2O-.

[0036] In some embodiments, R a Selected from hydrogen, fluorine, CH3O-, CD3O- or CHF2O-.

[0037] In some embodiments, R b Selected from hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy.

[0038] In some embodiments, R b Selected from C 1-6 In some embodiments, R b Selected from C 1-4 In some embodiments, R b Selected from C 1-3 In some embodiments, R b Selected from methyl.

[0039] In some embodiments, X is selected from CH, CF, C(CN) or N(CH3), and Y is selected from N, CH, C(O), C(OH), C(OCH3), C(OCHF2), C(OCH2F), CF or C(OCD3). In some embodiments, X is selected from CH, and Y is selected from C(OH), C(OCH3), C(OCHF2), C(OCH2F), CF or C(OCD3). In some embodiments, X is selected from CH, and Y is selected from N. In some embodiments, X is selected from N(CH3), and Y is selected from C(O). In some embodiments, X is selected from CF or C(CN), and Y is selected from CH or N.

[0040] In some embodiments, is a double bond. In some embodiments, For a single key.

[0041] In some embodiments, R 1 , R 2 are independently selected from C 1-6 Alkyl, NH(R c )-C1-6 Alkyl- or N(R c )(C 1-6 Alkyl)-C 1-6 Alkyl-, or R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more R c replace.

[0042] In some embodiments, R 1 , R 2 are independently selected from C 1-6 Alkyl, or R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more R c replace.

[0043] In some embodiments, R 1 , R 2 are independently selected from C 1-3 Alkyl, NH(R c )-C 1-3 Alkyl- or N(R c )(C 1-3 Alkyl)-C 1-3 alkyl-.

[0044] In some embodiments, R 1 , R 2 are independently selected from C 1-3 alkyl.

[0045] In some embodiments, R 1 , R 2 Each is independently selected from methyl, ethyl, propyl or isopropyl.

[0046] In some embodiments, R 1 , R 2 are independently selected from methyl or ethyl.

[0047] In some embodiments, R 1 , R 2 are each independently selected from methyl.

[0048] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-10 membered heterocyclic group, wherein the ring atoms of the 5-10 membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, and the 5-10 membered heterocyclic group is optionally replaced by one or more R c replace.

[0049] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-10 membered heterocyclic group, wherein the ring atoms of the 5-10 membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, and the 5-10 membered heterocyclic group is optionally replaced by one or more R c When the ring atoms contain N atoms, N and R c connect.

[0050] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-8 membered heterocyclic group, wherein the ring atoms of the 5-8 membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain N atoms, N is connected to Rc.

[0051] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 5- to 8-membered heterocycloalkyl group is formed, wherein the ring atoms of the 5- to 8-membered heterocycloalkyl group contain at least one nitrogen atom, and the nitrogen atom and the R c connect.

[0052] In some embodiments, R 1 , R 2 The phosphorus atom connected thereto forms a 5- or 6-membered heterocycloalkyl, a 9- or 10-membered spiroheterocycloalkyl, or a 9- or 10-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl, the 9- or 10-membered spiroheterocycloalkyl, or the 9- or 10-membered heterocycloalkyl is optionally substituted by one or more R c replace.

[0053] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-membered or 6-membered heterocyclic group, wherein the 5-membered or 6-membered heterocyclic group is optionally substituted by one or more R c replace.

[0054] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-membered or 6-membered heterocyclic group, wherein the ring atoms of the 5-membered or 6-membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, and when the ring atoms contain N atoms, N and R c In some embodiments, R 1 , R 2Together with the phosphorus atom connected thereto, it forms a 5-membered or 6-membered heterocyclic group, wherein the ring atoms of the 5-membered or 6-membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain N atoms, N and R c connect.

[0055] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain at least one nitrogen atom, and N and R c In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain only one N atom, and N and R c connect.

[0056] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 6-membered heterocyclic group, wherein the ring atoms of the 6-membered heterocyclic group contain only one O atom.

[0057] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, they form a 5-membered or 6-membered heterocyclic group, and the ring atoms of the 5-membered or 6-membered heterocyclic group are composed of carbon atoms and phosphorus atoms.

[0058] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocycloalkyl group is formed, wherein the ring atoms of the 6-membered heterocycloalkyl group contain at least one nitrogen atom, and the nitrogen atom and the R c In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocycloalkyl group is formed, wherein the ring atom of the 6-membered heterocycloalkyl group contains only one N atom, and N and R c In some embodiments, R 1 , R 2 Together with the phosphorus atom to which it is attached, it forms a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group contains only one O atom in the ring atom. 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-membered or 6-membered heterocycloalkyl group, and the ring atoms of the 5-membered or 6-membered heterocycloalkyl group are composed of carbon atoms and phosphorus atoms.

[0059] In some embodiments, the structural unit Can be selected from structural units The structural unit Optionally, one or more R c replace.

[0060] In some embodiments, the structural unit Can be selected from structural units

[0061] In some embodiments, the structural unit Can be selected from structural units

[0062] In some embodiments, the structural unit For structural units

[0063] In some embodiments, R 1 , R 2 are independently selected from methyl or ethyl, or structural units Selected from structural units

[0064] In some embodiments, R 1 , R 2 are independently selected from methyl, or structural units For structural units

[0065] In some embodiments, each R c are independently selected from hydrogen, C 1-6 Alkyl-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl-OC 1-6 Alkyl-, C 1-6 Alkyl-OC 1-6 Alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C(O)-, amino-C 1-6 Alkyl-C(O)-, mono(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, amino-C(O)-C 1-6 Alkyl-, mono(C 1-6 alkyl)amino-C(O)-C 1-6Alkyl-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 Alkyl-, C 6-10 Aryl-C 1-6 Alkyl- or C substituted with one or more hydroxyl groups 1-6 alkyl-.

[0066] In some embodiments, each R c are independently selected from hydrogen, O=, HN=, C 1-6 Alkyl-N=, C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, 3-6 membered cycloalkyl-S(O)2-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-OC 1-3 Alkyl-C(O)-, amino-C(O)-, mono(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-C(O)-, amino-C 1-3 Alkyl-C(O)-, mono(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, di(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, amino-C(O)-C 1-3 Alkyl-, mono(C 1-3 alkyl)amino-C(O)-C 1-3 Alkyl-, di(C 1-3 alkyl)amino-C(O)-C 1-3 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-3 alkyl-, 3- to 6-membered heterocycloalkyl-, 3- to 6-membered heterocycloalkyl-C(O)-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or C substituted with one or more hydroxyl or cyano groups 1-3 Alkyl-, wherein R c When other than hydrogen and O=, it is optionally substituted by one or more halogens.

[0067] In some embodiments, each R c are independently selected from hydrogen, C 1-3Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, 3-6 membered cycloalkyl-S(O)2-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-OC 1-3 Alkyl-C(O)-, amino-C(O)-, mono(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-C(O)-, amino-C 1-3 Alkyl-C(O)-, mono(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, di(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, amino-C(O)-C 1-3 Alkyl-, mono(C 1-3 alkyl)amino-C(O)-C 1-3 Alkyl-, di(C 1-3 alkyl)amino-C(O)-C 1-3 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-3 alkyl-, 3- to 6-membered heterocycloalkyl-, 3- to 6-membered heterocycloalkyl-C(O)-, 3- to 6-membered heterocycloalkyl-C 1-3 Alkyl-, phenyl-C 1-3 Alkyl- or C substituted with one or more hydroxyl or cyano groups 1-3 Alkyl-, wherein R c When not hydrogen it is optionally substituted by one or more halogens.

[0068] In some embodiments, each R c are independently selected from hydrogen, C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, 3- to 5-membered cycloalkyl-S(O)2-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3alkyl)amino-C(O)-CH2-, 3-5-membered cycloalkyl-, 3-5-membered cycloalkyl-C(O)-, 3-5-membered cycloalkyl-CH2-, 3-5-membered heterocycloalkyl-, phenyl-CH2-, or C(O)-substituted with one hydroxyl or cyano group 1-3 Alkyl-, wherein R c When not hydrogen it is optionally substituted by 1, 2 or 3 halogens.

[0069] In some embodiments, each R c are independently selected from hydrogen, C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O) 2- 、3-5 membered cycloalkyl-S(O)2-、C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-CH2-, 3-5-membered cycloalkyl-, 3-5-membered cycloalkyl-C(O)-, 3-5-membered cycloalkyl-CH2-, 3-5-membered heterocycloalkyl-, or C(O)-substituted with one hydroxyl or cyano group 1-3 Alkyl-, wherein R c When not hydrogen it is optionally substituted by 1, 2 or 3 halogens.

[0070] In some embodiments, each R c are independently selected from hydrogen, C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-CH2-, 3- to 5-membered cycloalkyl-, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, phenyl-CH2-, or C(O)-substituted with one hydroxyl group 1-3 alkyl-.

[0071] In some embodiments, each R care independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl,

[0072] In some embodiments, each R c are independently selected from methyl, ethyl, isopropyl, Acetyl,

[0073] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl, 8- to 12-membered benzocycloalkenyl or 8- to 12-membered benzoheterocyclyl.

[0074] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl, 8- to 12-membered benzocycloalkenyl, 8- to 12-membered benzoheterocycloalkyl or 8- to 12-membered benzoheterocycloalkenyl.

[0075] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl or 8- to 12-membered benzoheterocycloalkyl.

[0076] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 10-membered fused ring or 8- to 10-membered fused heterocyclic ring.

[0077] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl, 8- to 10-membered benzocycloalkenyl or 8- to 10-membered benzoheterocyclyl.

[0078] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl, 8- to 10-membered benzocycloalkenyl, 8- to 10-membered benzoheterocycloalkyl or 8- to 10-membered benzoheterocycloalkenyl.

[0079] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl or 8- to 10-membered benzoheterocycloalkyl.

[0080] In some embodiments, Ring A is selected from phenyl, thienyl, 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, or benzofuranyl.

[0081] In some embodiments, Ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.

[0082] In some embodiments, n is 0, 1, or 2; alternatively, n is 1, 2, or 3.

[0083] In some embodiments, n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.

[0084] In some embodiments, each R 3 are independently selected from amino, nitro, halogen, C 1-6 Alkyl- or phenyl, wherein the C 1-6 Alkyl- or phenyl- is optionally replaced by one or more R d replace.

[0085] In some embodiments, each R 3 are independently selected from amino, halogen, C 1-6 Alkyl- or phenyl, wherein the C 1-6 Alkyl- or phenyl- is optionally replaced by one or more R d replace.

[0086] In some embodiments, each R 3 are independently selected from amino, nitro, halogen, C 1-4 Alkyl- or phenyl, wherein the C 1-4 Alkyl- or phenyl- is optionally replaced by one or more R d replace.

[0087] In some embodiments, each R 3 are independently selected from amino, nitro, halogen, C 1-4 Alkyl- or phenyl, wherein the C 1-4 Alkyl- or phenyl is optionally substituted by 1, 2 or 3 R d replace.

[0088] In some embodiments, R d Selected from hydroxyl, halogen or C 1-3 Alkyl-NH-C 1-3 alkyl-.

[0089] In some embodiments, R d is selected from hydroxy, fluoro or methyl-NH-methyl-.

[0090] In some embodiments, each R 3 Each independently selected from amino, nitro, fluorine, methyl, trifluoromethyl, -CF2CH2OH, -CHF2, -CF2CH3, -CF2C(CH3)2OH or

[0091] In some embodiments, each R 3 Each independently selected from amino, fluorine, methyl, trifluoromethyl, -CF2CH2OH, -CHF2, -CF2CH3, -CF2C(CH3)2OH or

[0092] In some embodiments, each R 3 Each is independently selected from amino, nitro, fluoro, methyl or trifluoromethyl.

[0093] In some embodiments, the structural unit Selected from Further selected from

[0094] In some embodiments, R 4 , R 5 are independently selected from hydrogen, deuterium or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halogens.

[0095] In some embodiments, R 4 Selected from C 1-3 Alkyl, R 5 is selected from hydrogen or deuterium, wherein the C 1-3 Alkyl is optionally substituted with one or more halogens. 4 Selected from methyl, R 5 is selected from hydrogen or deuterium, wherein the methyl group is optionally substituted with one or more fluorine groups. 4 is selected from methyl or -CH2F, R 5 is selected from hydrogen or deuterium. In some embodiments, R 4 Selected from methyl, R 5 Selected from hydrogen.

[0096] In some embodiments, R 5 Selected from C 1-3 Alkyl, R 4 is selected from hydrogen or deuterium, wherein the C 1-3 Alkyl is optionally substituted with one or more halogens. 5 Selected from methyl, R 4 is selected from hydrogen or deuterium, wherein the methyl group is optionally substituted with one or more fluorine groups. 5 is selected from methyl or -CH2F, R 4 is selected from hydrogen or deuterium. In some embodiments, R5 Selected from methyl, R 4 Selected from hydrogen.

[0097] In some embodiments, R 6 Selected from hydrogen, halogen or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halogens.

[0098] In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or isopropyl, wherein the methyl, ethyl, propyl or isopropyl is optionally substituted with one or more halogens. 6 is selected from hydrogen, fluorine, chlorine or methyl, wherein the methyl is optionally substituted by 1, 2 or 3 fluorine. 6 is selected from hydrogen, chlorine, methyl or -CH2F. In some embodiments, R 6 Selected from methyl.

[0099] In some embodiments, the heteroatoms in the heterocyclyl, heteroaryl or heterocycloalkyl described herein are selected from N, O, S and P. In some embodiments, the heteroatoms in the heterocyclyl, heteroaryl or heterocycloalkyl described herein are selected from N, O and P. In some embodiments, the heteroatoms in the heterocyclyl, heteroaryl or heterocycloalkyl described herein are selected from N and P.

[0100] On the other hand, the present application provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0101]

[0102] in,

[0103] X and Y are independently selected from CR a , C(O), N or NR b ;

[0104] Depending on the difference between X and Y, they represent single bonds or double bonds;

[0105] R a Selected from hydrogen, hydroxyl, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens, the C 1-6 The alkoxy group is optionally substituted with one or more deuterium or halogen;

[0106] R b Selected from hydrogen, C 1-6 Alkyl or C 1-6Alkoxy;

[0107] R 1 , R 2 are independently selected from C 1-6 Alkyl, NH(R c )-C 1-6 Alkyl- or N(R c )(C 1-6 Alkyl)-C 1-6 Alkyl-, or R 1 , R 2 Together with the phosphorus atom connected thereto, a 5-8 membered heterocyclic group is formed, wherein the ring atoms of the 5-8 membered heterocyclic group contain at least one nitrogen atom, and nitrogen and R c connect;

[0108] Every R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl-OC 1-6 Alkyl-, C 1-6 Alkyl-OC 1-6 Alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C(O)-, amino-C 1-6 Alkyl-C(O)-, mono(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, amino-C(O)-C 1-6 Alkyl-, mono(C 1-6 alkyl)amino-C(O)-C 1-6 Alkyl-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 Alkyl-, C 6-10 Aryl-C 1-6 Alkyl- or C substituted with one or more hydroxyl groups 1-6 Alkyl, wherein the R c when not hydrogen, is optionally substituted by one or more halogens;

[0109] Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl or 8- to 12-membered fused ring;

[0110] n is 0, 1, 2 or 3;

[0111] Every R 3 are independently selected from amino, nitro, halogen, C 1-8 alkyl or 3-6 membered cycloalkyl, wherein the C 1-8 The alkyl group and the 3- to 6-membered cycloalkyl group are optionally substituted with one or more R d replace;

[0112] R d Selected from hydroxyl or halogen.

[0113] In some embodiments, the compound of formula (II), wherein R 1 , R 2 , R 3 , X, Y, n, ring A and The definition of is as mentioned above.

[0114] In some embodiments, X is selected from CR a , Y is selected from CR a , C(O), N or NR b In some embodiments, X is selected from CR a , Y is selected from CR a , C(O) or N. In some embodiments, X is selected from CR a , Y is selected from N.

[0115] In some embodiments, X and Y are both selected from CR a In some embodiments, X is selected from CH and Y is selected from CR a .

[0116] In some embodiments, R a Selected from hydrogen, halogen or C 1-4 Alkoxy, wherein the C 1-4 Alkoxy is optionally substituted with one or more deuterium or halogen. a Selected from hydrogen, halogen or C 1-4 Alkoxy, wherein the C 1-4 The alkoxy group is optionally substituted with 3 deuterium or one or more fluorine. a Selected from hydrogen, halogen or C 1-4 Alkoxy, wherein the C 1-4 The alkoxy group is optionally substituted with 3 deuterium or 2 fluorine.

[0117] In some embodiments, R a is selected from hydrogen, fluorine, methoxy or difluoromethoxy, wherein the methoxy is optionally substituted by 3 deuteriums.

[0118] In some embodiments, Ra Selected from hydrogen, fluorine, CH3O-, CD3O- or CHF2O-.

[0119] In some embodiments, R b Selected from C 1-6 In some embodiments, R b Selected from C 1-4 In some embodiments, R b Selected from C 1-3 In some embodiments, R b Selected from methyl.

[0120] In some embodiments, X is selected from CH and N(CH3), and Y is selected from N, C(O), C(OCH3), CF, or C(OCD3). In some embodiments, X is selected from CH, and Y is selected from C(OCH3), CF, or C(OCD3). In some embodiments, X is selected from CH, and Y is selected from N. In some embodiments, X is selected from N(CH3), and Y is selected from C(O).

[0121] In some embodiments, R 1 , R 2 are independently selected from C 1-3 Alkyl, NH(R c )-C 1-3 Alkyl- or N(R c )(C 1-3 Alkyl)-C 1-3 alkyl-.

[0122] In some embodiments, R 1 , R 2 are independently selected from C 1-3 alkyl.

[0123] In some embodiments, R 1 , R 2 are each independently selected from methyl.

[0124] In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain at least one nitrogen atom, and N and R c In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain only one N atom, and N and R c connect.

[0125] In some embodiments, R 1 , R2 Together with the phosphorus atom connected thereto, a 5- to 8-membered heterocycloalkyl group is formed, wherein the ring atoms of the 5- to 8-membered heterocycloalkyl group contain at least one nitrogen atom, and the nitrogen atom and the R c In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocycloalkyl group is formed, wherein the ring atoms of the 6-membered heterocycloalkyl group contain at least one nitrogen atom, and nitrogen and R c In some embodiments, R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocycloalkyl group is formed, wherein the ring atom of the 6-membered heterocycloalkyl group contains only one N atom, and N and R c connect.

[0126] In some embodiments, the structural unit Selected from structural units

[0127] In some embodiments, R 1 , R 2 are independently selected from methyl, or structural units Selected from structural units

[0128] In some embodiments, each R c are independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-OC 1-3 Alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-C(O)-, amino-C 1-3 Alkyl-C(O)-, mono(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, di(C 1-3 alkyl)amino-C 1-3 Alkyl-C(O)-, amino-C(O)-C 1-3 Alkyl-, mono(C 1-3 alkyl)amino-C(O)-C 1-3 Alkyl-, di(C 1-3 alkyl)amino-C(O)-C 1-3 alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C1-3 Alkyl-, phenyl-C 1-3 Alkyl- or C substituted with one or more hydroxyl groups 1-3 alkyl.

[0129] In some embodiments, each R c are independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-CH2-, 3- to 5-membered cycloalkyl, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, phenyl-CH2-, or C(O)-substituted with one hydroxyl group 1-3 alkyl.

[0130] In some embodiments, each R c are independently selected from methyl, ethyl, isopropyl, acetyl,

[0131] In some embodiments, Ring A is selected from C 6-10 Aryl, 5-6 membered heteroaryl or 8-10 membered fused ring.

[0132] In some embodiments, Ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.

[0133] In some embodiments, n is 0, 1, or 2; alternatively, n is 1, 2, or 3.

[0134] In some embodiments, n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.

[0135] In some embodiments, each R 3 are independently selected from amino, nitro, halogen or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R d replace.

[0136] In some embodiments, R d Selected from hydroxyl or fluorine.

[0137] In some embodiments, each R 3 Each is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF2CH2OH, -CHF2, -CF2CH3 or -CF2C(CH3)2OH.

[0138] In some embodiments, the structural unit Selected from Further selected from

[0139] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof

[0140]

[0141] Among them, R 1 , R 2 , R 3 , X, Y, n, ring A and The definition of is as mentioned above.

[0142] In some embodiments, in the compound of formula (I) of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof,

[0143] X and Y are independently selected from CR a and N, for example, X and Y are selected from CR a , or X is CR a and Y is N;

[0144] R a Selected from hydrogen or C 1-4 Alkoxy; preferably, R a is selected from hydrogen or methoxy;

[0145] represents a double bond;

[0146] R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain at least one N atom or O atom, and when the ring atoms contain N atoms, N and R c connection (preferably containing a N atom, and N and R c connect);

[0147] R c Selected from C 1-4 Alkyl-S(O)2- (preferably methylsulfonyl), C3-6 Cycloalkyl-S(O)2- (preferably cyclopropylsulfonyl);

[0148] Ring A is selected from C 6-10 Aryl, preferably C6 aryl (ie, phenyl);

[0149] n is 0, 1, 2 or 3, preferably 2;

[0150] Every R 3 are independently selected from halogen (preferably F), C 1-8 Alkyl (preferably C 1-4 alkyl, more preferably methyl or ethyl), wherein the C 1-8 The alkyl group is optionally substituted with one or more halogens (preferably F);

[0151] R 4 , R 5 are independently selected from hydrogen or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more fluorine groups (preferably R 4 Selected from hydrogen, R 5 is selected from methyl, or, R 4 Selected from methyl, R 5 selected from hydrogen);

[0152] R 6 Selected from hydrogen, halogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens, for example, R 6 It may be selected from hydrogen, methyl or methyl optionally substituted with one or more halogens (eg, -CH2F).

[0153] In some embodiments, in the compound of formula (II) of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof,

[0154] X and Y are independently selected from CR a and N, for example, X and Y are selected from CR a , or X is CR a and Y is N;

[0155] R a Selected from hydrogen or C 1-4 Alkoxy; preferably, R a is selected from hydrogen or methoxy; more preferably, R a Selected from hydrogen;

[0156] represents a double bond;

[0157] R 1 , R 2Together with the phosphorus atom connected thereto, a 6-membered heterocyclic group is formed, wherein the ring atoms of the 6-membered heterocyclic group contain at least one N atom (preferably one N atom), and N and R c connect;

[0158] R c Selected from C 1-4 Alkyl-S(O)2- (preferably methylsulfonyl), C 3-6 Cycloalkyl-S(O)2- (preferably cyclopropylsulfonyl);

[0159] Ring A is selected from C 6-10 Aryl, preferably C6 aryl (ie, phenyl);

[0160] n is 0, 1, 2 or 3, preferably 2;

[0161] Every R 3 are independently selected from halogen (preferably F), C 1-8 Alkyl (preferably C1-4, more preferably methyl or ethyl), wherein the C 1-8 The alkyl group is optionally substituted with one or more halogens (preferably F).

[0162] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III-1), the compound of formula (III-2), the compound of formula (III-3), the compound of formula (III-4), the compound of formula (III-5), the compound of formula (III-6), the compound of formula (III-7), the compound of formula (III-8) and the compound of formula (III-9), its stereoisomer or its pharmaceutically acceptable salt,

[0163]

[0164]

[0165] Among them, R 1 , R 2 , R 3 ,Y,n,ring A,R a , R b and R c The definition of is as mentioned above.

[0166] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV), the compound of formula (V) and the compound of formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof,

[0167]

[0168] Among them, R 3 ,Y,n,R b and R c The definition of is as mentioned above.

[0169] In some embodiments, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0170] In some embodiments, the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] In some embodiments, the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:

[0179]

[0180]

[0181]

[0182] On the other hand, the present application provides a method for preparing a compound of formula (I), comprising: reacting a compound of formula M3 with a compound of formula N3 to prepare a compound of formula (I)

[0183]

[0184] in,

[0185] Rx is selected from chlorine, bromine or iodine;

[0186] R 6 is selected from C optionally substituted by one or more halogens 1-6 alkyl;

[0187] R 1 , R 2 , R 3 , R4 , R 5 , X, Y, n and ring A are as defined above.

[0188] On the other hand, the present application provides a method for preparing a compound of formula M3, comprising:

[0189] Step (i): Under acidic conditions, the compound of formula M1 reacts with the compound of formula N1 to prepare a compound of formula M2;

[0190] Step (ii): reacting a compound of formula M2 with a compound of formula N2 to prepare a compound of formula M3;

[0191]

[0192] in,

[0193] Rx is selected from chlorine, bromine or iodine;

[0194] R 6 is selected from C optionally substituted by one or more halogens 1-6 alkyl;

[0195] R 3 , R 4 , R 5 , X, Y, n and ring A are as defined above.

[0196] On the other hand, the present application provides a method for preparing a compound of formula M3, comprising:

[0197]

[0198] Step (a): reacting the compound of formula M2 with thionyl chloride to prepare a compound of formula M2-1,

[0199] Step (b): Under alkaline conditions, a compound of formula M2-1 is subjected to a substitution reaction with a compound of formula N2 to prepare a compound of formula M3,

[0200] in,

[0201] Rx is selected from chlorine, bromine or iodine;

[0202] R 6 is selected from C optionally substituted by one or more halogens 1-6 alkyl;

[0203] R 3 , R 4 , R 5 , X, Y, n and ring A are as defined above.

[0204] In some embodiments, in the method for preparing the compound of formula (I), the compound of formula M3 is prepared by the method described above.

[0205] On the other hand, the present application provides a method for preparing a compound of formula (III-8), the method comprising:

[0206] The compound of formula M3-1 is reacted with 1-benzyl-1,4-azaphosphine-4-oxide to prepare the compound of formula M3-2, and then the compound of formula M3-3 is obtained by debenzylation, and finally a substitution reaction is carried out to prepare the compound of formula (III-8).

[0207]

[0208] wherein Rx is selected from chlorine, bromine or iodine;

[0209] R 3 , R c , n and ring A are as defined above.

[0210] In some embodiments, the preparation method of the compound of formula (III-8) provided in the present application comprises:

[0211] Step (1): reacting the compound of formula M3-1 with 1-benzyl-1,4-azaphosphane-4-oxide to obtain a compound of formula M3-2,

[0212] Step (2): reacting the compound of formula M3-2 to obtain a compound of formula M3-3,

[0213] Step (3): reacting the compound of formula M3-3 to obtain a compound of formula (III-8),

[0214] Optionally, step (2) is carried out in In the presence of

[0215] in,

[0216] Rx is selected from chlorine, bromine or iodine;

[0217] R 6 is selected from C1-6 alkyl optionally substituted by one or more halogens;

[0218] R 3 , R c , n and ring A are as defined above.

[0219] On the other hand, the present application also provides the following intermediate compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:

[0220]

[0221]

[0222] On the other hand, the present application provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0223] On the other hand, the present application provides a method for treating or preventing diseases and / or conditions associated with or regulated by SOS1 in mammals, the method comprising administering a therapeutically or preventively effective amount of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment or prevention.

[0224] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating or preventing diseases and / or disorders associated with or regulated by SOS1.

[0225] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating or preventing diseases and / or disorders associated with or regulated by SOS1.

[0226] In another aspect, the present application provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for treating or preventing diseases and / or disorders associated with SOS1 or regulated by SOS1.

[0227] In some embodiments, the diseases and / or conditions associated with or modulated by SOS1 are selected from diseases and / or conditions in which SOS1 interacts with RAS family proteins.

[0228] In some embodiments, the disease and / or condition associated with or modulated by SOS1 is selected from cancer, such as non-small cell lung cancer.

[0229] The compounds of the present application have good KRAS-G12C / SOS1 protein binding inhibitory activity, K562 cell proliferation inhibitory activity, in vivo and in vitro drug activity and good pharmacokinetic properties.

[0230] definition

[0231] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0232] Chemical Bond Depending on the different groups connected at both ends, they represent single bonds or double bonds. For example, when X and Y connected at both ends of the chemical bond are CRa or N, the chemical bond is a double bond; when one of the X and Y connected at both ends of the chemical bond is CO or NRa, the chemical bond It is a single bond. Those skilled in the art will appreciate that the selection of X and Y will not violate the valence bond rules.

[0233] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0234] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (-CH2CH3), monosubstituted (such as-CH2CH2F), polysubstituted (such as-CHFCH2F,-CH2CHF2, etc.) or fully substituted (-CF2CF3). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0235] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 ” means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0236] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0237] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0238] When a substituent's bond crosses between two atoms on a ring, the substituent may be bonded to any atom on the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0239] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0240] The term "hydroxy" refers to an -OH group.

[0241] The term "amino" refers to a -NH2 group.

[0242] The term "nitro" refers to a -NO2 group.

[0243] The term "cyano" refers to a -CN group.

[0244] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.

[0245] The term "alkoxy" refers to an -O-alkyl group.

[0246] The term "alkylamino" or "monoalkylamino" refers to an -NH-alkyl group.

[0247] The term "dialkylamino" refers to -N(alkyl)2.

[0248] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0249] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic radical is typically a 3 to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and / or nitrogen. Non-limiting examples of heterocyclic radicals include, but are not limited to, oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl or wait.

[0250] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycloalkyl is typically a 3 to 12-membered ring, a 3 to 7-membered ring or a 5 to 8-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxirane, thioethane, and cyclonitriles; non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, or Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, etc. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0251] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0252] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0253] The term "condensed ring" refers to a 7-20-membered, all-carbon polycyclic ring in which two rings share two adjacent carbon atoms, at least one of which has a completely conjugated π electron system, but the whole is not aromatic. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed ring, preferably a bicyclic or tricyclic, more preferably a 6-membered / 6-membered or 5-membered / 6-membered bicyclic ring. Non-limiting examples of condensed rings include:

[0254] The term "spiro heterocycloalkyl" refers to a fully saturated 5 to 20-membered polycyclic ring in which one carbon atom (called a spiro atom) is shared between monocyclic rings, and one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of sulfur, silicon, phosphorus, oxygen and / or nitrogen, and the remaining ring atoms are carbon atoms. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of spiro atoms shared between rings, the spiro heterocycle is divided into a single spiro heterocycle, a double spiro heterocycle or a multi-spiro heterocycle, preferably a single spiro heterocycle or a double spiro heterocycle, more preferably a 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-membered single spiro heterocycle. Non-limiting examples of spiro heterocycles include

[0255] The term "heterocycloalkyl" refers to a fully saturated polycyclic ring having 5 to 20 ring atoms and two rings sharing 2 ring atoms, wherein one or more ring atoms are selected from sulfur, silicon, phosphorus, oxygen and / or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic or polycyclic bridged heterocycle, preferably a bicyclic. Non-limiting examples of heterocycles include

[0256] The term "benzocycloalkyl" refers to a benzene ring fused to a cycloalkyl group (ie, the benzene ring and the cycloalkyl group share two adjacent carbon atoms). Non-limiting examples of benzocycloalkyl groups include: wait.

[0257] The term "cycloalkenyl" refers to an unsaturated carbocyclic ring containing at least one carbon-carbon double bond and not containing any carbon-carbon triple bonds, and can be a monocyclic, bridged or spirocyclic carbocyclic ring. Non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexadienyl.

[0258] The term "benzocycloalkenyl" refers to a benzene ring fused to a cycloalkenyl group (ie, the benzene ring and the cycloalkenyl group share two adjacent carbon atoms). Non-limiting examples of benzocycloalkenyl groups include:

[0259] The term "benzoheterocyclyl" refers to a benzene ring fused to a heterocyclyl (ie, the benzene ring and the heterocyclyl share two adjacent carbon atoms). Non-limiting examples of benzoheterocyclyl groups include:

[0260] The term "benzoheterocycloalkyl" refers to a benzene ring fused to a heterocycloalkyl (ie, the benzene ring and the heterocycloalkyl share two adjacent carbon atoms). Non-limiting examples of benzoheterocycloalkyl include:

[0261] The term "heterocycloalkenyl" refers to an unsaturated cyclic group that contains at least one carbon-carbon double bond or carbon-nitrogen double bond, and can be present as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is generally a heteroatom (preferably 1 or 2 heteroatoms) containing 1 to 3 independently selected from sulfur, oxygen, phosphorus and / or nitrogen. Non-limiting examples of heterocycloalkenyl include: 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 3-pyrrolinyl, 3,4-dihydro-2H-pyrans, dihydrofuranyl, dihydrothienyl and dihydrothiopyranyl.

[0262] The term "benzoheterocyclenyl" refers to a benzene ring fused to a heterocyclenyl group (ie, the benzene ring and the heterocyclenyl group share two adjacent carbon atoms). Non-limiting examples of benzoheterocyclenyl groups include:

[0263] The term "fused heterocycle" refers to a polycyclic ring of 7 to 20 members, in which two rings in the system share two adjacent atoms, which contains at least one ring atom selected from N, O, and S, and the remaining ring atoms are C, and at least one ring has a completely conjugated π electron system, but the whole is not aromatic. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring, preferably a bicyclic or tricyclic, and more preferably a 6-membered / 6-membered or 5-membered / 6-membered bicyclic ring. Non-limiting examples of fused heterocycles include:

[0264] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0265] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0266] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0267] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0268] The term "therapeutically or prophylactically effective amount" means an amount of the present invention compound that (i) treats or prevents a specific disease, condition, or disorder described herein, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the present invention compound that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0269] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0270] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0271] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0272] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0273] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0274] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass singular terms. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise stated, the use of "or" means "and / or".

[0275] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0276] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0277] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter.

[0278] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0279] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N.15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0280] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0281] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H or D)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0282] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0283] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0284] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0285] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0286] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0287] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0288] In all the methods of administration of the compounds of formula I described herein, the dosage administered per day is 0.01 to 200 mg / kg body weight, in the form of single or divided doses.

[0289] The compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0290] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0291] An important consideration in synthetic route planning in the art is to select a suitable protecting group for a reactive functional group (such as the amino group in the present application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited in this application are incorporated herein by reference in their entirety.

[0292] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0293] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:

[0294] Route 1:

[0295]

[0296] in,

[0297] Ring A, R c , R 3 , n are defined as above.

[0298] Route 2:

[0299]

[0300] in,

[0301] Ring A, R 3 , n are defined as above.

[0302] Route 3:

[0303]

[0304] in,

[0305] Ring A, R 3 , n are defined as above.

[0306] This application uses the following abbreviations:

[0307] PBS stands for fetal bovine serum; PBS stands for phosphate-buffered saline; PBST stands for phosphate-buffered saline Tween; BSA stands for bovine serum albumin; GAPDH stands for glyceraldehyde-3-phosphate dehydrogenase; DMSO stands for dimethyl sulfoxide; DTT stands for dithiothreitol; HTRF stands for homogeneous time-resolved fluorescence. DETAILED DESCRIPTION

[0308] For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present application. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present application are commercially available and can be used without further purification.

[0309] Example 1: Preparation of Compound 1

[0310]

[0311] Step A: Preparation of Compound 1-1

[0312] Add methyl 2-amino-4-methoxybenzoate (4 g) and anhydrous ethanol (16 mL) to a 250 mL three-necked flask, add water (28 mL) and concentrated hydrochloric acid (7 mL) respectively under room temperature stirring, cool to 0 ° C in an ice bath under mechanical stirring, slowly drop iodine monochloride (3.58 g) in concentrated hydrochloric acid (2 mL) solution, after the dropwise addition is complete, transfer the reaction solution to room temperature and continue stirring and reacting overnight. Add water (100 mL) to the reaction solution, stir vigorously for 5 min, filter, wash the filter cake with water (20 mL), collect the solid, and slurry with petroleum ether (50 mL) to obtain 6.45 g of compound 1-1.

[0313] MS (ESI, [M+H] + ): m / z = 307.81.

[0314] 1 H NMR (500MHz, DMSO-d6) δ7.99 (s, 1H), 6.38 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H).

[0315] Step B: Preparation of Compound 1-2

[0316] Compound 1-1 (15 g), acetonitrile (100 g) and methanesulfonic acid (37.6 g) obtained in step A were added to a 350 mL pressure bottle in sequence, and the reaction bottle was placed in an oil bath at 120°C and stirred for 6 h. The reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure. Water (150 mL) was added to the residual solid, and the mixture was stirred vigorously. The pH was adjusted to alkaline with a 2.5 M aqueous sodium hydroxide solution, and the mixture was filtered by suction. The filter cake was washed with a large amount of water, and the solid was collected. After drying, the mixture was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to obtain 5.9 g of compound 1-2.

[0317] MS (ESI, [M+H] + ): m / z = 316.79.

[0318] 1H NMR (500MHz, DMSO-d6) δ12.19 (s, 1H), 8.37 (s, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 2.32 (s, 3H).

[0319] Step C: Preparation of Compound 1-3

[0320] Compound 1-2 (1 g) obtained in step B and chloroform (10 mL) were added to a 25 mL three-necked flask, and thionyl chloride (2.94 g) and two drops of N, N-dimethylformamide were added in sequence under stirring at room temperature, and the reaction solution was heated to 70°C and stirred for 3 h. The reaction solution was concentrated to dryness, and water (40 mL) and dichloromethane (50 mL) were added to the residue. A saturated sodium bicarbonate aqueous solution was added dropwise under vigorous stirring to adjust the pH value to weak alkalinity, and the mixture was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated. 0.41 g of compound 1-3 was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 90: 10).

[0321] MS (ESI, [M+H] + ): m / z = 334.77.

[0322] 1 H NMR (500MHz, DMSO-d6) δ8.42 (s, 1H), 7.18 (s, 1H), 3.98 (s, 3H), 2.50 (s, 3H).

[0323] Step D: Preparation of Compound 1-4

[0324] Compound 1-3 (200 mg) obtained in step C, (R)-1-(m-tolyl)ethane-1-amine (98 mg), N,N-diisopropylethylamine (129 mg) and 1,4-dioxane (2 mL) were added to a 25 mL single-mouth bottle, and the mixture was heated to 100° C. and stirred for 5 h under nitrogen protection. The reaction was stopped, and the reaction solution was concentrated to dryness. The residue was dissolved in dichloromethane (20 mL), washed with saturated sodium bicarbonate aqueous solution, 1M hydrochloric acid, and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 160 mg of compound 1-4.

[0325] MS (ESI, [M+H] + ): m / z = 434.00.

[0326] 1H NMR (500MHz, DMSO-d6) δ8.88 (s, 1H), 8.29 (d, J=8.0Hz, 1H), 7.28-7.16 (m, 3H), 7.05-7.03 ( m, 2H), 5.58 (p, J=7.0Hz, 1H), 3.92 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.54 (d, J=7.0Hz, 3H).

[0327] Step E: Preparation of Compound 1

[0328] Compound 1-4 (0.09 g) obtained in step D, dimethylphosphine oxide (0.017 g), triethylamine (0.032 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (6.13 mg), tris(dibenzylideneacetone) dipalladium (4.85 mg) and 1,4-dioxane (2 mL) were added to a 15 mL pressure tube, and heated to 120° C. in an oil bath under nitrogen protection, stirred and reacted for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was purified by chromatography on a C18 column (120 g) (40% acetonitrile + 60% water) to obtain 58.5 mg of compound 1.

[0329] HRMS (ESI, [M+H] + ): m / z = 384.1855.

[0330] 1 H NMR (500MHz, DMSO-d6) δ8.80 (d, J=8.0Hz, 1H), 8.76 (d, J=13.6Hz, 1H), 7.32 (s, 1H), 7.30 (d, J=7.8Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 7.14 (d, J=4. 7Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 5.67 (p, J=7.1Hz, 1H), 3.99 (s, 3H), 2.4 3(s, 3H), 2.33(s, 3H), 1.75(s, 3H), 1.72(s, 3H), 1.60(d, J=7.1Hz, 3H).

[0331] Example 2: Preparation of Compound 2

[0332]

[0333] Step A: Preparation of Compound 2-1

[0334] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine to prepare compound 2-1.

[0335] MS (ESI, [M+H] + ): m / z = 487.94.

[0336] 1 H NMR (500MHz, DMSO-d6) δ8.86 (s, 1H), 8.39 (d, J=7.6Hz, 1H), 7.81 (s, 1H), 7.74 (t, J=7.9Hz, 1H), 7.60-7. 55 (m, 2H), 7.03 (d, J = 8.3Hz, 1H), 5.62 (p, J = 7.1Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H), 1.60 (d, J = 7.1Hz, 3H).

[0337] Step B: Preparation of Compound 2

[0338] Compound 2 was prepared by referring to the method of step E of example 1.

[0339] HRMS (ESI, [M+H] + ): m / z = 438.1599.

[0340] 1 H NMR (500MHz, DMSO-d6) δ8.88 (d, J=7.8Hz, 1H), 8.76 (d, J=13.6Hz, 1H), 7.91 (s, 1H), 7.82 (t, J=7.8Hz, 1H), 7.65-7.57 (m, 2H ), 7.15 (d, J=4.8Hz, 1H), 5.70 (p, J=7.1Hz, 1H), 3.99 (s, 3H), 2.42 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.66 (d, J=7.1Hz, 3H).

[0341] Example 3: Preparation of Compound 3

[0342]

[0343] Step A: Preparation of compound 3-1

[0344] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethane-1-ol to prepare compound 3-1.

[0345] MS (ESI, [M+H] + ): m / z = 499.95.

[0346] 1H NMR (500MHz, DMSO-d6) δ 8.87 (s, 1H), 8.37 (d, J = 7.8Hz, 1H), 7.63 (s, 1H), 7.57 (d, J = 7.7Hz, 1H), 7.44 (t, J = 7.7Hz, 1H), 7.38 (d .

[0347] Step B: Preparation of Compound 3

[0348] Compound 3 was prepared by referring to the method of step E of example 1.

[0349] HRMS (ESI, [M+H] + ): m / z = 450.1728.

[0350] 1 H NMR (500MHz, DMSO-d6) δ8.88 (d, J=7.9Hz, 1H), 8.76 (d, J=13.6Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=7.6Hz, 1H), 7.48 (t, J=7.7Hz, 1H), 7.42 (d, J=7.7Hz, 1H ), 7.15 (d, J=4.7Hz, 1H), 5.75-5.64 (m, 2H), 4.00 (s, 3H), 3.88 (td, J=14.1 , 4.3Hz, 2H), 2.44 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.65 (d, J=7.1Hz, 3H).

[0351] Example 4: Preparation of Compound 4

[0352]

[0353] Step A: Preparation of Compound 4-1

[0354] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-amine to prepare compound 4-1.

[0355] MS (ESI, [M+H] + ): m / z = 484.4.

[0356] 1H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.46 (d, J = 7.3Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.38 (d, J = 7.5Hz, 1H), 7.30 (dd, J = 13.8, 6.1Hz, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 5.73 (p, J=7.0Hz, 1H), 3.91 (s, 3H), 2.55 (s, 3H), 2.33 (s, 3H), 1.52 (d, J=7.0Hz, 3H).

[0357] Step B: Preparation of Compound 4

[0358] Compound 4 was prepared by referring to the method of step E of example 1.

[0359] MS (ESI, [M+H] + ): m / z = 434.17.

[0360] 1 H NMR (500MHz, CDCl3) δ8.41 (d, J=13.8Hz, 1H), 7.54 (d, J=7.8Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 7.28-7.27 (m, 1H), 7.12 (d, J=5.0Hz, 1H), 6.83 (t, J=5 5.5Hz, 1H), 6.32 (d, J=6.9Hz, 1H), 5.85 (p, J=6.9Hz, 1H), 3.96 (s, 3H), 2.54 (d, J=2.2Hz, 6H), 1.79 (dd, J=13.9, 2.7Hz, 6H), 1.60 (d, J=6.9Hz, 3H).

[0361] Example 5: Preparation of Compound 5

[0362]

[0363] Step A: Preparation of Compound 5-1

[0364] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethane-1-amine to prepare compound 5-1.

[0365] MS (ESI, [M+H] + ): m / z = 502.25.

[0366] 1H NMR (500MHz, CDCl3) δ8.14 (s, 1H), 7.50-7.41 (m, 2H), 7.14 (t, J=7.7Hz, 1H), 7.06 (s, 1H) , 5.88-5.68 (m, 2H), 3.96 (s, 3H), 2.52 (s, 3H), 2.02 (td, J=1.1, 18.6Hz, 3H), 1.70 (s, 3H).

[0367] Step B: Preparation of Compound 5

[0368] Compound 5 was prepared by referring to the method of step E of example 1.

[0369] MS (ESI, [M+H] + ): m / z = 452.5.

[0370] 1 H NMR (500MHz, CDCl3) δ8.48 (d, J=13.8Hz, 1H), 7.51-7.46 (m, 1H), 7.43 (td, J=1.7, 7.5Hz, 1H), 7.15-7.09 (m, 2H), 6.44 (d, J=7. 2Hz, 1H), 5.85 (p, J=7.0Hz, 1H), 3.97 (s, 3H), 2.52 (s, 3H), 2.07-1.97 (m, 3H), 1.82 (s, 3H), 1.79 (s, 3H), 1.66 (d, J=7.0Hz, 3H).

[0371] Example 6: Preparation of Compound 6

[0372]

[0373] Step A: Preparation of Compound 6-1

[0374]

[0375] Step a: Preparation of compound 6-1-1

[0376] Add ethyl 2-(3-bromophenyl)acetate (10 g) and anhydrous tetrahydrofuran (100 mL) to a 250 mL three-necked flask, and cool to -78 ° C under nitrogen protection. Add lithium bistrimethylsilylamide (103 mL, 1 mol / L) dropwise to the reaction solution, react for 30 min, and maintain -78 ° C. Then slowly add a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (25.9 g) in anhydrous tetrahydrofuran (50 mL) to the reaction system, and after the addition is complete, return to room temperature and continue stirring to react for 2 h. After the reaction is completed, add water (100 mL) to the reaction solution and stir vigorously, then extract twice with ethyl acetate (100 mL), spin dry, and silica gel column chromatography (petroleum ether: ethyl acetate = 97: 3) to obtain 10.1 g of compound 6-1-1.

[0377] 19 F-NMR(471MHz, Methanol-d4)δ-105.17-105.60(m).

[0378] 1 H-NMR (500MHz, Methanol-d4) δ7.76-7.69 (m, 2H), 7.57 (m, 1H), 7.44 (m, 1H), 4.31 (m, 2H), 1.28 (t, J=7.1Hz, 3H).

[0379] Step b: Preparation of compound 6-1-2

[0380] Add compound 6-1-1 (9 g) obtained in step a and anhydrous tetrahydrofuran (200 mL) to a 500 mL three-necked flask, and cool to -78 ° C under nitrogen protection. Slowly add methylmagnesium bromide (22 mL, 3 mol / L) to the reaction solution and add it dropwise. Return to 0 ° C and continue stirring the reaction for 1 h. After the reaction is completed, add saturated aqueous ammonium chloride solution (100 mL) to the reaction solution and stir vigorously, then extract twice with ethyl acetate (100 mL), combine the organic phases, wash with water (100 mL) once, dry over anhydrous sodium sulfate, and spin dry to obtain 7.0 g of compound 6-1-2.

[0381] Step c: Preparation of compound 6-1-3

[0382] Add compound 6-1-2 (6.8 g) obtained in step b, 1,4-dioxane (150 mL), tributyl(1-ethoxyethylene)tin (18.53 g), bistriphenylphosphine palladium dichloride (1.811 g), and triethylamine (7.77 g) to a 250 mL three-necked flask, and heat to 100 ° C in an oil bath under nitrogen protection for 3 h. Cool down and spin dry to obtain 20.0 g of compound 6-1-3.

[0383] MS (ESI, [M+H] +): m / z = 257.1.

[0384] Step d: Preparation of compound 6-1-4

[0385] Add compound 6-1-3 (20 g) obtained in step c, tetrahydrofuran (20 mL), and dilute hydrochloric acid (19 mL, 4 mol / L) to a 250 mL single-mouth bottle and react at room temperature for 2.5 h. After the reaction is completed, add water (200 mL) to the reaction solution and stir vigorously, then extract once with ethyl acetate (100 mL), spin dry, and silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 3.3 g of compound 6-1-4.

[0386] MS (ESI, [M+H] + ): m / z = 229.1.

[0387] 1 H NMR (500MHz, DMSO-d6) δ 8.14-8.04 (m, 1H), 8.02 (d, J = 1.8Hz, 1H), 7.79-7.69 (m, 1H), 7.63 (t, J = 7.8Hz, 1H), 2.62 (s, 3H), 1.18 (d, J = 1.5Hz, 6H).

[0388] Step e: Preparation of compound 6-1-5

[0389] Compound 6-1-4 (3 g) obtained in step d, tetrahydrofuran (30 mL), (S)-2-methylpropane-2-sulfenamide (2.390 g), and tetraethyl titanate (8.99 g) were added to a 100 mL three-necked flask, and the mixture was heated to 80° C. in an oil bath under nitrogen protection for 4.5 h. After the reaction was completed, water (50 mL) was added to the reaction solution and stirred vigorously, filtered, and the filter cake was washed three times with ethyl acetate (20 mL). The organic phase was separated, dried by spin drying, and chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain 4.2 g of compound 6-1-5.

[0390] MS (ESI, [M+H] + ): m / z = 332.2.

[0391] 1 H NMR (500MHz, Methanol-d4) δ8.13 (s, 1H), 8.05 (d, J=7.9Hz, 1H), 7.75-7.650 (m, 1H), 7.55 (t, J=7.8Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H), 1.28-1.23 (m, 6H).

[0392] Step f: Preparation of compound 6-1-6

[0393] Compound 6-1-5 (4.2 g) obtained in step e and anhydrous tetrahydrofuran (40 mL) were added to a 100 mL three-necked flask, cooled to -78°C, and lithium tri-sec-butyl borohydride (28.4 mL, 1 mol / L) was added dropwise to the reaction system, and the mixture was stirred at -78°C for 2 h. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution and stirred vigorously for 2 min, the temperature was raised to room temperature, the stratification was allowed to stand, the organic phase was separated, spin-dried, and silica gel column chromatography (dichloromethane: methanol = 98: 2) was performed to obtain 2.5 g of compound 6-1-6.

[0394] MS (ESI, [M+H] + ): m / z = 334.0.

[0395] 1 H NMR (500MHz, Methanol-d4) δ7.53 (d, J=1.9Hz, 1H), 7.47-7.35 (m, 3H), 4.59-4.49 (m, 1H), 1.55 (d, J=6.8Hz, 3H), 1.24 (d, J=1.2Hz, 6H), 1.20 (s, 9H).

[0396] Step g: Preparation of compound 6-1

[0397] Add compound 6-1-6 (2.3 g) obtained in step e and 1,4-dioxane hydrochloric acid solution (8 mL, 4 mol / L) into a 100 mL single-mouth bottle and react at room temperature for 2 h. After the reaction is completed, spin dry to obtain 2.0 g of compound 6-1.

[0398] 1 H NMR (500MHz, Methanol-d4) δ7.63 (d, J=1.8Hz, 1H), 7.63-7.53 (m, 2H), 7.54 (d, J=6.4Hz, 1H), 4.58-4.48 (m, 1H), 1.66 (d, J=6.9Hz, 3H), 1.26 (d, J=1.6Hz, 6H).

[0399] Step B: Preparation of compound 6-2

[0400] Referring to the method of step D of Example 1, compound 1-3 was reacted with compound 6-1 obtained in step A to prepare compound 6-2.

[0401] MS (ESI, [M+H] + ): m / z = 527.98.

[0402] Step C: Preparation of Compound 6

[0403] Compound 6 was prepared by referring to the method of step E of example 1.

[0404] MS (ESI, [M+H] + ): m / z = 478.09.

[0405] 1 H NMR (500MHz, Methanol-d4) δ8.58 (d, J=14.0Hz, 1H), 7.62 (s, 1H), 7.55 (t, J=4.2Hz, 1H), 7.38 (d, J=4.8Hz, 2H), 7.09 ( d, J=5.0Hz, 1H), 5.75-5.650 (m, 1H), 4.02 (s, 3H), 2.46 (s, 3H), 1.89-1.79 (m, 6H), 1.68 (d, J=7.0Hz, 3H), 1.21 (s, 6H).

[0406] Example 7: Preparation of Compound 7

[0407]

[0408] Step A: Preparation of Compound 7-1

[0409] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine to prepare compound 7-1.

[0410] MS (ESI, [M+H] + ): m / z = 532.89.

[0411] 1 H NMR (500MHz, DMSO-d6) δ8.82 (s, 1H), 8.61 (s, 1H), 8.48 (d, J = 7.3Hz, 1H), 8.33 (d, J = 11.2Hz , 2H), 7.04 (s, 1H), 5.65 (p, J=7.0Hz, 1H), 3.92 (s, 3H), 2.34 (s, 3H), 1.65 (d, J=7.1Hz, 3H).

[0412] Step B: Preparation of compound 7-2

[0413] Referring to the method of step E of example 1, compound 7-2 was prepared.

[0414] MS (ESI, [M+H] + ): m / z = 483.08.

[0415] 1H NMR (500MHz, DMSO-d6) δ8.92 (d, J=7.6Hz, 1H), 8.76-8.73 (m, 2H), 8.41-8.39 (m, 2H), 7.16 (d , J=4.7Hz, IH), 5.72 (p, J=7.1Hz, 1H), 3.98 (d, J=9.8Hz, 3H), 2.41 (s, 3H), 1.79-1.70 (m, 9H).

[0416] Step C: Preparation of Compound 7

[0417] Compound 7-2 (100 mg) obtained in step B, tetrahydrofuran (15 mL) and water (5.00 mL) were added to a 50 mL three-necked flask, and ammonium chloride (444 mg) and zinc powder (203 mg) were added thereto with stirring at room temperature. The reaction flask was placed in an oil bath at 70°C and stirred for 5 h. The reaction was stopped, the reaction solution was cooled to room temperature, saturated brine (15 mL) was added to the reaction solution, and ethyl acetate (15 mL×2) was used for extraction, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column (methanol: dichloromethane=7:93) to obtain 32 mg of compound 7.

[0418] HRMS (ESI, [M+H] + ): m / z = 453.1675.

[0419] 1 H NMR (500MHz, CDCl3) δ8.55 (d, J=13.9Hz, 1H), 7.14 (d, J=5.1Hz, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 6.78 (s, 1H), 6 .69 (s, 1H), 5.62-5.59 (m, 1H), 3.97 (s, 3H), 2.56 (s, 3H), 1.79 (dd, J=13.8, 1.7Hz, 6H), 1.61 (d, J=7.0Hz, 3H).

[0420] Example 8: Preparation of Compound 8

[0421]

[0422] Step A: Preparation of Compound 8-1

[0423] Referring to the method of step D of Example 1, compound 1-3 was reacted with (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethane-1-amine to prepare compound 8-1.

[0424] MS (ESI, [M+H] + ): m / z = 546.88.

[0425] 1 H NMR (500MHz, CD3OD) δ8.77 (s, 1H), 8.57 (d, J = 2.3Hz, 1H), 8.34 (d, J = 2.3Hz, 1H), 6.94 (s, 1H), 5. 75 (q, J=7.0Hz, 1H), 4.87 (s, 1H), 3.96 (s, 3H), 2.81 (s, 3H), 2.35 (s, 3H), 1.65 (d, J=7.1Hz, 3H).

[0426] Step B: Preparation of compound 8-2

[0427] Referring to the method of step E of example 1, compound 8-2 was prepared.

[0428] MS (ESI, [M+H] + ): m / z = 497.08.

[0429] 1 H NMR (500MHz, CD3OD) δ8.65 (d, J=14.0Hz, 1H), 8.60 (d, J=2.3Hz, 1H), 8.35 (d, J=2.3Hz, 1H), 5.80 (q, J=7.0Hz, 1H), 4.02 (s, 3H), 2.82 (s, 3H), 2.39 (s, 3H), 1.86 (d, J=14.0Hz, 6H), 1.69 (d, J=7.0Hz, 3H).

[0430] Step C: Preparation of Compound 8

[0431] In a 25 mL single-mouth bottle, compound 8-2 (0.16 g), methanol (10 mL), water (2 mL) and tetrahydroxydiboron (0.231 g) obtained in step B were added in sequence, stirred for 10 min, and a solution of sodium hydroxide (0.129 g) in water (2 mL) was added thereto, and stirred overnight at room temperature. The reaction solution was poured into water (20 mL), the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, ethyl acetate (10 mL) was added for separation, the organic phase was taken, the aqueous phase was extracted with ethyl acetate (10 mL × 2), the organic phases were combined and washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 120 mg of compound 8.

[0432] MS (ESI, [M+H] + ): m / z = 467.16.

[0433] 1H NMR (500MHz, CD3OD) δ8.61 (s, 1H), 7.08 (d, J = 5.1Hz, 1H), 7.04 (d, J = 2.2Hz, 1H), 6.90 (d, J = 2.4Hz, 1H), 5.75 (q, J = 6.9Hz, 1H), 4.86 (s, 3H), 4.01 (s, 3H), 2.45 (t, J=2.9Hz, 6H), 1.84 (dd, J=14.0, 4.3Hz, 6H), 1.59 (d, J=7.0Hz, 3H).

[0434] Example 9: Preparation of Compound 9

[0435]

[0436] Step A: Preparation of compound 9-1

[0437] 5-Amino-2-chloroisonicotinic acid (15 g), ammonium acetate (67.0 g), triethyl orthoacetate (141 g) and methanol (100 mL) were added to a 500 mL pressure bottle, and the mixture was stirred in an oil bath at 125°C for 9 h. The reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (50 mL), and the solid was collected and dried to obtain 8.1 g of compound 9-1.

[0438] MS (ESI, [MH] - ): m / z = 194.1.

[0439] 1 H NMR (500MHz, DMSO-d6) δ8.79 (s, 1H), 7.90 (s, 1H), 2.38 (s, 3H).

[0440] Step B: Preparation of compound 9-2

[0441] Compound 9-1 (10 g) obtained in step A, 2,4,6-triisopropylbenzenesulfonyl chloride (18.58 g), triethylamine (15.52 g), 4-dimethylaminopyridine (0.625 g) and dichloromethane (100 mL) were added to a 250 mL single-mouth bottle, and the mixture was stirred at room temperature for overnight reaction. The reaction was stopped, the reaction solution was poured into water (50 mL), separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 85: 15) to obtain 9.7 g of compound 9-2.

[0442] Step C: Preparation of Compound 9-3

[0443] Compound 9-2 (3 g) obtained in step B, (R)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride (1.76 g), N,N-diisopropylethylamine (2.52 g) and 1,4-dioxane (20 mL) were added to a 25 mL single-mouth bottle, and the mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was stopped, the reaction solution was poured into water (100 mL), extracted with dichloromethane (30 mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 85:15) to obtain 2.2 g of compound 9-3.

[0444] MS (ESI, [M+H] + ): m / z = 367.26.

[0445] 1 H NMR (500MHz, DMSO-d6) δ8.87-8.80 (m, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 7.78-7.76 (t, J=6 .6Hz, 1H), 7.62-7.56 (m, 2H), 5.62 (p, J=7.1Hz, 1H), 2.43 (s, 3H), 1.63 (d, J=7.1Hz, 3H).

[0446] Step D: Preparation of compound 9

[0447] Compound 9 was prepared by referring to the method of step E of example 1.

[0448] MS (ESI, [M+H] + ): m / z = 409.4.

[0449] 1 H NMR (500MHz, DMSO-d6) δ9.25 (d, J=7.6Hz, 1H), 9.09 (s, 1H), 8.93 (d, J=6.4Hz, 1H), 7.86 (s, 1H), 7.79 (d, J=7.3Hz, 1 H), 7.59 (dt, J=15.2, 7.7Hz, 2H), 5.67 (p, J=7.0Hz, 1H), 2.47 (s, 3H), 1.72 (d, J=13.5Hz, 6H), 1.64 (d, J=7.1Hz, 3H).

[0450] Example 10: Preparation of Compound 10

[0451]

[0452] Step A: Preparation of Compound 10-1

[0453] Compound 7-1 (1.1 g) obtained in step A of Example 7, 1-benzyl-1,4-azaphosphane 4-oxide (0.441 g), triethylamine (0.294 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.113 g), tris(dibenzylideneacetone) dipalladium (0.090 g) and 1,4-dioxane (10 mL) were added to a 25 mL three-necked flask, and stirred at 100° C. for 1 h under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 95: 5) to obtain 0.94 g of compound 10-1.

[0454] MS (ESI, [M+H] + ): m / z = 614.40.

[0455] 1 H NMR (500MHz, DMSO-d6) δ8.86 (d, J=7.5Hz, 1H), 8.72-8.65 (m, 2H), 8.35-8.34 (m, 2H), 7.40-7.34 (m, 4H), 7.30-7.26 (m, 1H), 7.14 (d, J=4.7Hz, 1H), 5.68 (p , J=7.1Hz, 1H), 3.99 (s, 3H), 3.69 (s, 2H), 3.04-2.96 (m, 2H), 2.88-2.82 (m, 2 H), 2.48-2.45 (m, 2H), 2.37 (s, 3H), 1.83-1.76 (m, 2H), 1.67 (d, J=7.1Hz, 3H).

[0456] Step B: Preparation of compound 10-2

[0457] Add compound 10-1 (0.699 g) obtained in step A and 1,2-dichloroethane (10 mL) to a 25 mL three-necked flask and stir in an ice-water bath. Add 1-chloroethyl chloroformate (0.195 g) and reflux the mixture for 2 h. Concentrate the reaction solution to dryness, add methanol (5 mL) to the residue, heat reflux and stir for 15 min. Concentrate the reaction solution to dryness, and chromatograph the residue on a silica gel column (dichloromethane: methanol = 94: 6) to obtain 348 mg of compound 10-2.

[0458] MS (ESI, [M+H] + ): m / z = 524.07.

[0459] 1H NMR (500MHz, DMSO-d6) δ8.85 (d, J=7.5Hz, 1H), 8.71-8.65 (m, 2H), 8.35 (d, J=6.7Hz, 2H), 7.12 (d, J=4.6Hz, 1H), 5. 68 (p, J=7.1Hz, 1H), 3.96 (s, 3H), 3.20-3.06 (m, 4H), 2.42-2.30 (m, 5H), 1.80-1.70 (m, 2H), 1.68 (d, J=7.1Hz, 3H).

[0460] Step C: Preparation of Compound 10-3

[0461] Compound 10-2 (150 mg) obtained in step B, tetrahydrofuran (1 mL), triethylamine (87 mg) and acetic anhydride (32.2 mg) were added to a 10 mL single-mouth bottle, and the reaction solution was stirred at room temperature for 1 h. Water (10 mL) was added to the reaction solution, stirred at room temperature for 5 min, extracted with dichloromethane (15 mL×2), dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column (dichloromethane: methanol = 96: 4) to obtain 144 mg of compound 10-3.

[0462] MS (ESI, [M+H] + ): m / z = 566.03.

[0463] 1 H NMR (500MHz, DMSO-d6) δ8.91 (dd, J=7.2, 5.3Hz, 1H), 8.70 (dd, J=13.8, 5.1Hz, 1H), 8. 67 (s, 1H), 8.35 (d, J=6.1Hz, 2H), 7.12 (d, J=4.8Hz, 1H), 5.69-5.67 (m, 1H), 4.46 (dd, J =25.9, 13.2Hz, 1H), 4.12-4.00(m, 1H), 3.91(s, 3H), 3.74-3.72(m, 1H), 3.32-3.27(m , 1H), 2.48-2.39 (m, 1H), 2.39-2.30 (m, 4H), 1.98-1.79 (m, 2H), 1.68 (d, J=7.1Hz, 3H).

[0464] Step D: Preparation of Compound 10

[0465] Compound 10-3 (114 mg) obtained in step C, tetrahydrofuran (1.5 mL) and ethanol (4.5 mL) were added to a 25 mL three-necked flask, and stannous chloride dihydrate (182 mg) was added under stirring at room temperature, and the reaction flask was placed in a 50°C oil bath and stirred for 1 h. The reaction was stopped, and the reaction solution was concentrated to dryness and separated and purified on a silica gel column (dichloromethane: methanol = 94: 6) to obtain 89 mg of compound 10.

[0466] HRMS (ESI, [M+H] + ): m / z = 536.2073.

[0467] 1 H NMR (500MHz, DMSO-d6) δ8.76 (d, J=7.5Hz, 1H), 8.68 (d, J=13.8Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 6.91 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.61-5.50 (m, 3H), 4.45- 4.30(m, 1H), 4.04-3.96(m, 1H), 3.91(s, 3H), 3.77-3.67(m, 1H), 3.40-3.35(m, 1H), 2.48-2.29(m, 5H), 2.12(s, 3H), 2.03-1.81(m, 2H), 1.55(d, J=7.1Hz, 3H).

[0468] Example 11: Preparation of Compound 11

[0469]

[0470] Step A: Preparation of Compound 11-1

[0471] Referring to the method of step A of example 10, compound 11-1 was prepared using compound 2-1 obtained in step A of example 2.

[0472] HRMS (ESI, [M+H] + ): m / z = 569.2283.

[0473] 1H NMR (500MHz, DMSO-d6) δ8.78 (d, J=7.7Hz, 1H), 8.69 (d, J=13.6Hz, 1H), 7.84 (s, 1H), 7.77 (d, J=7.1Hz, 1H), 7.59-7.54 (m, 2H), 7.39-7.34 (m, 4H), 7.31-7.24 (m, 1H), 7.13 (d, J=4.6 Hz, 1H), 5.66 (p, J=7.1Hz, 1H), 3.99 (s, 3H), 3.67 (s, 2H), 3.00-2.92 (m, 2H), 2.85 (q, J=11 .5Hz, 2H), 2.48-2.45 (m, 2H), 2.38 (s, 3H), 1.82 (t, J=16.1Hz, 2H), 1.62 (d, J=7.1Hz, 3H).

[0474] Step B: Preparation of compound 11-2

[0475] Referring to the method of step B of Example 10, compound 11-2 was prepared.

[0476] HRMS (ESI, [M+H] + ): m / z = 479.1814.

[0477] 1 H NMR (500MHz, DMSO-d6) δ8.80 (d, J=7.7Hz, 1H), 8.68 (d, J=13.6Hz, 1H), 7.84 (s, 1H), 7.78 (d, J=7.1Hz, 1H), 7.60-7.55 (m, 2H), 7.11 (d, J=4.6Hz, 1H), 5.67 (p, J=7.1Hz, 1H), 3.96 (s, 3H), 3.17-3.06 (m, 4H), 2.43-2.34 (m, 5H), 1.79 (t, J=16.1Hz, 2H), 1.62 (d, J=7.1Hz, 3H).

[0478] Step C: Preparation of Compound 11

[0479] Compound 11 was prepared by referring to the method of step C of example 10.

[0480] HRMS (ESI, [M+H] + ): m / z = 521.1961.

[0481] 1H NMR (500MHz, DMSO-d6) δ8.83 (dd, J=7.6, 2.3Hz, 1H), 8.70 (dd, J=13.8, 3.5Hz, 1H), 7.84 (s , 1H), 7.77 (d, J=6.7Hz, 1H), 7.61-7.53 (m, 2H), 7.12 (d, J=4.8Hz, 1H), 5.71-5.62 (m, 1H), 4 .46-4.37(m, 1H), 4.09-3.97(m, 1H), 3.91(s, 3H), 3.76-3.71(m, 1H), 3.32-3.30(m, 1H), 2. 48-2.39 (m, 1H), 2.39-2.30 (m, 4H), 2.12 (s, 3H), 1.99-1.80 (m, 2H), 1.62 (d, J=7.1Hz, 3H).

[0482] Example 12: Preparation of Compound 12

[0483]

[0484] Step A: Preparation of Compound 12-1

[0485] Referring to the method of step A of example 10, compound 12-1 was prepared using compound 4-1 obtained in step A of example 4.

[0486] MS (ESI, [M+H] + ): m / z = 565.55.

[0487] 1 H NMR (500MHz, DMSO-d6) δ8.95 (s, 1H), 8.73 (d, J=13.6Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.41-7.33 (m, 5H), 7.33-7.20 (m, 3H), 7.11 (d, J=4.7Hz, 1H), 5.80- 5.73 (m, 1H), 3.98 (s, 3H), 3.69 (s, 2H), 2.91 (dd, J=56.9, 16.5Hz, 4H), 2.55 (s, 3H), 2.49-2.43 (m, 2H), 2.36 (s, 3H), 1.84 (s, 2H), 1.54 (d, J=7.0Hz, 3H).

[0488] Step B: Preparation of compound 12-2

[0489] Referring to the method of step B of Example 10, compound 12-2 was prepared.

[0490] MS (ESI, [M+H] +): m / z = 475.18.

[0491] 1 H NMR (500MHz, DMSO-d6) δ8.86 (d, J=7.3Hz, 1H), 8.70 (d, J=13.5Hz, 1H), 7.71 (d, J=7.7Hz, 1H), 7.38 (d, J=7.5Hz, 1H), 7.34-7.18 (m, 2H), 7.13-7.06 (m, 1 H), 5.76 (p, J=6.9Hz, 1H), 3.95 (s, 3H), 3.17-3.06 (m, 4H), 2.55 (s, 3H), 2.4 3-2.36 (m, 2H), 2.35 (s, 3H), 1.77 (d, J=18.6Hz, 2H), 1.54 (d, J=7.0Hz, 3H).

[0492] Step C: Preparation of Compound 12

[0493] Compound 12 was prepared by referring to the method of step C of Example 10.

[0494] MS (ESI, [M+H] + ): m / z = 517.12.

[0495] 1 H NMR (500MHz, CDCl3) δ8.47 (d, J=14.1Hz, 1H), 7.55 (d, J=7.5Hz, 1H), 7.43 (d, J=7.6Hz, 1H ), 7.27 (s, 1H), 7.10 (d, J=5.3Hz, 1H), 6.82 (t, J=55.5Hz, 1H), 6.46-6.45 (m, 1H), 5.87-5. 83(m, 1H), 4.96-4.87(m, 1H), 4.18-4.10(m, 1H), 3.93(s, 3H), 3.91-3.88(m, 1H), 2.54(d , J=5.1Hz, 6H), 2.51-2.40 (m, 2H), 2.22 (s, 3H), 2.19-2.05 (m, 2H), 1.61 (d, J=6.8Hz, 3H).

[0496] Example 13: Preparation of Compound 13

[0497]

[0498] Referring to the method of step C of example 10, compound 12-2 was reacted with N,N-dimethylglycine to prepare compound 13.

[0499] MS (ESI, [M+H] +): m / z = 560.11.

[0500] 1 H NMR (500MHz, CDCl3) δ8.53 (d, J=14.0Hz, 1H), 7.59-7.53 (m, 1H), 7.43 (d, J=7.6Hz, 1H), 7.30- 7.23 (m, 1H), 7.09 (d, J=5.2Hz, 1H), 6.83 (t, J=55.5Hz, 1H), 6.61-6.56 (m, 1H), 5.89-5.82 (m, 1H), 4.99-4.91(m, 1H), 4.52-4.44(m, 1H), 3.90(s, 3H), 3.83-3.77(m, 1H), 3.38-3.35(m, 1H) , 3.10-3.07(m, 1H), 2.60-2.46(m, 8H), 2.34(s, 6H), 2.30-2.23(m, 2H), 1.61(d, J=6.9Hz, 3H).

[0501] Example 14: Preparation of Compound 14

[0502]

[0503] Referring to the method of step C of Example 10, compound 12-2 was reacted with cyclopropanecarboxylic acid to prepare compound 14.

[0504] MS (ESI, [M+H] + ): m / z = 543.10.

[0505] 1 H NMR (500MHz, CDCl3) δ8.47 (d, J=14.1Hz, 1H), 7.55 (d, J=7.7Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 7.30-7.23 (m, 1H), 7.09 (d, J=5.2Hz, 1H), 6.83 (t, J=55.5Hz, 1H), 6.47-6.42 (m, 1 H), 5.89-5.81(m, 1H), 4.92-4.84(m, 1H), 4.62-4.47(m, 1H), 4.02-3.93(m, 1H), 3.91( s, 3H), 2.61-2.48 (m, 8H), 2.06-1.89 (m, 3H), 1.61 (d, J=6.9Hz, 3H), 1.11-1.02 (m, 4H).

[0506] Example 15: Preparation of Compound 15

[0507]

[0508] Step A: Preparation of Compound 15-1

[0509] Referring to the method of Example 10, step A, compound 15-1 was prepared.

[0510] MS (ESI, [M+H] + ): m / z = 583.1.

[0511] 1 H NMR (500MHz, CDCl3) δ8.57 (dd, J=3.6, 13.9Hz, 1H), 7.48 (d, J=6.4Hz, 1H), 7.42 (t, J=7.4Hz, 1H), 7.39-7.34 ( m, 4H), 7.31-7.27 (m, 1H), 7.14-7.07 (m, 2H), 6.66 (d, J = 7.6Hz, 1H), 5.84 (p, J = 7.1Hz, 1H), 4.02 (d, J = 1.3Hz, 3H), 3.73-3.69 (m, 2H), 3.16 (dd, J=12.3, 29.5Hz, 2H), 2.99 (dt, J=9.6, 19.6Hz, 2H), 2.62 (td, J=6.0, 12.7, 1 3.2Hz, 2H), 2.52 (s, 3H), 2.02 (t, J=18.6Hz, 3H), 1.78 (ddt, J=2.9, 14.8, 20.3Hz, 2H), 1.65 (d, J=7.0Hz, 3H).

[0512] Step B: Preparation of compound 15-2

[0513] Referring to the method of step B of Example 10, compound 15-2 was prepared.

[0514] MS (ESI, [M+H] + ): m / z = 493.08.

[0515] 1H NMR (500MHz, CDCl3) δ8.56 (d, J=13.9Hz, 1H), 7.52-7.47 (m, 1H), 7.42 (t, J=7. 4Hz, 1H), 7.12 (t, J=7.0Hz, 2H), 6.60 (s, 1H), 5.84 (p, J=7.0Hz, 1H), 4.00 (s, 3 H), 3.40 (ddd, J=3.2, 9.3, 21.8Hz, 4H), 2.52 (s, 5H), 2.02 (t, J=18.6Hz, 3H), 1 .85 (ddt, J=2.8, 14.6, 20.0Hz, 2H), 1.66 (d, J=7.0Hz, 3H), 1.34-1.20 (m, 1H).

[0516] Step C: Preparation of Compound 15

[0517] Compound 15 was prepared by referring to the method of step C of Example 10.

[0518] MS (ESI, [M+H] + ): m / z = 535.13.

[0519] 1 H NMR (500MHz, CDCl3) δ8.55 (dd, J=3.3, 14.2Hz, 1H), 7.49 (q, J=6.8Hz, 1H), 7.46-7.40 (m, 1H), 7.12 (dd, J=6.3, 11.4Hz, 2H), 6.65 (dd, J=4.3, 7.3Hz, 1H), 5.84 (pd, J=2.7, 6.7Hz, 1H), 4.92 (dd, J=13.7, 28.7Hz, 1H), 4.20-4. 08 (m, 1H), 3.93 (s, 3H), 3.89 (dd, J=6.6, 13.9Hz, 1H), 3.36 (td, J=6.6, 13.0Hz, 1H), 2.52 (d, J=1.9Hz, 3H), 2.4 5 (dp, J=4.7, 13.9Hz, 1H), 2.23 (s, 4H), 2.02 (t, J=18.6Hz, 3H), 1.97-1.82 (m, 2H), 1.67 (dd, J=1.7, 7.0Hz, 3H).

[0520] Example 16: Preparation of Compound 16

[0521]

[0522] Referring to the method of step C of example 10, compound 15-2 was reacted with N,N-dimethylglycine to prepare compound 16.

[0523] MS (ESI, [M+H] + ): m / z = 578.14.

[0524] 1 H NMR (500MHz, CDCl3) δ8.55 (dd, J=4.3, 14.2Hz, 1H), 7.49 (q, J=7.5Hz, 1H), 7.43 (t, J=7.4Hz, 1H), 7.12 (d, J =5.4Hz, 2H), 6.56 (d, J=6.6Hz, 1H), 5.85 (td, J=3.3, 7.1Hz, 1H), 4.96 (dd, J=13.6, 29.1Hz, 1H), 4.48 (dd, J= 14.0, 27.4Hz, 1H), 3.91 (s, 3H), 3.81 (td, J=6.1, 13.3Hz, 1H), 3.40-3.32 (m, 2H), 3.09 (d, J=13.2Hz, 1H), 2 .58-2.49 (m, 5H), 2.35 (s, 6H), 2.02 (t, J=18.6Hz, 3H), 1.88 (q, J=12.4, 13.7Hz, 2H), 1.67 (d, J=7.0Hz, 3H).

[0525] Example 17: Preparation of Compound 17

[0526]

[0527] Referring to the method of step C of Example 10, compound 15-2 was reacted with cyclopropanecarboxylic acid to prepare compound 17.

[0528] MS (ESI, [M+H] + ): m / z = 561.11.

[0529] 1H NMR (500MHz, CDCl3) δ8.56 (d, J=14.2Hz, 1H), 7.58-7.38 (m, 2H), 7.18-7.06 (m, 2H), 6.63 (d, J= 7.0Hz, 1H), 5.85 (p, J=7.0Hz, 1H), 4.88 (dd, J=13.2, 28.4Hz, 1H), 4.54 (dd, J=15.2, 26.9Hz, 1H ), 3.96 (s, 1H), 3.92 (s, 3H), 2.61-2.54 (m, 2H), 2.52 (s, 3H), 2.03 (s, 2H), 1.86 (tt, J=4.5, 7.9 Hz, 2H), 1.67 (d, J=7.0Hz, 3H), 1.32-1.21 (m, 2H), 1.11 (s, 1H), 1.02 (s, 1H), 0.93-0.77 (m, 3H).

[0530] Example 18: Preparation of Compound 18

[0531]

[0532] Step A: Preparation of Compound 18-1

[0533] Referring to the method of step A of example 10, compound 18-1 was prepared using compound 8-1 obtained in step A of example 8.

[0534] MS (ESI, [M+H] + ): m / z = 628.18.

[0535] 1 H NMR (500MHz, CD3OD): δ8.65 (d, J=14.0Hz, 1H), 8.57 (d, J=2.3Hz, 1H), 8.35 (d, J=2.2Hz, 1H), 7. 39 (d, J=7.2Hz, 2H), 7.34 (dd, J=12.5, 4.8Hz, 3H), 7.28 (d, J=7.2Hz, 1H), 7.10 (d, J=4.8Hz, 1H), 5.79 (q, J=7.0Hz, 1H), 4.05 (s, 3H), 3.72 (s, 2H), 3.12 (dd, J=26.6, 12.6Hz, 2H), 3.02-2.90 (m, 2 H), 2.82 (s, 3H), 2.73-2.61 (m, 2H), 2.39 (s, 3H), 2.04 (t, J=15.7Hz, 2H), 1.68 (d, J=7.0Hz, 3H).

[0536] Step B: Preparation of compound 18-2

[0537] Referring to the method of step B of Example 10, compound 18-2 was prepared.

[0538] MS (ESI, [M+H] + ): m / z = 538.09.

[0539] Step C: Preparation of Compound 18-3

[0540] Referring to the method of step C of example 10, compound 18-3 was prepared.

[0541] MS (ESI, [M+H] + ): m / z = 580.07.

[0542] Step D: Preparation of Compound 18

[0543] Compound 18 was prepared by referring to the method of step C of example 8.

[0544] MS (ESI, [M+H] + ): m / z = 550.09.

[0545] 1 H NMR (500MHz, CD3OD): δ8.62 (d, J=14.3Hz, 1H), 7.08 (d, J=5.0Hz, 1H), 7.03 (s, 1H), 6.9 0 (s, 1H), 5.76 (dt, J=6.8, 5.0Hz, 1H), 4.86 (s, 3H), 4.70-4.54 (m, 1H), 4.25-4.12 (m, 1H ), 3.99 (s, 3H), 3.87 (dd, J=23.5, 11.3Hz, 1H), 3.50 (dd, J=23.2, 12.5Hz, 1H), 2.65-2.5 2 (m, 2H), 2.44 (d, J=5.8Hz, 6H), 2.23 (s, 3H), 2.16-1.99 (m, 2H), 1.59 (d, J=7.0Hz, 3H).

[0546] Example 19: Preparation of Compound 19

[0547]

[0548] Step A: Preparation of Compound 19-1

[0549] Compound 9-1 (0.13 g), N,N-dimethylformamide (1.3 mL), benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (0.45 g) and 1,8-diazabicycloundec-7-ene (0.152 g) were added sequentially into a 25 mL single-necked bottle. A mixed solution of (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (0.178 g) and 1,8-diazabicycloundec-7-ene (0.152 g) in N,N-dimethylformamide (1.3 mL) was added dropwise to the above mixture under stirring at room temperature. After the addition was completed, the mixture was stirred at 50°C overnight. After the reaction was completed, the reaction solution was poured into water (15 mL), extracted with ethyl acetate (30 mL), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 70: 30) to obtain 0.14 g of compound 19-1.

[0550] MS (ESI, [M+H] + )m / z=385.06.

[0551] 1 H NMR (500MHz, DMSO-d6) δ8.91 (d, J=6.8Hz, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 7.82 (t, J=6.9Hz, 1H) , 7.66 (t, J=7.2Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 5.72 (m, 1H), 2.38 (s, 3H), 1.63 (d, J=7.1Hz, 3H).

[0552] Step B: Preparation of compound 19-2

[0553] Compound 19-1 (0.14 g) obtained in step A, 1-benzyl-1,4-azaphosphine-4-oxide (0.075 g), N,N-diisopropylethylamine (0.070 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.021 g, 0.036 mmol), tris(dibenzylideneacetone)dipalladium (0.017 g, 0.018 mmol) and N,N-dimethylformamide (3 mL) were added to a 10 mL microwave tube. After nitrogen replacement, the microwave reactor was heated to 165° C. at 150 watts and reacted for 50 minutes. The mixture was filtered, the filtrate was poured into water (30 mL), extracted with ethyl acetate (30 mL×2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column (dichloromethane: methanol = 97: 3) to obtain 0.15 g of compound 19-2.

[0554] MS (ESI, [M+H] + )m / z=558.16.

[0555] 1 H NMR (500MHz, DMSO-d6) δ9.31 (d, J=6.9Hz, 1H), 9.13 (s, 1H), 8.99 (d, J=6.4Hz , 1H), 7.84 (t, J=7.0Hz, 1H), 7.66 (t, J=7.1Hz, 1H), 7.41-7.31 (m, 5H), 7.30- 7.24(m, 1H), 5.80-5.72(m, 1H), 3.66(s, 2H), 3.03-2.91(m, 2H), 2.83(q, J=1 2.0Hz, 2H), 2.45-2.32 (m, 5H), 1.92 (t, J=14.6Hz, 2H), 1.64 (d, J=7.1Hz, 3H).

[0556] Step C: Preparation of Compound 19-3

[0557] Compound 19-2 (0.15 g) obtained in step B and 1,2-dichloroethane (14 mL) were added to a 50 mL single-mouth bottle, and 1-chloroethyl chloroformate (0.077 g) was added dropwise under ice bath, and the mixture was heated to reflux for 2.5 h. The reaction solution was concentrated to dryness, and methanol (5 mL) was added to the residue and refluxed for 30 minutes. The reaction solution was concentrated to dryness to obtain 0.16 g of compound 19-3.

[0558] MS (ESI, [M+H] + )m / z=468.13.

[0559] 1 H NMR (500MHz, DMSO-d6) δ11.11 (s, 1H), 9.75-9.44 (m, 2H), 9.38 (s, 1H), 8.04 (t, J = 7.1Hz, 1H), 7.72 (t, J = 7.0Hz, 1H) , 7.50-7.27 (m, 2H), 5.96 (m, 1H), 3.56 (s, 2H), 3.38 (s, 2H), 2.83 (s, 2H), 2.53-2.41 (m, 4H), 1.74 (d, J=7.1Hz, 3H).

[0560] Step D: Preparation of Compound 19

[0561] Under ice-water bath, methanesulfonyl chloride (0.043 g) was added dropwise to a tetrahydrofuran (3.2 mL) solution of compound 19-3 (0.16 g) obtained in step C and triethylamine (0.104 g). After the addition was complete, the temperature was maintained for 2 h. The reaction solution was concentrated to dryness, water (10 mL) was added to the reaction solution, and dichloromethane (10 mL×3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by C18 column chromatography (acetonitrile: water = 40: 60) to obtain 86 mg of compound 19.

[0562] HRMS (ESI, [M+H] + )m / z=546.13611.

[0563] 1 H NMR (500MHz, CD3OD) δ9.11 (d, J=0.8Hz, 1H), 8.85 (dd, J=0.9, 6.8Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.54 (m, 1H), 7.28 (t, J=7.8Hz, 1H), 5 .85 (q, J=7.1Hz, 1H), 3.93 (m, 2H), 3.82-3.73 (m, 2H), 2.98 (s, 3H), 2.65 (m, 2H), 2.50 (s, 3H), 2.27-2.18 (m, 2H), 1.73 (d, J=7.1Hz, 3H).

[0564] 31 P NMR (202 MHz, CD3OD) δ 31.1.

[0565] Example 20: Preparation of Compound 20

[0566]

[0567] Step A: Preparation of Compound 20-1

[0568] Referring to the method of step B of Example 19, compound 20-1 was prepared.

[0569] MS (ESI, [M+H] + )m / z=369.09.

[0570] 1 H NMR (500MHz, DMSO-d6) δ12.80 (s, 1H), 9.14 (s, 1H), 8.42 (d, J=5.6Hz, 1H), 7.37-7.29 (m, 5H ), 3.63 (s, 2H), 2.95-2.76 (m, 4H), 2.44 (s, 3H), 2.41-2.31 (m, 2H), 1.94 (t, J=15.5Hz, 2H).

[0571] Step B: Preparation of Compound 20-2

[0572] Referring to the method of step A of Example 19, compound 20-1 was reacted with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to prepare compound 20-2.

[0573] MS (ESI, [M+H] + )m / z=540.16.

[0574] 1 H NMR (500MHz, CDCl3) δ9.18 (s, 1H), 8.78 (d, J=6.6Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.31 (m, 5H), 7.13 (t, J=7.7Hz, 1H), 6.89 (t, J=55.0Hz, 1H), 5.78 (p, J=7.1Hz, 1H), 3.67 (s, 2H), 3.05-3.00 (m, 4H), 2.57 (s, 4H), 2.05 (s, 3H), 1.68 (d, J=7.0Hz, 3H).

[0575] Step C: Preparation of Compound 20-3

[0576] Referring to the method of step C of example 19, compound 20-3 was prepared.

[0577] MS (ESI, [M+H] + )m / z=450.16.

[0578] Step D: Preparation of compound 20

[0579] Compound 20 was prepared by referring to the method of Step D of Example 19.

[0580] HRMS (ESI, [M+H] + )m / z=528.1443.

[0581] 1H NMR (500MHz, DMSO-d6) δ9.40 (d, J=7.2Hz, 1H), 9.11 (d, J=4.0Hz, 2H), 7.75 (t, J=7.4Hz, 1H), 7.52 (t, J=7.0Hz, 1H), 7.36-7.30 (m, 1H), 7.30- 7.13 (m, 1H), 5.82 (p, J = 7.0Hz, 1H), 3.76-3.64 (m, 4H), 3.34 (s, 2H), 3.02 (s, 3H), 2.44 (s, 3H), 2.10 (d, J = 13.7Hz, 2H), 1.65 (d, J = 7.1Hz, 3H).

[0582] Example 21: Preparation of Compound 21

[0583]

[0584] Under an ice-water bath, cyclopropanesulfonyl chloride (0.13 g) was added dropwise to a solution of compound 20-3 (0.1 g) and triethylamine (0.055 g) in dichloromethane (2 mL), and the temperature was maintained for 20 minutes after the addition was complete. After the reaction was completed, water (10 mL) was added to the reaction solution, and dichloromethane (15 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by C18 column chromatography (acetonitrile: water = 40: 60) to obtain 49 mg of compound 21.

[0585] HRMS (ESI, [M+H] + )m / z=554.1635.

[0586] 1 H NMR (500MHz, CD3OD) δ9.11 (s, 1H), 8.85 (dd, J=6.8, 0.9Hz, 1H), 7.64 (t, J=7.4Hz, 1H), 7.49 (t, J=7.1Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 7.00 (m, 1H), 5.87 ( q, J=7.1Hz, 1H), 4.05-3.78 (m, 4H), 2.72-2.59 (m, 4H), 2.51 (s, 3H), 2.29-2 .14(m, 1H), 1.72(d, J=7.1Hz, 3H), 1.11(m, 2H), 1.08(dt, J=8.2, 2.2Hz, 2H).

[0587] Example 22: Preparation of Compound 22

[0588]

[0589] Step A: Preparation of Compound 22-1

[0590] Referring to the method of step A of Example 19, compound 9-1 was reacted with (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethane-1-amine hydrochloride to prepare compound 22-1.

[0591] MS (ESI, [M+H] + )m / z=377.10.

[0592] 1 H NMR (500MHz, Acetone-d6) δ8.81 (s, 1H), 8.26 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.48 (dd, J=7.6, 1.2Hz, 1H), 7.08 (t, J=7.6Hz, 1H), 5.80 (p, J=7.1Hz, 1H), 4.81 (t, J=16.3Hz, 2H), 2.46 (s, 3H), 1.69 (d, J=7.0Hz, 3H).

[0593] Step B: Preparation of Compound 22-2

[0594] Referring to the method of step B of Example 19, compound 22-2 was prepared.

[0595] MS (ESI, [M+H] + )m / z=550.13.

[0596] 1 H NMR (500MHz, DMSO-d6) δ9.17 (d, J=7.4Hz, 1H), 9.12 (d, J=0.8Hz, 1H), 8.99 (d, J=6.4Hz, 1H), 7.60 (d, J=7.5Hz, 1H), 7.51 (dd, J=7.6, 1.4Hz, 1H), 7.35 (d, J=6.0Hz, 3H), 7.27 (s, 1 H), 7.09 (dd, J=7.6Hz, 1H), 5.74 (m, 1H), 4.87 (t, J=16.6Hz, 2H), 3.65 (s, 3H), 2.99-2.7 9(m, 4H), 2.44(s, 3H), 2.43-2.34(m, 2H), 1.93(t, J=10.5Hz, 2H), 1.60(d, J=7.0Hz, 3H).

[0597] Step C: Preparation of Compound 22-3

[0598] Referring to the method of step C of example 19, compound 22-3 was prepared.

[0599] MS (ESI, [M+H] +)m / z=460.17.

[0600] Step D: Preparation of compound 22

[0601] Compound 22 was prepared by referring to the method of Step D of Example 19.

[0602] HRMS (ESI, [M+H] + )m / z=538.1596.

[0603] 1 H NMR (500MHz, CD3OD) δ9.10 (s, 1H), 8.82 (d, J=6.8Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.47-7.40 (m, 1H), 7.05 (t, J=7.6Hz, 1H), 5.80 (q, J=7 .0Hz, 1H), 4.72 (t, J = 16.2Hz, 2H), 3.97-3.72 (m, 4H), 2.97 (s, 3H), 2.65 (m, 2H), 2.52 (s, 3H), 2.32-2.16 (m, 2H), 1.70 (d, J = 7.0Hz, 3H).

[0604] 31 P NMR (202 MHz, CD3OD) δ 31.22.

[0605] Example 23: Preparation of Compound 23

[0606]

[0607] Referring to the preparation method of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was replaced with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to synthesize Compound 23.

[0608] HRMS (ESI, [M+H] + )m / z=542.1608.

[0609] 1H NMR (500MHz, DMSO-d6) δ9.18 (s, 1H), 8.64 (d, J=6.8Hz, 1H), 7.45 (t, J=7.6Hz, 2H), 7.13 (t, J=7.8Hz, 1H), 6.91-6.90 (m, 1H), 5.82 (p, J=7.1Hz , 1H), 4.07-4.01(m, 2H), 3.83-3.77(m, 2H), 2.93(s, 3H), 2.65-2.58(m , 5H), 2.20-2.14 (m, 2H), 2.00 (t, J=18.6Hz, 3H), 1.70 (d, J=7.0Hz, 3H).

[0610] Example 24: Preparation of Compound 24

[0611]

[0612] Step A: Preparation of Compound 24-1

[0613] 5-amino-2-chloropyridine-4-carboxylic acid (3 g) and methanol (11.14 g) were added to a 50 mL single-mouth bottle in sequence, and the mixture was stirred in an ice-salt water bath. Thionyl chloride (4.14 g) and two drops of N, N-dimethylformamide were added dropwise. After the addition was complete, the mixture was heated to 65°C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the pH was adjusted to alkaline with a saturated sodium bicarbonate aqueous solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.8 g of compound 24-1.

[0614] MS (ESI, [M+H] + ): m / z = 186.97.

[0615] Step B: Preparation of Compound 24-2

[0616] In a 15 mL pressure bottle, compound 24-1 (1.7 g) obtained in step A, fluoroacetonitrile (2.69 g) and methanesulfonic acid (7.0 g) were added in sequence, and the reaction was heated to 105° C. and stirred for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and the pH was adjusted to alkaline with 4 M sodium hydroxide aqueous solution, extracted with dichloromethane (20 mL×5), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by silica gel column (dichloromethane: methanol = 97: 3) to obtain 0.43 g of compound 24-2.

[0617] MS (ESI, [M+H] + ): m / z = 214.02.

[0618] 1 H NMR (500MHz, DMSO-d6) δ12.90 (br, 1H), 8.93 (s, 1H), 7.99 (s, 1H), 5.40 (s, 1H), 5.31 (s, 1H).

[0619] Step C: Preparation of Compound 24-3

[0620] Referring to the method of step A of example 19, compound 24-3 was prepared.

[0621] MS (ESI, [M+H] + ): m / z = 403.06.

[0622] 1 H NMR (500MHz, DMSO-d6) δ9.13 (d, J=6.8Hz, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.84 (t, J=7.2Hz, 1H) , 7.67 (t, J=7.1Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 5.74 (m, 1H), 5.26 (m, 2H), 1.64 (d, J=7.1Hz, 3H).

[0623] Step D: Preparation of Compound 24-4

[0624] Referring to the method of step B of Example 19, compound 24-4 was prepared.

[0625] MS (ESI, [M+H] + ): m / z = 576.11.

[0626] 1 H NMR (500MHz, CD3OD) δ9.23 (s, 1H), 8.86 (d, J = 6.5Hz, 1H), 7.75 (t, J = 7.2Hz, 1H), 7.57 (t, J = 7.1Hz, 1H), 7.38 (d, J = 7.3Hz, 2H), 7.33 (t, J = 7.5Hz, 2H) ,7.27(m,2H),5.83(q,J=7.1Hz,1H),5.30(m,2H),3.70(s,2H),3.12-2.93 (m, 4H), 2.67-2.57 (m, 2H), 2.09 (t, J=15.5Hz, 2H), 1.73 (d, J=7.1Hz, 3H).

[0627] Step E: Preparation of Compound 24-5

[0628] Referring to the method of step C of example 19, compound 24-5 was prepared.

[0629] MS (ESI, [M+H] + ): m / z = 486.11.

[0630] Step F: Preparation of Compound 24

[0631] Referring to the method of step D of example 19, compound 24-5 was reacted with methanesulfonyl chloride to prepare compound 24.

[0632] HRMS (ESI, [M+H] + ): m / z = 564.1277.

[0633] 1 H NMR (500MHz, CD3OD) δ9.24 (s, 1H), 8.90 (d, J = 6.8Hz, 1H), 7.76 (t, J = 7.2Hz, 1H), 7.58 (t, J = 7.0Hz, 1H), 7.29 (t, J = 7.8Hz, 1H), 5.83 ( m, 1H), 5.30 (m, 2H), 4.01-3.88 (m, 2H), 3.82-3.74 (m, 2H), 2.98 (s, 3H), 2.69-2.62 (m, 2H), 2.27-2.20 (m, 2H), 1.74 (d, J=7.1Hz, 3H).

[0634] Example 25: Preparation of Compound 25

[0635]

[0636] Step A: Preparation of Compound 25-2

[0637]

[0638] Step a: Preparation of compound 25-2-1

[0639] 2-Fluoro-3-trifluoromethylbenzoic acid (15 g), N, N-dimethylformamide (100 mL), dimethylhydroxylamine hydrochloride (7.17 g), N, N-diisopropylethylamine (37.3 g) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (32.9 g) were added to a 500 mL single-mouth bottle, and the mixture was stirred at room temperature for 2.5 h. The reaction was stopped, the reaction solution was poured into water (500 mL), extracted with ethyl acetate (200 mL), the organic phase was washed with water (200 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified on silica gel (petroleum ether: ethyl acetate = 60: 40) to obtain 17.4 g of compound 25-2-1.

[0640] MS (ESI, [M+H] + )m / z=252.04.

[0641] 1 H NMR (500MHz, DMSO-d6) δ7.93-7.83 (m, 2H), 7.52 (t, J=7.8Hz, 1H), 3.31 (s, 3H), 2.70 (s, 3H).

[0642] Step b: Preparation of compound 25-2-2

[0643] At 0°C and under nitrogen protection, a 1M methylmagnesium bromide tetrahydrofuran solution (29.9 mL) was slowly dripped into a stirred solution of compound 25-2-1 (5 g) obtained in step a in ultra-dry tetrahydrofuran (50 mL). After the addition was complete, the mixture was heated to 35°C and stirred for 2 h. The reaction was stopped, and a saturated aqueous solution of ammonium chloride (150 mL) was slowly added to the reaction solution, stirred at room temperature for 10 minutes, allowed to stand for separation, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 4 g of compound 25-2-2.

[0644] 1H NMR (500MHz, DMSO-d6) δ 8.17-8.10 (m, 1H), 8.09-7.99 (m, 1H), 7.54 (t, J=7.8Hz, 1H), 2.64 (d, J=4.1Hz, 3H).

[0645] Step c: Preparation of compound 25-2-3

[0646] Compound 25-2-2 (4 g) obtained in step b, dry tetrahydrofuran (40 mL), (R)-(+)-tert-butylsulfenamide (2.352 g) and tetraethyl titanate (11.07 g) were added to a 100 mL single-mouth bottle, and the mixture was heated to 80°C for 3 h. The reaction was stopped, and ice water (150 mL) and ethyl acetate (150 mL) were added to the reaction solution under stirring at room temperature, stirred for 5 minutes, filtered, and the filtrate was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 5.8 g of compound 25-2-3.

[0647] MS (ESI, [M+H] + )m / z=309.97.

[0648] Step d: Preparation of compound 25-2-4

[0649] Compound 25-2-3 (3 g) obtained in step c and tetrahydrofuran (30 mL) were added to a 250 mL three-necked flask in sequence. Under nitrogen protection, the temperature was lowered to -50 ° C. Sodium borodeuteride (0.731 g) was added in batches. After the addition, the temperature was maintained and the reaction was stirred for 3 h. The reaction solution was added dropwise to heavy water (20 mL) to quench the reaction. The resulting solution was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 60: 40) to obtain 0.62 g of compound 25-2-4.

[0650] MS (ESI, [M+H] + )m / z=313.00.

[0651] 1 H NMR (500MHz, DMSO-d6) δ7.89 (t, J=7.2Hz, 1H), 7.67 (t, J=7.2Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 5.89 (s, 1H), 1.43 (s, 3H), 1.10 (s, 9H).

[0652] Step e: Preparation of compound 25-2

[0653] Compound 25-2-4 (0.6 g), 1,4-dioxane (2 mL) and 4M dioxane hydrochloride solution (2.5 mL) were added to a 100 mL single-necked bottle in sequence. The reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness under reduced pressure. The residue was slurried with methyl tert-butyl ether (5 mL) to obtain 0.38 g of compound 25-2.

[0654] MS (ESI, [M-HCl+H] + )m / z=209.04.

[0655] 1 H NMR (500MHz, DMSO-d6) δ 8.87 (s, 3H), 8.12 (t, J = 7.2Hz, 1H), 7.82 (t, J = 7.3Hz, 1H), 7.53 (t, J = 7.8Hz, 1H), 1.57 (s, 3H).

[0656] Step B: Preparation of compound 25-3

[0657] Referring to the method of step A of Example 19, compound 25-2 prepared in the above step A was combined with compound 20-1 to prepare compound 25-3.

[0658] MS (ESI, [M+H] + )m / z=559.14.

[0659] 1 H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 9.13 (s, 1H), 8.99 (d, J = 6.4Hz, 1H), 7.84 (t, J = 7.1Hz, 1H), 7.65 (t, J = 7.1Hz, 1H), 7.40-7.31 (m, 5 H), 7.30-7.24 (m, 1H), 3.66 (s, 2H), 3.05-2.92 (m, 2H), 2.83 (q, J=12.1Hz, 2H), 2.45-2.35 (m, 5H), 1.92 (t, J=14.7Hz, 2H), 1.64 (s, 3H).

[0660] Step C: Preparation of Compound 25-4

[0661] Referring to the method of step C of example 19, compound 25-4 was prepared.

[0662] MS (ESI, [M+H] + ): m / z = 469.28.

[0663] Step D: Preparation of compound 25

[0664] Referring to the method of step D of example 19, compound 25-4 was reacted with methanesulfonyl chloride to prepare compound 25.

[0665] HRMS (ESI, [M+H] + ): m / z = 547.1432.

[0666] 1 H NMR (500MHz, CD3OD) δ9.11 (s, 1H), 8.85 (d, J = 6.8Hz, 1H), 7.75 (t, J = 7.1Hz, 1H), 7.57 (t, J = 7.1Hz, 1H), 7.28 (t, J = 7.8Hz, 1H), 4.00-3.86(m, 2H), 3.81-3.74(m, 2H), 2.98(s, 3H), 2.68-2.62(m, 2H), 2.50(s, 3H), 2.23-2.20(m, 2H), 1.72(s, 3H).

[0667] Example 26: Preparation of Compound 26

[0668]

[0669] Step A: Preparation of Compound 26-1

[0670]

[0671] Step a: Preparation of compound 26-1-1

[0672] Referring to the method of step a of Example 25, 2-fluoro-3-trifluoromethylbenzoic acid was replaced with 2-methyl-3-trifluoromethylbenzoic acid to prepare compound 26-1-1.

[0673] MS (ESI, [M+H] + )m / z=248.07.

[0674] 1 H NMR (500MHz, CD3OD) δ7.73 (d, J=7.9Hz, 1H), 7.53 (d, J=7.6Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 3.44 (s, 3H), 2.83 (s, 3H), 2.39 (s, 3H).

[0675] Step b: Preparation of compound 26-1-2

[0676] Referring to the method of step b of Example 25, compound 26-1-2 was prepared.

[0677] GCMS: [M] + =202.

[0678] 1 H NMR (500MHz, CD3OD) δ7.83 (d, J=7.8Hz, 1H), 7.77 (dd, J=8.0, 1.2Hz, 1H), 7.45 (t, J=7.8Hz, 1H), 2.58 (s, 3H), 2.48 (q, J=1.8Hz, 3H).

[0679] Step c: Preparation of compound 26-1-3

[0680] To a 100mL three-necked flask, 1M tetrahydrofuran solution (17.68mL) of lithium bis(trimethylsilylamide) and dry tetrahydrofuran (50mL) were added in sequence. Under nitrogen protection at -74°C, a tetrahydrofuran (5mL) solution of compound 26-1-2 (2.75g) obtained in step b was slowly added dropwise to the above reaction solution, and the mixture was stirred at -74°C for 10 minutes. Trimethylchlorosilane (1.921g) was slowly added to the above reaction solution, and the addition was completed after 2 minutes. The reaction was stirred at -74°C for 1h, and then the temperature was raised to room temperature and the reaction was continued for 20 minutes. After the reaction was completed, a saturated ammonium chloride solution (10mL) was added to the reaction solution and stirred vigorously for 5 minutes. Extract with ethyl acetate (10 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, dissolve the residue in acetonitrile (50 mL), stir at 0 ° C, add the selective fluorine reagent (5.30 g), warm to room temperature and continue to stir and react for 5 h. After the reaction is completed, the reaction solution is concentrated to dryness. Add water (20 mL) to the residue, extract with ethyl acetate (40 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, and the residue is separated and purified by silica gel column (petroleum ether: ethyl acetate = 91: 10) to obtain 1.34 g of compound 26-1-3.

[0681] 1 H NMR (500MHz, CD3OD) δ7.84 (dd, J=8.0, 1.2Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 7.48 (t, J=7.9Hz, 1H), 5.43 (d, J=46.9Hz, 2H), 2.50 (q, J=1.8Hz, 3H).

[0682] Step d: Preparation of compound 26-1-4

[0683] Referring to the method of step c of example 25, the compound 26-1-3 obtained in step c was reacted with S-tert-butylsulfenamide to prepare compound 26-1-4.

[0684] MS (ESI, [M+H] + )m / z=324.10.

[0685] Step e: Preparation of compound 26-1

[0686] Under nitrogen protection at -78°C, compound 26-1-4 (940 mg) obtained in step d and dry tetrahydrofuran (10 mL) were added to a 100 mL three-necked flask in sequence, and 1M lithium tri-sec-butylborohydride tetrahydrofuran solution (51.0 mL) was slowly dripped into the above reaction solution. After the addition was complete, the mixture was stirred at -78°C for 0.5 h. The reaction was completed. Saturated ammonium chloride solution (30 mL) was dripped into the reaction solution, and after vigorous stirring for 10 minutes, the mixture was warmed to room temperature, extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (dichloromethane: methanol = 98: 2) to obtain 360 mg of yellow oily liquid. The yellow oily liquid obtained above, 1,4-dioxane (20 mL), and 4M hydrogen chloride 1,4-dioxane solution (0.857 mL) were added to a 100 mL single-necked bottle in sequence, and stirred at room temperature for 4 h. The reaction solution was concentrated to dryness, and the residue was slurried with methyl tert-butyl ether (10 mL) to obtain 250 mg of compound 26-1.

[0687] MS (ESI, [M+H] + )m / z=221.99.

[0688] 1 H NMR (500MHz, D2O) δ7.83 (d, J=7.9Hz, 1H), 7.66 (d, J=7.9Hz, 1H), 7.52 (t, J=7.9Hz, 1H) , 5.22 (m, 1H), 4.90 (dd, J=10.8, 3.9Hz, 1H), 4.86-4.81 (m, 1H), 2.53 (d, J=1.5Hz, 3H).

[0689] Step B: Preparation of Compound 26-2

[0690] Referring to the method of step A of Example 19, compound 26-2 was prepared by replacing compound 9-1 with 6-bromo-2-methylquinazolin-4(3H)-one.

[0691] MS (ESI, [M+H+2] + )m / z=444.04.

[0692] Step C: Preparation of Compound 26-3

[0693] Referring to the method of step B of Example 19, compound 26-3 was prepared.

[0694] MS (ESI, [M+H] + )m / z=571.78.

[0695] Step D: Preparation of compound 26-4

[0696] Referring to the method of step C of example 19, compound 26-4 was prepared.

[0697] MS (ESI, [M+H] + )m / z=481.31.

[0698] Step E: Preparation of Compound 26

[0699] Compound 26 was prepared by referring to the method of Step D of Example 19.

[0700] HRMS(ESI,[M+H]+)m / z=559.1558.

[0701] 1 H NMR (500MHz, CD3OD) δ8.72 (dd, J=13.3, 1.7Hz, 1H), 8.04 (ddd, J=10.2, 8.5, 1.7Hz, 1H), 7.70 (dd, J= 8.7, 2.5Hz, 1H), 7.63 (d, J=7.8Hz, 1H), 7.51 (d, J=7.9Hz, 1H), 7.24 (t, J=7.9Hz, 1H), 6.06 (m, 1H), 4. 83 (dd, J=9.9, 7.9Hz, 0.5H), 4.73-4.69 (m, 1H), 4.62 (dd, J=9.9, 4.8Hz, 0.5H), 3.97 (m, 2H), 3.51 (q , J=11.8, 10.9Hz, 2H), 2.88 (s, 3H), 2.61 (s, 3H), 2.53-2.43 (m, 2H), 2.40 (s, 3H), 2.23-2.10 (m, 2H).

[0702] 31 P NMR (202 MHz, CD3OD) δ 32.62.

[0703] Example 27: Preparation of Compound 27

[0704]

[0705] Step A: Preparation of Compound 27-1

[0706] Referring to the method of step A of Example 19, compound 27-1 was prepared by replacing compound 9-1 with 6-bromo-2-methylquinazolin-4(3H)-one.

[0707] MS (ESI, [M+H] + )m / z=410.05.

[0708] Step B: Preparation of Compound 27-2

[0709] Referring to the method of step B of Example 19, compound 27-2 was prepared.

[0710] MS (ESI, [M+H] + )m / z=539.15.

[0711] Step C: Preparation of Compound 27-3

[0712] Referring to the method of step C of example 19, compound 27-3 was prepared.

[0713] MS (ESI, [M+H] + )m / z=449.15.

[0714] Step D: Preparation of compound 27

[0715] Referring to the method of step D of example 19, compound 27-3 was reacted with methanesulfonyl chloride to prepare compound 27.

[0716] HRMS (ESI, [M+H] + )m / z=527.1489.

[0717] 1 H NMR (500MHz, CD3OD) δ8.80 (dd, J=13.2, 1.1Hz, 1H), 8.20-8.04 (m, 1H), 7.78 (dd, J=8.6, 2 .4Hz, 1H), 7.63 (t, J=7.4Hz, 1H), 7.48 (t, J=6.9Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 7.01 (t, J =54.9Hz, 1H), 5.87 (q, J = 7.1Hz, 1H), 4.05 (m, 2H), 3.62 (q, J = 11.1Hz, 2H), 3.00-2.96 (m, 3H), 2.63-2.53(m, 2H), 2.49-2.44(m, 3H), 2.25(t, J=16.0Hz, 2H), 1.72(d, J=7.1Hz, 3H).

[0718] Example 28: Preparation of Compound 28

[0719]

[0720] Step A: Preparation of Compound 28-1

[0721] 2-Amino-4-methoxybenzoic acid (1 g), ethylene glycol monomethyl ether (10 mL), and N-iodosuccinimide (1.48 g) were added to a 25 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 3 h. The reaction was stopped, and a saturated sodium chloride solution (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL × 2), and the organic phases were combined and concentrated. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 2) to obtain 1.34 g of compound 28-1.

[0722] MS (ESI, [MH] - )m / z=291.79.

[0723] 1 H NMR (500MHz, DMSO-d6) δ7.98 (s, 1H), 6.35 (s, 1H), 3.78 (s, 3H), 2.57 (s, 2H).

[0724] Step B: Preparation of Compound 28-2

[0725] Compound 28-1 (1.3 g), 2-methoxyethanol (13 mL) and formamidine acetate (0.924 g) were added to a 50 mL single-mouth bottle in sequence, stirred at 120 ° C for 2 h, the reaction was stopped, cooled to room temperature, filtered, the filter cake was washed with methanol (10 mL), the filter cake was collected and slurried with methanol (30 mL), filtered, and the filter cake was collected and dried to obtain 0.95 g of compound 28-2. MS (ESI, [M+H] + )m / z=302.81

[0726] Step C: Preparation of Compound 28-3

[0727] Compound 28-2 (0.5 g) obtained in step B above, N, N-dimethylformamide (10 mL), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.723 g) were added to a 50 mL single-mouth bottle in sequence, and a solution of 2,3,4,6,7,8,9,10-octahydropyrimidinyl[1,2-a]azepine (0.756 g) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (0.344 g) in N, N-dimethylformamide (10 mL) was added dropwise under stirring at room temperature. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction was stopped, purified water (100 mL) was added to the reaction solution, and ethyl acetate (100 mL×2) was used for extraction. The organic phases were combined and concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 0.422 g of compound 28-3.

[0728] MS (ESI, [M+H] + )m / z=473.97.

[0729] 1 H NMR (500MHz, DMSO-d6) δ9.01 (s, 1H), 8.51 (d, J = 7.3Hz, 1H), 8.36 (s, 1H), 7.65 (t, J = 7.2Hz, 1H), 7.50 (t , J=7.1Hz, 1H), 7.37-7.12 (m, 2H), 7.10 (s, 1H), 5.81-5.71 (m, 1H), 3.96 (s, 3H), 1.59 (d, J=7.1Hz, 3H).

[0730] Step D: Preparation of Compound 28-4

[0731] Referring to the method of step A of Example 10, compound 28-4 was prepared using compound 28-3.

[0732] MS (ESI, [M+H] + )m / z=555.14.

[0733] 1 H NMR (500MHz, DMSO-d6) δ8.94 (d, J=7.4Hz, 1H), 8.81 (d, J=13.6Hz, 1H), 8.39 (s, 1H), 7.67 (t, J=7.5Hz, 1H), 7.50 (t, J=7.1Hz, 1H), 7.39-7.3 4 (m, 4H), 7.31-7.12 (m, 4H), 5.86-5.76 (m, 1H), 4.02 (s, 3H), 3.70 (s, 2H), 3.08-2.82 (m, 4H), 2.51 (d, J=22.5Hz, 4H), 1.60 (d, J=7.1Hz, 3H).

[0734] Step E: Preparation of Compound 28-5

[0735] To a 100 mL single-mouth bottle, acetonitrile (50 mL), ammonium cerium nitrate (2.471 g), and water (10 mL) were added in sequence, and after stirring for 2 minutes until completely dissolved, the compound 28-4 (0.5 g) obtained in the above step D was added, and the reaction was stirred at room temperature for 1 hour. The reaction was stopped, and a saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction. The reaction solution was extracted with dichloromethane (100 mL×2), and the organic phases were combined, washed with water (100 mL) and a saturated sodium chloride aqueous solution (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 20: 1) to obtain 0.208 g of compound 28-5.

[0736] MS (ESI, [M+H] + )m / z=465.2

[0737] 1 H NMR (500MHz, DMSO-d6) δ8.93 (d, J=7.4Hz, 1H), 8.79 (d, J=13.5Hz, 1H), 8.38 (s, 1H), 7.68 (t, J=7.4Hz, 1H), 7.50 (t, J=7.1Hz, 1H), 7.36-7 .12 (m, 3H), 5.86-5.76 (m, 1H), 3.99 (s, 3H), 3.16-3.06 (m, 4H), 2.44-2.34 (m, 2H), 1.84-1.74 (m, 2H), 1.61 (d, J=7.2Hz, 3H), 1.40 (s, 1H).

[0738] Step F: Preparation of compound 28

[0739] Referring to the method of step C of example 10, compound 28-5 was reacted with acetic anhydride to prepare compound 28.

[0740] HRMS (ESI, [M+H] + )m / z=507.1772.

[0741] 1 H NMR (500MHz, DMSO-d6) δ8.97 (d, J=7.3Hz, 1H), 8.87-8.77 (m, 1H), 8.39 (d, J=1.7Hz , 1H), 7.73-7.63 (m, 1H), 7.50 (t, J=7.1Hz, 1H), 7.36-7.12 (m, 3H), 5.86-5.76 (m, 1H ), 4.47-4.37(m, 1H), 4.09-3.99(m, 1H), 3.94(s, 3H), 3.81-3.69(m, 1H), 3.41-3.3 1(m, 1H), 2.49-2.30(m, 2H), 2.13(s, 3H), 2.03-1.84(m, 2H), 1.61(d, J=7.1Hz, 3H).

[0742] Example 29: Preparation of Compound 29

[0743]

[0744] Step A: Preparation of Compound 29

[0745] Referring to the method of step D of example 19, compound 28-5 was reacted with methanesulfonyl chloride to prepare compound 29.

[0746] HRMS (ESI, [M+H] +)m / z=543.1441.

[0747] 1 H NMR (500MHz, DMSO-d6) δ8.98 (d, J=7.4Hz, 1H), 8.86 (d, J=14.0Hz, 1H), 8.40 (s, 1H), 7.68 (t, J=7.3Hz, 1H), 7.51 (t, J=7.1Hz, 1H), 7.37-7.10 (m, 3H), 5 .86-5.76(m, 1H), 3.98(s, 3H), 3.97-3.87(m, 2H), 3.55-3.450(m, 2H), 3.0 4 (s, 3H), 2.55 (d, J = 13.7Hz, 2H), 2.09-1.96 (m, 2H), 1.61 (d, J = 7.1Hz, 3H).

[0748] Example 30: Preparation of Compound 30

[0749]

[0750] Step A: Preparation of Compound 30-1

[0751] Compound 1-1 (1 g), fluoroacetonitrile (1.923 g), and methanesulfonic acid (2.504 g) were added to a 15 mL pressure bottle in sequence, and the reaction bottle was placed in a 120 ° C oil bath and stirred for 4 h. The reaction was stopped and the reaction solution was naturally cooled to room temperature. The reaction solution was concentrated, and the pH was directly adjusted to alkaline with 4M sodium hydroxide aqueous solution, filtered, and the filter cake was washed with a large amount of water. The solid was collected and dried to obtain 0.68 g of compound 30-1.

[0752] MS (ESI, [M+H] + )m / z=334.74.

[0753] Step B: Preparation of compound 30-2

[0754] Referring to the method of step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to prepare compound 30-2.

[0755] MS (ESI, [M+H] + )m / z=505.99.

[0756] 1H NMR (500MHz, DMSO-d6) δ8.99 (s, 1H), 8.63 (d, J=7.3Hz, 1H), 7.70 (t, J=7.3Hz, 1H), 7.51 (t, J=6.9Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.23 (t, J=54.4Hz, 1H), 7.16 (s, 1H), 5.82-5.76 (m, 1H), 5.29-5.09 (m, 2H), 3.96 (s, 3H), 1.60 (d, J=7.1Hz, 3H).

[0757] Step C: Preparation of Compound 30-3

[0758] Referring to the method of Example 10, Step A, compound 30-3 was prepared.

[0759] MS (ESI, [M+H] + )m / z=587.20.

[0760] 1 H NMR (500MHz, DMSO-d6) δ9.06 (d, J=7.4Hz, 1H), 8.80 (d, J=13.6Hz, 1H), 7.72 (t, J=7.3Hz, 1H), 7.50 (t, J=6.9Hz, 1H), 7.40-7.34 (m, 4H), 7.32-7.25 (m, 3H), 7.23 (t, J=54.5Hz, 1H) , 5.82 (p, J=7.0Hz, 1H), 5.32-5.13 (m, 2H), 4.02 (s, 3H), 3.69 (s, 2H), 3.03-2.95 (m, 2H), 2.86 (q, J=11.7Hz, 2H), 2.50-2.47 (m, 2H), 1.85 (t, J=16.4Hz, 2H), 1.62 (d, J=7.1Hz, 3H).

[0761] Step D: Preparation of compound 30-4

[0762] Referring to the method of step B of Example 10, compound 30-4 was prepared.

[0763] MS (ESI, [M+H] + )m / z=497.16.

[0764] Step E: Preparation of compound 30

[0765] Referring to the method of step C of Example 10, compound 30-4 was reacted with acetic anhydride to prepare compound 30.

[0766] HRMS (ESI, [M+H]+ )m / z=539.1835.

[0767] 1 H NMR (500MHz, CD3OD) δ8.69 (d, J=14.3Hz, 1H), 7.63 (t, J=7.4Hz, 1H), 7.47 (t, J=7.0Hz , 1H), 7.26-7.24 (m, 2H), 7.00 (m, 1H), 5.83 (q, J=7.0Hz, 1H), 5.24 (dt, J=48.0, 13.5H z, 2H), 4.67-4.59 (m, 1H), 4.24-4.16 (m, 1H), 4.02 (s, 3H), 3.90-3.87 (m, 1H), 3.54-3 .47(m, 1H), 2.67-2.54(m, 2H), 2.24(s, 3H), 2.20-2.02(m, 2H), 1.70(d, J=7.1Hz, 3H).

[0768] Example 31: Preparation of Compound 31

[0769]

[0770] Step A: Preparation of compound 31-1

[0771] Referring to the method of step B of Example 24, compound 31-1 was prepared by replacing compound 24-1 with methyl 2-amino-5-bromobenzoate.

[0772] MS (ESI, [M+H] + )m / z=256.94.

[0773] 1 H NMR (500MHz, DMSO-d6) δ12.74 (br, 1H), 8.20 (d, J=2.0Hz, 1H), 7.99 (dd, J=8.7, 2.3Hz, 1H), 7.65 (d, J=8.7Hz, 1H), 5.36 (s, 1H), 5.26 (s, 1H).

[0774] Step B: Preparation of compound 31-2

[0775] Referring to the method of Example 19 Step A, compound 31-2 was prepared.

[0776] MS (ESI, [M+H] + )m / z=428.03.

[0777] 1H NMR (500MHz, DMSO-d6) δ8.79 (t, J=4.9Hz, 2H), 7.93 (dd, J=8.9, 1.9Hz, 1H), 7.70 (t, J=7.8Hz, 1H), 7.66 (d, J=8.9Hz, 1H), 7.51 (t, J=6.9Hz, 1H), 7.30 (t, J=7.7Hz, 1H), 7.23 (t, J=54.4Hz, 1H), 5.83-5.75 (m, 1H), 5.33-5.13 (m, 2H), 1.62 (d, J=7.0Hz, 3H).

[0778] Step C: Preparation of Compound 31-3

[0779] Referring to the method of step B of Example 19, compound 31-3 was prepared.

[0780] MS (ESI, [M+H] + )m / z=557.13.

[0781] 1 H NMR (500MHz, DMSO-d6) δ9.08 (d, J=7.2Hz, 1H), 8.90 (d, J=12.2Hz, 1H), 8.14 (t, J=9.0Hz, 1 H), 7.81 (dd, J=8.5, 1.8Hz, 1H), 7.71 (t, J=7.3Hz, 1H), 7.51 (t, J=6.9Hz, 1H), 7.37-7.34 (m , 4H), 7.31-7.25(m, 2H), 7.23(m, 1H), 5.83(m, 1H), 5.25(m, 2H), 3.66(s, 2H), 3.02-2.88(m , 2H), 2.85-2.78 (m, 2H), 2.42-2.35 (m, 2H), 1.99 (t, J=15.6Hz, 2H), 1.65 (d, J=7.1Hz, 3H).

[0782] Step D: Preparation of compound 31-4

[0783] Referring to the method of step B of Example 10, compound 31-4 was prepared.

[0784] MS (ESI, [M+H] + )m / z=467.20.

[0785] Step E: Preparation of compound 31

[0786] Referring to the method of step E of example 30, compound 31-4 was reacted with acetic anhydride to prepare compound 31.

[0787] HRMS (ESI, [M+H] + )m / z=509.1730.

[0788] 1 H NMR (500MHz, CD3OD) δ8.81 (d, J=13.1Hz, 1H), 8.22-8.11 (m, 1H), 7.91 (dd, J=8.6, 2.4Hz, 1H), 7.6 4(t, J=7.3Hz, 1H), 7.48 (t, J=7.0Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 7.00 (t, J=54.9Hz, 1H), 5.85 (q, J=7.0Hz, 1H), 5.27(td, J=47.5, 13.5Hz, 2H), 4.61-4.47(m, 1H), 4.18-4.09(m, 1H), 3.96-3.89(m , 1H), 3.62 (dd, J=22.6, 10.9Hz, 1H), 2.57-2.41 (m, 2H), 2.29-2.11 (m, 5H), 1.72 (d, J=7.1Hz, 3H).

[0789] 31 P NMR (202 MHz, CD3OD) δ 34.37.

[0790] Example 32: Preparation of Compound 32

[0791]

[0792] Step A: Preparation of compound 32-1

[0793] Referring to the method of step A of Example 24, compound 32-1 was prepared by replacing 5-amino-2-chloropyridine-4-carboxylic acid with 2-amino-5-bromo-4-fluorobenzoic acid.

[0794] MS (ESI, [M+H] + )m / z=249.05.

[0795] 1 H NMR (500MHz, DMSO-d6) δ7.90 (d, J=8.1Hz, 1H), 7.01 (s, 2H), 6.72 (d, J=11.5Hz, 1H), 3.79 (s, 3H).

[0796] Step B: Preparation of compound 32-2

[0797] Referring to the method of step B of Example 24, compound 32-2 was prepared.

[0798] 1H NMR (500MHz, DMSO-d6) δ12.78 (s, 1H), 8.35 (d, J=7.6Hz, 1H), 7.69 (d, J=9.7Hz, 1H), 5.36 (s, 1H), 5.27 (s, 1H).

[0799] Step C: Preparation of Compound 32-3

[0800] Referring to the method of Example 19, Step A, compound 32-3 was prepared.

[0801] MS (ESI, [M+H+2] + )m / z=448.02.

[0802] 1 H NMR (500MHz, DMSO-d6) δ8.98 (d, J=7.5Hz, 1H), 8.85 (d, J=7.2Hz, 1H), 7.70 (dd, J=7.5Hz, 1H), 7.65 (d, J=9.9Hz, 1H), 7.52 (dd, J=7.1Hz, 1H), 7.35-7.10 (m, 2H), 5.78 (p, J=7.1Hz, 1H), 5.33-5.11 (m, 2H), 1.62 (d, J=7.1Hz, 3H).

[0803] Step D: Preparation of compound 32-4

[0804] Referring to the method of step B of Example 19, compound 32-4 was prepared.

[0805] MS (ESI, [M+H] + )m / z=575.11.

[0806] 1 H NMR (500MHz, CD3OD) δ8.70-8.64 (m, 1H), 7.52 (dd, J=7.9Hz, 1H), 7.37 (m, 2H), 7.28-7.24 (m, 2H), 7.21 (dd, J=7.5Hz, 2H), 7.17-7.10 (m, 2H), 6.88 (t, J=54.9Hz, 1H), 5.72 (q, J=7.0Hz, 1H), 5.14 (m, 2H), 3.58 (s, 2H), 3.05-2.79 (m, 4H), 2.44 (m, 2H), 2.10m, 2H), 1.60 (d, J=7.1Hz, 3H).

[0807] Step E: Preparation of compound 32-5

[0808] Referring to the method of step C of example 19, compound 32-5 was prepared.

[0809] MS (ESI, [M+H] + )m / z=485.15.

[0810] Step F: Compound 32 was prepared by referring to the method of Step C of Example 10.

[0811] HRMS (ESI, [M+H] + )m / z=527.1646.

[0812] 1 H NMR (500MHz, CD3OD) δ8.80 (dd, J=13.5, 6.7Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.49 (m, 2H), 7.24 (t, J=7.7Hz, 1H), 6.99 (t, J=54.9Hz, 1H), 5.84 (q , J=7.1Hz, 1H), 5.25 (m, 2H), 4.64-4.11 (m, 2H), 4.00-3.57 (m, 2H), 2.5 9-2.43 (m, 2H), 2.38-2.24 (m, 2H), 2.22 (s, 3H), 1.72 (d, J=7.2Hz.3H).

[0813] 31 P NMR (202 MHz, CD3OD) δ 31.37.

[0814] Example 33: Preparation of Compound 33

[0815]

[0816] Step A: Preparation of compound 33-1

[0817] 6-Bromo-2,4-dichloroquinazoline (0.5 g), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (0.447 g), N,N-diisopropylethylamine (0.689 g) and acetonitrile (3 mL) were added to a 25 mL single-mouth bottle, and the reaction solution was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 80: 20) to obtain 0.7 g of compound 33-1.

[0818] MS (ESI, [M+H+2] + )m / z=432.00.

[0819] 1H NMR (500MHz, DMSO-d6) δ9.10 (d, J=7.3Hz, 1H), 8.81 (d, J=2.1Hz, 1H), 7.96 (dd, J=8.8, 2.1Hz, 1H), 7.70 (t, J=7.5Hz, 1H) , 7.58 (d, J=8.9Hz, 1H), 7.54 (t, J=7.1Hz, 1H), 7.37-7.32 (m, 1H), 7.32-7.07 (m, 1H), 5.70 (m, 1H), 1.62 (d, J=7.0Hz, 3H).

[0820] Step B: Preparation of compound 33-2

[0821] Add compound 33-1 (0.5 g) obtained in step A, 1-benzyl-1,4-azaphosphane 4-oxide (0.267 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.134 g), tris(dibenzylideneacetone)dipalladium (0.106 g), N,N-diisopropylethylamine (0.225 g) and 1,4-dioxane (10 mL) to a 25 mL single-mouth bottle. Heat to 70° C. in an oil bath under nitrogen protection and stir to react for 2 h. The reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated to dryness. The residue is separated and purified by silica gel column (dichloromethane: methanol = 95: 5) to obtain 0.5 g of compound 33-2.

[0822] MS (ESI, [M+H] + )m / z=559.09.

[0823] 1 H NMR (500MHz, DMSO-d6) δ9.41 (d, J=7.3Hz, 1H), 8.92 (d, J=12.1Hz, 1H), 8.27 (br, 1H), 8.17 (t, J=9 .1Hz, 1H), 7.77-7.68 (m, 2H), 7.55 (t, J=7.2Hz, 1H), 7.39-7.34 (m, 4H), 7.33 (d, J=7.9Hz, 1H), 7.2 9 (dd, J=6.0, 2.9Hz, 1H), 5.82-5.69 (m, 1H), 3.62 (dt, J=6.6, 3.3Hz, 1H), 3.15 (m, 1H), 3.03-2.86 (m, 2H), 2.81 (q, J=11.8Hz, 2H), 2.43-2.31 (m, 2H), 1.98 (t, J=15.7Hz, 2H), 1.66 (d, J=7.0Hz, 3H).

[0824] Step C: Preparation of compound 33-3

[0825] Compound 33-2 (0.18 g) obtained in step B, ammonium cerium nitrate (0.883 g), acetonitrile (20 mL) and water (4 mL) were added to a 100 mL single-mouth bottle and stirred at room temperature for 1 h. Saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with water and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 0.3 g of crude compound 33-3, which was directly used for the next step.

[0826] MS (ESI, [M+H] + )m / z=469.12.

[0827] Step D: Preparation of compound 33

[0828] Referring to the method of step C of example 10, compound 33-3 was reacted with acetic anhydride to prepare compound 33.

[0829] HRMS (ESI, [M+H] + )m / z=511.1277.

[0830] 1 H NMR (500MHz, CDCl3) δ8.79 (d, J=13.0Hz, 1H), 7.81 (q, J=6.2, 5.6Hz, 2H), 7.6 5-7.41 (m, 3H), 7.17 (q, J=7.5Hz, 1H), 6.88 (td, J=55.0, 3.0Hz, 1H), 5.79 (t, J=7.1Hz, 1H), 4.76-4.54(m, 1H), 4.14-3.84(m, 2H), 3.58(q, J=12.0Hz, 1H), 2.33-2.24 (m, 1H), 2.20 (d, J=8.8Hz, 3H), 2.09 (s, 3H), 1.71 (t, J=6.0Hz, 3H).

[0831] 31 P NMR (202 MHz, CDCl3) δ 29.70.

[0832] Example 34: Preparation of Compound 34

[0833]

[0834] Step A: Preparation of Compound 34-1

[0835] Referring to the method of step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to react with compound 1-2 to prepare compound 34-1.

[0836] MS (ESI, [M+H] + )m / z=488.02.

[0837] Step B: Preparation of compound 34

[0838] Compound 34-1 (0.075 g) obtained in step A, diethylphosphine oxide (0.016 g), N, N-diisopropylethylamine (0.04 g), 4, 5-bis(diphenylphosphine)-9, 9-dimethylxanthene (8.9 mg), tris(dibenzylideneacetone) dipalladium (7.05 mg), and N, N-dimethylformamide (3 mL) were added to a 5 mL microwave tube. After the addition was completed and nitrogen was replaced, the microwave reactor was heated to 170° C. at 150 watts for 35 minutes. After the reaction was completed, the sample was taken out. The reaction solution was filtered through diatomaceous earth, the filtrate was poured into water (30 mL), extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column (dichloromethane: methanol = 97: 3) to obtain 29 mg of compound 34.

[0839] HRMS (ESI, [M+H] + )m / z=466.1886.

[0840] 1 H NMR (500MHz, CD3OD) δ8.59 (d, J=13.0Hz, 1H), 7.64 (t, J=7.3Hz, 1H), 7.48 (t, J=7.1Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 7 .13-6.88 (m, 2H), 5.87 (q, J=7.1Hz, 1H), 4.00 (s, 3H), 2.44 (s, 3H), 2.13 (m, 4H), 1.69 (d, J=7.1Hz, 3H), 1.07 (m, 6H).

[0841] 31 P NMR (202 MHz, CD3OD) δ 49.9.

[0842] Example 35: Preparation of Compound 35

[0843]

[0844] Step A: Preparation of compound 35-1

[0845] Referring to the method of step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to react with compound 9-1 to prepare compound 35-1.

[0846] MS (ESI, [M+H] + )m / z=367.05.

[0847] 1 H NMR (500MHz, CD3OD) δ8.76 (s, 1H), 8.33 (s, 1H), 7.60 (t, J=7.3Hz, 1H), 7.48 (t, J=6.9Hz, 1H), 7.24 ( t, J=7.7Hz, 1H), 7.01 (t, J=54.9Hz, 1H), 5.80 (q, J=7.1Hz, 1H), 2.46 (s, 3H), 1.69 (d, J=7.1Hz, 3H).

[0848] Step B: Preparation of compound 35-2

[0849]

[0850] Step a: Preparation of compound 35-2-1

[0851] Add ammonium hypophosphite (28g, 337mmol) to a 500mL three-necked flask, add hexamethyldisilazane (109g) dropwise, and heat the reaction solution to 120°C under nitrogen protection, stir and react for 4h, add bis(2-bromoethyl)ether (78g) dropwise to the reaction flask, and keep the temperature to continue the reaction for 4h. Stir and cool the reaction solution in an ice-water bath, add anhydrous ethanol (150mL) dropwise, and heat the reaction solution to reflux for 1h. Stop the reaction, cool the reaction solution to room temperature, filter with suction, wash the filter cake with dichloromethane, and concentrate the filtrate to obtain 42.4g of crude compound 35-2-1.

[0852] GCMS: [M] + =136.

[0853] Step b: Preparation of compound 35-2-2

[0854] Add compound 35-2-1 (1 g) obtained in step a and dichloromethane (20 mL) to a 25 mL three-necked flask, cool to below 0°C in an ice-salt bath under nitrogen protection, add oxalyl chloride (1.578 g) dropwise, and stir at room temperature overnight. Concentrate the reaction solution to dryness, dissolve the residue in toluene (10 mL) and concentrate to dryness to obtain 1.8 g of crude compound 35-2-2, which is used directly in the next step without purification.

[0855] Step c: Preparation of compound 35-2

[0856] Under nitrogen protection at -70°C, 1M diisobutylaluminum hydride toluene solution (6.48 mL) was slowly added to the stirred solution of compound 35-2-2 (1.8 g) obtained in step b in dichloromethane (15 mL), and the mixture was stirred at -70°C for 2 h. After the reaction was completed, methanol (3 mL) was added to the reaction solution at -70°C and stirred for 5 minutes. The reaction solution was transferred to an ice-water bath and continued to be stirred until the temperature of the reaction solution rose to 0°C. A 10 vol% acetic acid aqueous solution (10 mL) was added thereto and stirred at room temperature for 10 minutes. The resulting solution was separated, the aqueous phase was extracted with dichloromethane (20 mL×5), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 1.7 g of crude compound 35-2, which was directly used in the next step without purification.

[0857] Step C: Preparation of compound 35

[0858] Referring to the method of step B of Example 19, compound 35-1 was reacted with compound 35-2 to prepare compound 35.

[0859] HRMS (ESI, [M+H] + )m / z=451.1510.

[0860] 1 H NMR (500MHz, CD3OD) δ9.12 (s, 1H), 8.83 (d, J=6.8Hz, 1H), 7.63 (t, J=7.3Hz, 1H), 7.49 (t, J=7.0Hz, 1H), 7.24 (t, J=7.7Hz, 1H), 7.00 (t, J=5 4.9Hz, 1H), 5.87 (q, J=7.1Hz, 1H), 4.23-4.02 (m, 4H), 2.65 (dt, J=15.6, 7.4Hz, 2H), 2.51 (s, 3H), 2.22-2.08 (m, 2H), 1.72 (d, J=7.1Hz, 3H).

[0861] 31 P NMR (202 MHz, CD3OD) δ 30.08.

[0862] Example 36: Preparation of Compound 36

[0863]

[0864] Step A: Preparation of Compound 36-1

[0865] Referring to the method of step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to prepare compound 36-1.

[0866] MS (ESI, [M+H] + )m / z=411.96.

[0867] 1 H NMR (500MHz, DMSO-d6) δ9.50 (s, 1H), 8.75 (d, J=2.2Hz, 1H), 7.96 (s, 1H), 7.87 (dd, J=8.9, 2.1Hz, 1H), 7. 72-7.68 (m, 1H), 7.56-7.53 (m, 1H), 7.36-7.11 (m, 2H), 5.79 (m, 1H), 2.37 (s, 3H), 1.61 (d, J=7.0Hz, 3H).

[0868] Step B: Preparation of compound 36

[0869] Compound 36 was prepared by referring to the method of step B of Example 19.

[0870] HRMS (ESI, [M+H] + )m / z=450.1552.

[0871] 1 H NMR (500MHz, CD3OD) δ8.69 (dd, J=13.1, 1.7Hz, 1H), 8.02 (m, 1H), 7.68 (dd, J=8.6, 2.5Hz, 1H), 7.53 (t, J=7.4Hz, 1H), 7.38 (t, J=7.1Hz, 1H), 7.14 (t, J=7.7Hz, 1H), 6.91(t, J=54.9Hz, 1H), 5.78(q, J=7.1Hz, 1H), 4.13-3.94(m , 4H), 2.50 (m, 2H), 2.36 (s, 3H), 2.11-1.96 (m, 2H), 1.62 (d, J=7.1Hz, 3H).

[0872] 31 P NMR (202 MHz, CD3OD) δ 31.65.

[0873] Example 37: Preparation of Compound 37

[0874]

[0875] Step A: Preparation of Compound 37-1

[0876] Referring to the method of step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was reacted with 6-bromo-2-methylquinazolin-4(3H)-one to prepare compound 37-1.

[0877] MS (ESI, [M+H] + )m / z=428.08.

[0878] Step B: Preparation of compound 37

[0879] Referring to the method of step B of Example 19, compound 37-1 was reacted with compound 35-2 to prepare compound 37.

[0880] HRMS (ESI, [M+H] + )m / z=468.1479.

[0881] 1 H NMR (500MHz, CD3OD) δ8.80 (dd, J=13.1, 1.4Hz, 1H), 8.13 (m, 1H), 7.79 (dd, J=8.6, 2.5Hz, 1H), 7.74 (t, J=7.0Hz, 1H), 7.56 (t, J=6.9Hz, 1H) , 7.27 (t, J=7.8Hz, 1H), 5.86 (q, J=7.1Hz, 1H), 4.26-4.01 (m, 4H), 2.61 (m, 2H), 2.45 (s, 3H), 2.14 (t, J=16.1Hz, 2H), 1.73 (d, J=7.1Hz, 3H).

[0882] 31 P NMR (202 MHz, CD3OD) δ 31.62.

[0883] Example 38: Preparation of Compound 38

[0884]

[0885] Step A: Preparation of compound 38-1

[0886] Referring to the method of step A of Example 19, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was reacted with 6-bromo-7-fluoro-2-methylquinazolin-4(3H)-one to prepare compound 38-1.

[0887] MS (ESI, [M+H] + )m / z=428.05.

[0888] 1 H NMR (500MHz, DMSO-d6) δ8.91 (d, J=7.5Hz, 1H), 8.63 (d, J=7.1Hz, 1H), 7.68 (t, J=7.3Hz, 1H) , 7.51 (t, J=7.8Hz, 2H), 7.37-7.18 (m, 2H), 5.78 (m, 1H), 2.34 (s, 3H), 1.60 (d, J=7.1Hz, 3H).

[0889] Step B: Preparation of compound 38

[0890] Compound 38 was prepared by referring to the method of Step B of Example 19.

[0891] HRMS (ESI, [M+H] + )m / z=468.1463.

[0892] 1 H NMR (500MHz, CD3OD) δ8.66 (dd, J=13.5, 6.7Hz, 1H), 7.53 (t, J=7.5Hz, 1H), 7.38 (t, J=7.1Hz, 1H), 7.26 (dd, J=11.4, 4.4Hz, 1H), 7.14 (t, J=7 .7Hz, 1H), 6.90 (t, J=54.9Hz, 1H), 5.77 (q, J=7.1Hz, 1H), 4.04 (m, 4H), 2.52 (m, 2H), 2.35 (s, 3H), 2.22-2.02 (m, 2H), 1.61 (d, J=7.1Hz, 3H).

[0893] 31 P NMR (202 MHz, CD3OD) δ 28.87.

[0894] Example 39: Preparation of Compound 39

[0895]

[0896] Step A: Preparation of compound 39-1

[0897] 2-Amino-3-fluorobenzoic acid (10 g) and dichloromethane (170 mL) were added to a 500 mL single-mouth bottle in sequence, stirred at room temperature, and N-iodosuccinimide (14.50 g) was added thereto. After the addition, the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, and the filter cake was slurried with dichloromethane (50 mL), filtered, and dried to obtain 12.9 g of compound 39-1.

[0898] 1H NMR (500MHz, DMSO-d6) δ7.81-7.80 (m, 1H), 7.57 (dd, J=10.8, 2.0Hz, 1H).

[0899] Step B: Preparation of compound 39-2

[0900] Referring to the method of Example 24, Step A, compound 39-2 was prepared.

[0901] 1 H NMR (500MHz, DMSO-d6) δ7.84-7.79 (m, 1H), 7.61-7.59 (m, 1H), 6.69 (s, 2H), 3.82 (s, 3H).

[0902] Step C: Preparation of Compound 39-3

[0903] Referring to the method of step B of Example 1, compound 39-3 was prepared.

[0904] MS (ESI, [M+H] + )m / z=304.75.

[0905] Step D: Preparation of compound 39-4

[0906] Referring to the method of step E of example 1, compound 39-4 was prepared.

[0907] MS (ESI, [M+H] + )m / z=297.04.

[0908] 1 H NMR (500MHz, DMSO-d6) δ 12.64 (br, 1H), 8.30 (dd, J=11.7, 1.3Hz, 1H), 8.09 (m, 1H), 4.06-3.83 (m, 4H), 2.49-2.39 (m, 5H), 2.02-1.95 (m, 2H).

[0909] Step E: Preparation of compound 39

[0910] Compound 39 was prepared by referring to the method of Example 19, Step A.

[0911] HRMS (ESI, [M+H] + )m / z=468.1466.

[0912] 1H NMR (500MHz, CD3OD) δ8.50 (d, J=12.9Hz, 1H), 7.81 (t, J=10.6Hz, 1H), 7.53 (t, J=7.3Hz, 1H), 7.39 (t, J=7.0Hz, 1H), 7.14 (t, J=7.7Hz, 1H), 6.91 (t, J=54.9Hz, 1H), 5.77 (q, J=7.1Hz, 1H), 4.14-3.91 (m, 4H), 2.50 (m, 2H), 2.39 (s, 3H), 2.04 (t, J=16.5Hz, 2H), 1.62 (d, J=7.1Hz, 3H).

[0913] 31 P NMR (202 MHz, CD3OD) δ 31.53.

[0914] Example 40: Preparation of Compound 40

[0915]

[0916] Step A: Preparation of Compound 40-1

[0917] 4,6-dichloro-2-methylpyrimidine (16.3 g) and aqueous ammonia (80 mL) were added to a 350 mL pressure-resistant reaction bottle in sequence, and the mixture was sealed and heated to 90°C for overnight reaction. The reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was collected, and dried under reduced pressure to obtain 14 g of compound 40-1.

[0918] MS (ESI, [M+H] + )m / z=143.93.

[0919] Step B: Preparation of compound 40-2

[0920] Compound 40-1 (2 g) obtained in step A and methanol (20 mL) were added to a 100 mL three-necked flask in sequence. When the temperature was cooled to 0°C in an ice-salt bath, a solution of iodine monochloride (15.58 g) in methanol (20 mL) was added dropwise. After the addition, the mixture was transferred to room temperature and stirred overnight. After the reaction was completed, the reaction solution was poured into water (100 mL), and then a saturated sodium sulfite solution (200 mL) was added. The pH was adjusted to 6-7 with a 2M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.3 g of compound 40-2.

[0921] MS (ESI, [M+H] + )m / z=269.86.

[0922] 1H NMR (500MHz, DMSO-d6) δ7.28 (d, 2H), 2.29 (s, 3H).

[0923] Step C: Preparation of Compound 40-3

[0924] Compound 40-2 (2.8 g) obtained in step B, N,N-dimethylformamide (28 mL), tert-butyl acrylate (1.598 g), triethylamine (2.103 g), palladium acetate (0.058 g) and tri-o-tolylphosphine (0.158 g) were added to a 250 mL single-mouth bottle in sequence, and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, the mixture was heated to 100° C. for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (80 mL×3), the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 70: 30) to obtain 1.7 g of compound 40-3.

[0925] MS (ESI, [M+H] + )m / z=270.38.

[0926] 1 H NMR (500MHz, DMSO-d6) δ7.45-7.40 (m, 3H), 6.34 (d, J=16.4Hz, 1H), 2.31 (s, 3H), 1.48 (s, 9H).

[0927] Step D: Preparation of compound 40-4

[0928] Compound 40-3 (0.4 g) obtained in step C and acetonitrile (8 mL) were added to a 25 mL reaction bottle in sequence, and the reaction bottle was placed under 365 nm wavelength light and stirred at room temperature for 4 h. The reaction was stopped, filtered, and the filter cake was collected to obtain 0.22 g of compound 40-4.

[0929] MS (ESI, [M+H] + )m / z=270.08.

[0930] 1 H NMR (500MHz, DMSO-d6) δ6.88 (s, 2H), 6.70 (d, J=11.6Hz, 1H), 6.05 (d, J=11.6Hz, 1H), 2.30 (s, 3H), 1.29 (s, 9H).

[0931] Step E: Preparation of Compound 40-5

[0932] Compound 40-4 (2.8 g), trifluoroethanol (1.038 g), and potassium tert-butoxide (2.56 g) obtained in step D were added to a 250 mL reaction bottle in sequence, and the mixture was heated to 80°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was added with methyl tert-butyl ether (20 mL) and slurried to obtain 2.2 g of compound 40-5.

[0933] MS (ESI, [M+H] + )m / z=260.05.

[0934] 1 H NMR (500MHz, DMSO-d6) δ12.46 (s, 1H), 7.86 (d, J=9.6Hz, 1H), 6.51 (d, J=9.6Hz, 1H), 5.19 (q, J=8.9Hz, 2H), 2.55 (s, 3H).

[0935] Step F: Preparation of compound 40-6

[0936] Compound 40-5 (2 g) obtained in step E and N, N-dimethylformamide (20 mL) were added to a 250 mL single-mouth bottle in sequence, cooled to below 5°C in an ice-water bath, sodium hydride (0.370 g) was added, stirred at room temperature for 5 minutes, and then iodomethane (1.314 g) was added dropwise to the reaction bottle in an ice bath, and stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 70: 30) to obtain 1.7 g of compound 40-6.

[0937] MS (ESI, [M+H] + )m / z=274.03.

[0938] 1 H NMR (500MHz, DMSO-d6) δ7.90 (d, J=9.6Hz, 1H), 6.64 (d, J=9.6Hz, 1H), 5.21 (q, J=8.9Hz, 2H), 3.60 (s, 3H), 2.62 (s, 3H).

[0939] Step G: Preparation of compound 40-7

[0940] Compound 40-6 (0.65 g) obtained in step F and 48% aqueous hydrobromic acid solution (8 mL) were added to a 100 mL single-mouth bottle in sequence, and the reaction was stirred at room temperature. Sodium bromate (1.077 g) was added in batches. After the addition was completed, the reaction bottle was transferred to a 60°C oil bath and stirred for 2 h. After the reaction was completed, the reaction solution was poured into ice water (10 mL), and then a saturated sodium sulfite solution (30 mL) was added. The mixture was stirred vigorously for 5 minutes, and the pH was adjusted to 6-7 with a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 80: 20) to obtain 0.7 g of compound 40-7.

[0941] MS (ESI, [M+H] + )m / z=351.92.

[0942] 1 H NMR (500MHz, DMSO-d6) δ8.31 (s, 1H), 5.23 (q, J=8.9Hz, 2H), 3.68 (s, 3H), 2.62 (s, 3H).

[0943] Step H: Preparation of Compound 40-8

[0944] Compound 40-7 (0.7 g) obtained in step G and 48% aqueous hydrobromic acid solution (7 mL) were added to a 100 mL single-mouth bottle in sequence. After the addition, the mixture was heated to 100°C for 2.5 h. After the reaction was completed, the reaction solution was cooled to room temperature and poured into ice water (100 mL). The pH was adjusted to 6-7 with saturated sodium bicarbonate solution, filtered, and the filter cake was collected and dried to obtain 0.537 g of compound 40-8.

[0945] MS (ESI, [M+H+2] + )m / z=271.96.

[0946] 1 H NMR (500MHz, DMSO-d6) δ12.90 (s, 1H), 8.24 (s, 1H), 3.63 (s, 3H), 2.41 (s, 3H).

[0947] Step I: Preparation of compound 40-9

[0948] Referring to the method of Example 19, Step A, compound 40-9 was prepared.

[0949] 1H NMR (500MHz, DMSO-d6) δ8.93 (s, 1H), 8.44 (d, J = 6.9Hz, 1H), 7.73 (d, J = 7.8Hz, 1H), 7.54 (d, J = 7.6Hz, 1H), 7 .36 (t, J=7.8Hz, 1H), 5.64 (p, J=6.9Hz, 1H), 3.57 (s, 3H), 2.59 (s, 3H), 2.31 (s, 3H), 1.52 (d, J=7.0Hz, 3H).

[0950] Step J: Preparation of compound 40

[0951] Referring to the method of step B of Example 19, compound 40-9 was reacted with compound 35-2 obtained in step c of Example 35 to prepare compound 40.

[0952] HRMS (ESI, [M+H] + )m / z=495.1768.

[0953] 1 H NMR (500MHz, CD3OD) δ8.78 (d, J=14.5Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 5.79 (q, J=7.0Hz, 1H), 4.19 (m, 2H), 4.07 (q, J=11.3Hz, 2H), 3.64 (s, 3H), 2.81 (m, 2H), 2.62 (s, 3H), 2.41 (s, 3H), 1.87 (t, J=16.8Hz, 2H), 1.60 (d, J=7.0Hz, 3H).

[0954] Example 41: Preparation of Compound 41

[0955]

[0956] Step A: Preparation of Compound 41-1

[0957] 5-Amino-2-chloroisonicotinic acid methyl ester (2g), N,N-dimethylformamide (20mL), and N-bromosuccinimide (1.9g) were added to a 100mL single-mouth bottle in sequence, and the reaction solution was heated to 80°C for 3h. After the reaction was completed, the reaction solution was poured into water (200mL), extracted with methyl tert-butyl ether (50mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 80: 20) to obtain 2.6g of compound 41-1.

[0958] MS (ESI, [M+H+2]+ )m / z=266.87.

[0959] 1 H NMR (500MHz, DMSO-d6) δ7.63 (s, 1H), 6.78 (s, 2H), 3.88 (s, 3H).

[0960] Step B: Preparation of compound 41-2

[0961] Compound 41-1 (1.1 g), acetonitrile (3.40 g), and methanesulfonic acid (3.98 g) were added to a 35 mL microwave tube in sequence. After stirring at room temperature for 10 minutes, the mixture was placed in a microwave reactor and heated to 120° C. at 50 W for 2 h. After the reaction was completed, the obtained sample solution was concentrated to dryness under reduced pressure, diluted with water (20 mL), and the pH was adjusted to alkaline with 15% aqueous sodium hydroxide solution, and filtered to obtain 0.8 g of compound 41-2.

[0962] MS (ESI, [MH] - )m / z=273.89.

[0963] 1 H NMR (500MHz, CD3OD) δ7.94 (s, 1H), 2.48 (s, 3H).

[0964] Step C: Preparation of Compound 41-3

[0965] Compound 41-2 (0.2 g) obtained in step B, N,N-dimethylformamide (2 mL), zinc cyanide (39.4 mg) and tetrakis(triphenylphosphine)palladium (78 mg) were added to a 5 mL microwave tube in sequence, and the mixture was replaced with nitrogen three times and placed in a microwave reactor, heated to 110° C. at 50 W for 1 h. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol=80:20) to obtain 136 mg of compound 41-3.

[0966] MS (ESI, [MH] - )m / z=218.95.

[0967] 1 H NMR (500MHz, CD3OD) δ7.97 (s, J=7.2Hz, 1H), 2.51 (s, 3H).

[0968] Step D: Preparation of Compound 41-4

[0969] Referring to the method of Example 19, Step A, compound 41-4 was prepared.

[0970] MS (ESI, [M+H] + )m / z=410.12.

[0971] Step E: Preparation of Compound 41

[0972] Referring to the method of step B of Example 19, compound 41-1 prepared in the above step D was reacted with compound 35-2 to prepare compound 41.

[0973] HRMS (ESI, [M+H] + )m / z=494.1365.

[0974] 1 H NMR (500MHz, CD3OD) δ8.97 (d, J=6.1Hz, 1H), 7.71-7.62 (m, 1H), 7.51-7.45 (m, 1H), 7.19 (t, J=7.8Hz, 1H) , 5.73 (q, J=7.1Hz, 1H), 4.15-3.94 (m, 4H), 2.54 (m, 2H), 2.42 (s, 3H), 2.08 (m, 2H), 1.64 (d, J=7.1Hz, 3H).

[0975] 31 P NMR (202 MHz, CD3OD) δ 29.64.

[0976] Example 42: Preparation of Compound 42

[0977]

[0978] Step A: Preparation of Compound 42

[0979] Referring to the method of step B of Example 19, compound 19-1 was reacted with 1-phosphinane oxide to prepare compound 42.

[0980] HRMS (ESI, [M+H] + ): m / z = 467.1620.

[0981] 1H NMR (500MHz, CD3OD) δ9.10 (s, 1H), 8.81-8.78 (m, 1H), 7.75 (t, J = 6.9Hz, 1H), 7.57 (t, J = 7.0Hz, 1H), 7.28 (t, J = 7.8Hz, 1H), 5.85 ( q, J=7.1Hz, 1H), 2.50 (s, 3H), 2.47-2.39 (m, 2H), 2.13-1.94 (m, 6H), 1.85-1.79 (m, 1H), 1.73 (d, J=7.1Hz, 3H), 1.66-1.59 (m, 1H).

[0982] Example 43: Preparation of Compound 43

[0983]

[0984] Step A: Preparation of Compound 43

[0985] Referring to the method of step B of Example 19, compound 19-1 was reacted with 1-phospholane oxide to prepare compound 43.

[0986] HRMS (ESI, [M+H] + ): m / z = 453.1594.

[0987] 1 H NMR (500MHz, CD3OD) δ9.09 (s, 1H), 8.81 (dd, J=6.5, 0.7Hz, 1H), 7.75 (t, J=6.9Hz, 1H), 7.57 (t, J=7.1Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 5.85 (q, J=7.1Hz, 1H), 2.50 (s, 3H), 2.33-2.29 (m, 2H), 2.20-2.10 (m, 4H), 2.02-1.94 (m, 2H), 1.72 (d, J=7.1Hz, 3H).

[0988] The following Examples 44 to 47 (Table 1) can refer to the method of Example 1, replacing 2-amino-4-methoxybenzoic acid methyl ester with the following fragment 1-1, and replacing (R)-1-(m-tolyl)ethane-1-amine with the following fragment 1-2 for reaction, and finally referring to the method of Step C of Example 7 to prepare Compounds 44 to 47.

[0989] Table 1:

[0990]

[0991]

[0992] The following intermediates (Table 2-1) can be prepared by referring to the method of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with the following fragment a, and reacting with the corresponding fragment b to prepare intermediate compounds 2a-1 to 2a-6.

[0993] Table 2-1:

[0994]

[0995]

[0996] Examples 48 to 60 (Table 2) can refer to the method of Example 10, replacing compound 7-1 with the intermediates 2a-1 to 2a-6 prepared above, and replacing acetic anhydride with the following fragment 2 for substitution, reductive amination or condensation reaction to prepare compounds 48 to 60.

[0997] Table 2:

[0998]

[0999]

[1000]

[1001]

[1002] The following intermediates (Table 3-1) can be prepared by referring to the method of Step A of Example 9, replacing 5-amino-2-chloroisonicotinic acid with the following fragment 2a, to obtain the following intermediate compounds 3a-1 to 3a-2.

[1003] Table 3-1:

[1004]

[1005] The following Examples 61 to 64 (Table 3) can refer to the method of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with the following fragment 3-1, and replacing compound 9-1 with the intermediate compound prepared above to prepare compounds 61 to 64.

[1006] Table 3:

[1007]

[1008]

[1009] The following Example 65 (Table 4) can refer to the method of Example 35, replace compound 9-1 with intermediate 3a-2, replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with the corresponding fragment 4-1, and replace compound 35-2 with the corresponding fragment 4-2 for reaction, and finally refer to the method of step C of Example 7 to prepare compound 65. The following Examples 66 to 71 (Table 4) can refer to the method of Example 35, replace compound 9-1 with intermediate 3a-2, replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with the following fragment 4-1, and replace compound 35-2 with the following fragment 4-2 to prepare compounds 66 to 71.

[1010] Table 4:

[1011]

[1012]

[1013] Test Example 1 In vitro cell level phosphorylation activity inhibition test

[1014] 1.1 Test reagents and instruments

[1015] 1.1.1 Test reagents

[1016]

[1017]

[1018] 1.1.2 Instruments

[1019]

[1020] 1.2 In vitro cell-level phosphorylation activity inhibition test method

[1021] Take a dish of H358 human non-small cell lung cancer cells (Nanjing Kebai Biotechnology Co., Ltd.) in good exponential growth phase, collect the cells into a centrifuge tube, centrifuge at a low speed desktop centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and use a pipette to add 5mL of 5% FBS seeding medium to resuspend the cells. Count using a cell counter, dilute with seeding medium, and adjust the cell density to 1.5×10 5 / mL. Use a multichannel pipette to inoculate on a black bottom transparent 384-well plate, 40μL / well, place in a cell culture incubator at 37℃ and 5% CO2 saturated humidity overnight, and use a Tecan D300e ultra-micropipette to add compounds. After 1 hour, discard the culture medium, add 40μL 4% paraformaldehyde to each well, incubate at room temperature for 20min, and wash with PBS. Add 40μL methanol to each well, incubate at room temperature for 10min, and wash with PBST. Add 20μL 5% BSA blocking buffer to each well, block at room temperature for 1h, discard the blocking solution, add 20μL primary antibody mixture to each well, in which Rabbit anti-pERK is diluted at 1:1000 (final concentration) and mouse anti-GAPDH is diluted at 1:5000 (final concentration), incubate at 4℃ overnight, and wash with PBST. 20 μL of secondary antibody mixture was added to each well, in which goat anti rabbit 800 and goat anti mouse 647 were diluted at 1:1000 (final concentration), incubated at room temperature in the dark for 45 min, and washed with PBST. Azure Biosystems scanned the readings, with the logarithm of the compound concentration as the horizontal axis and the phosphorylation inhibition rate as the vertical axis. The EC was calculated and analyzed using a four-parameter logistic model. 50 The results are shown in Table 5.

[1022] Table 5

[1023] Example <![CDATA[EC 50 (nM)]]> 12 103 14 108 15 148 17 82 18 71 .

[1024] Test Example 2 Guanine nucleotide exchange test

[1025] This test quantitatively examines the ability of SOS1 to mediate KRAS activation. KRAS G12C with a His tag is added to the system, and an anti-His antibody labeled with the lanthanide element Eu is bound to it. Then, the auxiliary protein SOS1cat and the GTP analogue EDA-GTP-DY-647P1 with a fluorescent group are added. The GTP analogue with a fluorescent group is loaded onto KRASG12C with the assistance of the auxiliary protein, so that energy resonance transfer occurs between Anti-6HIS-Cryptate (FRET donor) and EDA-GTP-DY-647P1 (FRET acceptor). After being treated with SOS1 inhibitor compounds in advance, the ability of SOS1 to bind and mediate KRAS activation is weakened, and the FRET ability between the donor and the acceptor is weakened.

[1026] 2.1 Test reagents and instruments

[1027] 2.1.1 Test reagents

[1028] name Manufacturer / Source Part Number / Test Number His-KRAS G12C In-house production TQB3822PP01a SOS1cat In-house production TQB3822PP02 Anti-6HIS-Cryptate Cisbio 61HISKLA EDA-GTP-DY-647P1 Jena Bioscience NU-820-647P1 HEPES pH 7.4 Thermo 15630080 NaCl Shanghai Test 10019318 <![CDATA[MgCl2]]> Sigma M8266 DTT Promega V3151 BSA Sigma B2604 DMSO Sigma D4540 Igepal Sigma I3021

[1029] 2.1.2 Instruments

[1030] name Manufacturer model Pipette Thermo 100-1000μl Pipette Thermo 20-200μl Pipette Thermo 10-100 μl Pipette RNIN 2-20μl Pipette RNIN 0.5-10μl Ultra-micropipette Tecan D300E

[1031] 2.2 Nucleotide exchange test process

[1032] Preparation of His-KRAS G12C: Codon optimization and gene synthesis of K-Ras4B-G12C (UniProt P01116-2, amino acid 1-169) sequence were performed, and finally subcloned into pET-30a(+) vector, transformed into BL21(DE3) competent cells, and suitable clones were selected, cultured in TB medium and induced by IPTG at low temperature, and the bacteria were collected. The cells were broken by ultrasonic crusher, and the supernatant was collected by centrifugation. Ni Sepharose HP and Superdex 200pg (16 / 60) were used for purification to obtain a protein with a purity of >90%, and the activity was measured for later use.

[1033] Preparation of SOS1cat: The human SOS1 (UniProt Q07889, amino acid 564-1049) sequence was codon optimized and gene synthesized, and finally subcloned into the pET-30a (+) vector, transformed into the BL21 (DE3) competent cell, selected suitable clones, cultured in TB medium and induced expression at low temperature with IPTG, and the bacteria were collected. The cells were disrupted by ultrasonic disruptor, and the supernatant was collected by centrifugation. The protein with purity > 90% was purified by Ni Sepharose HP, Superdex 200pg (16 / 60) and Superdex 200pg (16 / 60), and the activity was measured for later use.

[1034] The assay buffer was prepared, the components of which were: HEPES pH 7.4: 20 mM; NaCl: 150 mM; MgCl2: 0.5 mM; DTT: 2 mM; BSA: 0.05%; Igepal: 0.0025%.

[1035] The KRAS G12C working solution, SOS1cat working solution and blank control solution were prepared with the test buffer, wherein the KRAS G12C working solution contained 100nM His-KRAS G12C and 2nM anti-His-terbium; the SOS1cat working solution contained 20nM SOS1cat and 200nM EDA-GTP-DY-647P1; and the blank control solution contained 100nM EDA-GTP-DY-647P1.

[1036] The entire experimental process was completed at 20°C. 5 μL of SOS1cat working solution was added to each well of the experimental group, and 5 μL of blank control working solution was added to each well of the control group, and incubated at 20°C for 10 minutes. Then, the compound was added using a Tecan D300e ultra-micropipette, with the highest final concentration of the compound being 10 μM. The compound was diluted in sequence by 2 times, with a total of 8 concentration gradients set, and incubated at 20°C for 30 minutes. Finally, 5 μL of KRAS G12C working solution was added to each well, incubated at 20°C for 15 minutes, and the Envision microplate reader was used to detect the 665nm / 620nm fluorescence ratio, which reflects the degree of nucleotide conversion. Calculate the inhibition rate, inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%, where the negative control group did not contain compounds, and the other conditions were the same as the experimental group. The logarithm of the compound concentration was used as the horizontal axis, and the inhibition rate was used as the vertical axis. The four-parameter logistic model was used to calculate and analyze the IC 50 The results are shown in Table 6.

[1037] Test Example 3 KRAS / SOS1 protein binding test

[1038] This assay can be used to test the potency of compounds in inhibiting the protein-protein interaction between SOS1 and KRAS G12C on the one hand, and to validate the molecular mode of action of compounds on the other hand. 50 The values ​​indicate that SOS1 inhibitor compounds can effectively inhibit protein interactions.

[1039] 3.1 Assay reagents and buffers

[1040] 3.1.1 Reagents:

[1041] GST-SOS1 (564-1049), internal production: The human SOS1 (UniProt Q07889, amino acid 564-1049) sequence was codon optimized and gene synthesized, and finally subcloned into the pGEX-4T-1 vector, transformed into BL21 (DE3) competent cells, selected suitable clones, cultured in TB medium and induced by IPTG at low temperature, and the bacteria were collected. The cells were disrupted by ultrasonic disruptor, and the supernatant was collected by centrifugation. Ni Sepharose HP and Superdex200pg (16 / 60) were used for purification to obtain a protein with a purity of > 90%, and the activity was measured for later use;

[1042] Kras-G12C-6xHis(1-169), internal production: K-Ras4B-G12C(UniProt P01116-2, aminoacid 1-169) sequence was codon optimized and gene synthesized, and finally subcloned into pET-30a(+) vector, transformed into BL21(DE3) competent cells, selected suitable clones, cultured in TB medium and induced expression at low temperature with IPTG, and collected bacteria. Cells were disrupted by ultrasonic disruptor, and supernatant was collected by centrifugation. Protein with purity>90% was purified by Ni Sepharose HP and Superdex 200pg(16 / 60), and activity was measured for later use;

[1043] GDP (Sigma, catalog number G7127);

[1044] MAb Anti-GST-XL665 (Cisbio, catalog number 61GSTXLA);

[1045] MAb Anti-6HIS-Tb cryptate Gold (Cisbio, cat. no. 61HI2TLA).

[1046] 3.1.2 Buffer:

[1047] Diluent Buffer (Cisbio, catalog number 62DLBDDF);

[1048] Detection buffer (Cisbio, catalog number 62DB2FDG);

[1049] GST-SOS1 working solution: Prepared with Diluent Buffer, concentration is 92nM;

[1050] GDP-Kras-G12C-His working solution: Prepared with Diluent Buffer, the final concentration of GDP is 40μM, and the final concentration of Kras-G12C-His is 100nM;

[1051] Antibody working solution: Prepared with detection buffer, MAb Anti-GST-XL665 and MAb Anti-6HIS-Tb cryptate Gold concentrations are both 4X, mixed 1:1.

[1052] 3.2 Testing process:

[1053] 5 μL of GST-SOS1 working solution was added to each well of the test group and the negative group, and 5 μL of Diluent Buffer was added to each well of the control group. Then, the compound was added to the test group using a Tecan D300e ultra-micropipette, up to 5000 nM, and diluted 3 times in sequence, with a total of 7 concentration gradients, and incubated at room temperature for 30 min; then 5 μL of the GDP-Kras-G12C-His working solution prepared in advance was added to each well (GDP and Kras-G12C-His were incubated at room temperature for 10 min), and incubated at room temperature for 15 min; finally, 10 μL of antibody working solution was added to each well, incubated at room temperature for 50 min, and the 665nm / 620nm fluorescence ratio was detected by Envision microplate reader. The inhibition rate was calculated, inhibition rate (%) = (average value of negative control group - average value of test group) / (average value of negative control group - average value of blank group) × 100%, where the negative control group did not contain compounds, and the other conditions were the same as the test group. The IC was calculated using a four-parameter logistic model with the logarithm of the compound concentration as the horizontal axis and the inhibition rate as the vertical axis. 50 The results are shown in Table 6.

[1054] Test Example 4 K562 cell proliferation inhibitory activity assay

[1055] The K562 cell line can be purchased from the American Type Culture Collection (ATCC).

[1056] Take K562 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 / mL, inoculated on a 96-well plate (100μL / well), cultured overnight in a cell culture incubator, and used a nanoliter pipette to add compounds to a final concentration of 10000nM-4.6nM, 2 replicates, and set up controls. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (Cell Counting Kit-8, Tongren Chemical Research Institute, 10μL / well) was added. After incubation in the cell culture incubator for 1 hour, the absorbance was detected at 450nm using an Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 , the results are shown in Table 6.

[1057] Table 6

[1058]

[1059]

[1060] Experimental Example 5 Pharmacodynamic evaluation of SOS1 inhibitors in the MIA PaCa-2 human pancreatic cancer xenograft model in nude mice

[1061] SPF female BALB / C nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) were inoculated subcutaneously in the right axilla with 1×10 7 MIA PaCa-2 cells (Kras G12C mutant tumor cells, Nanjing Kebai Biotechnology Co., Ltd.). When the average tumor volume reaches 200mm 3 At about 14:00 p.m., the animals were divided into a treatment group and a control group, with 8 mice in each group. The day of grouping was d0, and oral administration began on d1, twice a day, with a dosing volume of 10 mL / kg for the treatment group. The control group was given a vehicle control. The administration was continued, and the tumor volume was measured 2-3 times a week. The mice were weighed and the data were recorded at the same time; the general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

[1062] Tumor volume calculation formula:

[1063] Tumor volume (mm 3 )=1 / 2×(a×b 2 )(where a represents the major diameter and b represents the minor diameter);

[1064] Relative tumor proliferation rate, T / C%, is the percentage value of the relative tumor volume between the treatment group and the control group at a certain time point;

[1065] The relative tumor inhibition rate, TGI (%), was calculated as follows: TGI% = (1-tumor weight of treatment group / tumor weight of control group) × 100%;

[1066] Weight change rate (WCR) (%), calculated as: WCR = (Wt t -Wt0) / Wt0×100%, Wt0 is the weight of the animals at the time of grouping (i.e., day 0), Wt t is the animal weight at each measurement.

[1067] The compounds of the present application have good in vivo pharmacodynamic activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, is a double bond, and X and Y are independently selected from CR a and N; or is a single bond, and X is NR b , Y is C(O); R a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 Alkyl or C 1-4 The alkoxy group is optionally substituted with one or more deuterium or halogen; R b Selected from hydrogen or C 1-6 alkyl; R 1 , R 2 are independently selected from C 1-6 Alkyl, or R 1 , R 2 Together with the phosphorus atom connected thereto, a 5- to 6-membered heterocyclic group is formed, wherein the C 1-6 The alkyl group or the 5- to 6-membered heterocyclic group is optionally substituted with one or more R c replace; Every R c are independently selected from hydrogen, C 1-6 Alkyl-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, 3-6 membered cycloalkyl-S(O)2-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl-OC 1-6 Alkyl-, C 1-6 Alkyl-OC 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocycloalkyl-, phenyl-C 1-3 Alkyl- or C substituted with one or more hydroxyl or cyano groups 1-6 Alkyl-, wherein R c when not hydrogen, is optionally substituted by one or more halogens; Ring A is selected from phenyl, thienyl, 2,3-dihydrobenzofuranyl or benzofuranyl; n is 0, 1, 2 or 3; Every R 3 are independently selected from amino, nitro, halogen, C 1-6 Alkyl- or phenyl, wherein the C 1-6 The alkyl or phenyl group is optionally replaced by one or more R d replace; R d Selected from hydroxyl, halogen or C 1-3 Alkyl-NH-C 1-3 alkyl-; R 4 is selected from methyl, wherein the methyl is optionally substituted with one or more fluorine; R 5 is selected from hydrogen or deuterium; R 6 Selected from hydrogen, halogen or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted with one or more halogens; And the compound of formula (I) is not the following compound:

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X and Y are both selected from CR a .

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from CH, Y is selected from CR a .

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from CH, and Y is selected from C(OH), C(OCH3), C(OCHF2), C(OCH2F), CF or C(OCD3).

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X is selected from CH, and Y is selected from N.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from N(CH3), and Y is selected from C(O).

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X is selected from CF or C(CN), and Y is selected from CH or N.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 Alkoxy, wherein the C 1-4 The alkoxy group is optionally substituted with 3 deuterium or one or more fluorine.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R a Selected from hydrogen, hydroxyl, fluorine, cyano, CH3O-, CD3O-, CH2FO- or CHF2O-.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R a Selected from hydrogen, halogen or C 1-4 Alkoxy, wherein the C 1-4 The alkoxy groups are optionally substituted with one or more deuterium or halogen.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R a Selected from hydrogen, fluorine, CH3O-, CD3O- or CHF2O-.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R b Selected from C 1-4 alkyl.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: R b Selected from C 1-3 alkyl.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: R b Selected from methyl.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 , R 2 are independently selected from C 1-3 alkyl.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein: R 1 , R 2 are independently selected from methyl or ethyl.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 , R 2 Together with the phosphorus atom connected thereto, a 5- to 6-membered heterocyclic group is formed, wherein the ring atoms of the 5- to 6-membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain N atoms, N and R c connect.

18. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 , R 2 Together with the phosphorus atom connected thereto, a 5- to 6-membered heterocycloalkyl group is formed, wherein the ring atoms of the 5- to 6-membered heterocycloalkyl group contain at least one nitrogen atom, and the nitrogen atom and the R c connect.

19. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 , R 2 Together with the phosphorus atom connected thereto, a 6-membered heterocycloalkyl group is formed, wherein the ring atom of the 6-membered heterocycloalkyl group contains only one N atom, and N and R c connect.

20. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-membered or 6-membered heterocyclic group, wherein the ring atoms of the 5-membered or 6-membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain N atoms, N and R c connect.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Structural unit For structural units 22. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Structural unit For structural units 23. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Every R c are independently selected from C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl-S(O)2-, 3- to 5-membered cycloalkyl-S(O)2-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-CH2-, 3-5-membered cycloalkyl-, 3-5-membered cycloalkyl-C(O)-, 3-5-membered cycloalkyl-CH2-, 3-5-membered heterocycloalkyl-, phenyl-CH2-, or C(O)-substituted with one hydroxyl or cyano group 1-3 Alkyl, wherein the R c When not hydrogen it is optionally substituted by 1, 2 or 3 halogens.

24. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Every R c are independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, 25. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Every R c are independently selected from hydrogen, C 1-3 Alkyl-, C 1-3 Alkyl-C(O)-, C 1-3 Alkyl OC(O)-, C 1-3 Alkyl-OC 1-3 Alkyl-, C 1-3 Alkyl-O-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-CH2-C(O)-, di(C 1-3 alkyl)amino-C(O)-CH2-, 3- to 5-membered cycloalkyl-, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, phenyl-CH2-, or C(O)-substituted with one hydroxyl group 1-3 alkyl-.

26. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Every R c are independently selected from methyl, ethyl, isopropyl, acetyl, 27. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is selected from phenyl, thienyl or 2,3-dihydro-1H-indenyl.

28. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: n is 1, 2 or 3.

29. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: n is 2.

30. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 3 are independently selected from amino, nitro, halogen, C 1-4 Alkyl or phenyl, wherein the C 1-4 The alkyl or phenyl group is optionally replaced by one or more R d Replacement, R d Selected from hydroxyl, halogen or C 1-3 Alkyl-NH-C 1-3 alkyl-.

31. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 3 are independently selected from amino, nitro, halogen, C 1-4 Alkyl or phenyl, wherein the C 1-4 The alkyl or phenyl group is optionally replaced by 1, 2 or 3 R d Replacement, R d Selected from hydroxy and fluorine or methyl-NH-methyl-.

32. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 3 are independently selected from amino, nitro, halogen or C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more R d Replacement, R d Selected from hydroxyl or halogen.

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein: R 3 Each independently selected from amino, nitro, fluorine, methyl, trifluoromethyl, -CF2CH2OH, -CHF2, -CF2CH3, -CF2C(CH3)2OH or 34. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the structural unit Selected from 35. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the structural unit Selected from 36. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Structural unit Selected from 37. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein: R 4 is selected from methyl or -CH2F, R 5 Selected from hydrogen or deuterium.

38. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein: R 4 Selected from methyl, R 5 Selected from hydrogen.

39. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 6 is selected from hydrogen, fluorine, chlorine or methyl, wherein the methyl is optionally substituted by 1, 2 or 3 fluorine groups.

40. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 39, wherein: R 6 is selected from hydrogen, chlorine, methyl or -CH2F.

41. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 39, wherein: R 6 Selected from methyl.

42. A compound of formula (II) or a pharmaceutically acceptable salt thereof, in, is a double bond, and X and Y are independently selected from CR a and N; or is a single bond, and X is NR b , Y is C(O); R a Selected from hydrogen, hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally substituted with one or more halogens, 1-4 The alkoxy group is optionally substituted with one or more deuterium or halogen; R b Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy; R 1 , R 2 are independently selected from C 1-6 Alkyl, or R 1 , R 2 Together with the phosphorus atom connected thereto, it forms a 5-6 membered heterocyclic group, wherein the ring atoms of the 5-6 membered heterocyclic group contain at least one nitrogen atom, and nitrogen and R c connect; Every R c are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl-OC 1-6 Alkyl-, C 1-6 Alkyl-OC 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 Alkyl-, phenyl-C 1-3 Alkyl- or C substituted with one or more hydroxyl groups 1-6 Alkyl, wherein R c when not hydrogen, is optionally substituted by one or more halogens; Ring A is selected from phenyl, thienyl, 2,3-dihydrobenzofuranyl or benzofuranyl; n is 0, 1, 2 or 3; Every R 3 are independently selected from amino, nitro, halogen, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 The alkyl group and the 3- to 6-membered cycloalkyl group are optionally substituted with one or more R d replace; R d Selected from hydroxyl or halogen.

43. A compound of formula (III) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , X, Y, n, ring A and As defined in any one of claims 1 to 36.

44. A compound of formula (III) or a pharmaceutically acceptable salt thereof as claimed in claim 43, wherein Structural unit As defined in claim 21 or 22.

45. A compound of formula (III) or a pharmaceutically acceptable salt thereof as claimed in claim 43, wherein Structural unit As defined in any one of claims 34 to 36.

46. ​​A compound of formula (III) or a pharmaceutically acceptable salt thereof as claimed in claim 43, wherein The compound of formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III-1), the compound of formula (III-2), the compound of formula (III-4) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , Y, n, and R b As defined in any one of claims 1 to 22 and 28 to 33.

47. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, or a compound of formula (II) or a pharmaceutically acceptable salt thereof as claimed in claim 42, selected from a compound of formula (IV), a compound of formula (V) and a compound of formula (VI) or a pharmaceutically acceptable salt thereof, in, R 3 ,Y,n,R b and R c As defined in any one of claims 1-14, 23-26 and 28-33.

48. The following compound or a pharmaceutically acceptable salt thereof, 49. The following compound or a pharmaceutically acceptable salt thereof:

50. A pharmaceutical composition comprising the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof.

51. Use of a compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 50, in the preparation of a medicament for treating a disease and / or condition associated with or regulated by SOS1.

52. The use according to claim 51, wherein The disease and / or condition associated with or modulated by SOS1 is selected from non-small cell lung cancer.

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