Phosphorus-containing SOS1 inhibitors

Abstract

The present application is in the field of medicinal chemistry and relates to phosphorus-containing SOS1 inhibitors, i.e. compounds of formula (I), as well as processes for their preparation, pharmaceutical compositions containing said compounds, and their use in the manufacture of medicaments for the treatment of diseases and / or conditions associated with or modulated by SOS1. [Case B1] JPEG2023524864000192.jpg5043

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Chinese Patent Application No. 202010387620.0 filed with the State Intellectual Property Office of China on May 9, 2020, and Chinese Patent Application No. 202110450032.1 filed with the State Intellectual Property Office of China on April 25, 2021, which are hereby incorporated by reference in their entireties. [Technical Field]

[0002] The present application relates to phosphorus-containing SOS1 inhibitors, methods for their preparation, pharmaceutical compositions containing the inhibitors, and their use in the treatment of diseases and / or conditions associated with or modulated by SOS1. [Background technology]

[0003] RAS is the most frequently mutated oncogene in human cancers, with KRAS being the most common subtype of the RAS family, accounting for 86% of all RAS mutations.

[0004] Binding of the guanine nucleotide exchange factor (GEF) Son of Sevenless1 (SOS1) promotes the release of GDP from RAS family proteins, allowing GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). In the GTP-bound state, RAS family proteins are activated and promote the RAF / mitogen- or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway by engaging effector proteins such as c-RAF and phosphatidylinositol 3-kinase (PI3K) (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 a variety of cellular processes, including 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).

[0005] Selective inhibition of the binding of the catalytic site of SOS1 to RAS family proteins can prevent SOS1-mediated activation of RAS family proteins to GTP-bound forms. Therefore, SOS1 inhibitor compounds can inhibit signal transduction (e.g., ERK phosphorylation) in cells downstream of RAS family proteins. An ideal SOS1 inhibitor compound should be able to selectively and efficiently inhibit SOS1:RAS-family protein binding and ERK phosphorylation in cells.

[0006] Recently, researchers at Bayer reported the discovery of a series of selective SOS1 inhibitors containing a quinazoline core structure (Proc Natl Acad Sci. 2019;116(7):2551-2560), a representative compound being BAY-293. This class of inhibitors can block RAS activation by disrupting the RAS-SOS1 interaction. [ka]

[0007] We provide herein novel SOS1 inhibitor compounds that can inhibit ERK phosphorylation in cells by disrupting the RAS-SOS1 interaction. Summary of the Invention

[0008] In one aspect of the present application, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X and Y are independent of each other. a , C(O), N or NR b Selected from [ka] represents a single bond or a double bond by X and Y, R a is hydrogen, hydroxyl group, halogen, cyano group, C 1~6 Alkyl group or C 1~6 alkoxy groups, provided that the C 1~6 Alkyl group or C 1~6 the alkoxy group is optionally substituted with one or more deuterium or halogen atoms; R b is hydrogen, C 1~6 Alkyl group or C 1~6 selected from alkoxy groups, R 1 , R 2 are each independently C 1~6Alkyl group, NH(R c )-C 1~6 Alkyl- or N(R c )(C 1~6 Alkyl)-C 1~6 alkyl- or R 1 , R 2 forms a 5- to 10-membered heterocyclyl group together with the phosphorus atom attached thereto, provided that said C 1~6 The alkyl group or the 5- to 10-membered heterocyclyl group may optionally be one or more R c is replaced by Each R c are independently 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- to 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-, C6~10 Aryl-C 1~6 Alkyl- or C substituted by one or more hydroxy or cyano groups 1~6 alkyl-, provided that R c is optionally substituted by one or more halogens when not hydrogen or O=; Ring A is C 6~10 selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring, or an 8- to 12-membered fused heterocyclic ring; n is 0, 1, 2 or 3; Each R 3 are each independently an amino group, a nitro group, a halogen, or C 1~8 alkyl-, 3- to 6-membered cycloalkyl-, or phenyl group, provided that the C 1~8 The alkyl-, 3- to 6-membered cycloalkyl-, or phenyl group may optionally be one or more R d is replaced by R d is a hydroxy group, a halogen or C 1~6 Alkyl-NH-C 1~6 alkyl-, R 4 , R 5 are each independently hydrogen, deuterium, or C 1~6 alkyl groups, provided that the C 1~6 the alkyl group is optionally substituted with one or more halogens; R 6 is hydrogen, halogen or C 1~6 alkyl groups, provided that the C 1~6 The alkyl group is optionally substituted with one or more halogens.

[0009] In certain embodiments, X is CR a or NR b Y is selected from CR a , C(O), N or NR b In certain embodiments, X is selected from CR a or NR b Y is selected from CR a , C(O) or N.

[0010] In certain embodiments, X is CR a Y is selected from CR a , C(O), N or NR b In certain embodiments, X is selected from CR a Y is selected from CR a , C(O) or N. In certain embodiments, X is selected from CR a and Y is selected from N.

[0011] In certain embodiments, X is NR b Y is selected from CR a , C(O), N or NR b In certain embodiments, X is selected from NR b Y is selected from CR a , C(O) or N. In certain embodiments, X is selected from NR b and Y is selected from C(O).

[0012] In certain embodiments, X and Y are both CR a In certain embodiments, X is selected from CH and Y is CR a Selected from.

[0013] In certain embodiments, R a is hydrogen, hydroxyl group, halogen, cyano group, C 1~4 Alkyl group or C 1~4 alkoxy groups, provided that the C 1~4 Alkyl group or C 1~4 The alkoxy group is optionally substituted with one or more deuterium or halogen.

[0014] In certain embodiments, R a is hydrogen, hydroxyl group, halogen, cyano group, C 1~4 Alkyl group or C 1~4 alkoxy groups, provided that the C 1~4The alkyl group is optionally substituted with one or more halogens, and 1~4 The alkoxy group is optionally substituted with one or more deuterium or halogen. In certain embodiments, R a is hydrogen, hydroxyl group, halogen, cyano group, C 1~3 Alkyl group or C 1~3 alkoxy groups, provided that the C 1~3 The alkyl group is optionally substituted with one or more halogens, and 1~3 The alkoxy group is optionally substituted with one or more deuterium or halogen.

[0015] In certain embodiments, R a is hydrogen, a hydroxy group, a halogen, a cyano group or C 1~6 alkoxy groups, provided that the C 1~6 The alkoxy group is optionally substituted with one or more deuterium or halogen.

[0016] In certain embodiments, R a is hydrogen, a hydroxy group, a halogen, a cyano group or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with one or more deuterium or halogen. In certain embodiments, R a is hydrogen, a hydroxy group, a halogen, a cyano group or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with three deuterium atoms or one or more fluorines. a is hydrogen, a hydroxy group, a halogen, a cyano group or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with three deuterium atoms or one or two fluorine atoms.

[0017] In certain embodiments, R ais selected from hydrogen, hydroxy, fluorine, cyano, methoxy, monofluoromethoxy or difluoromethoxy, with the proviso that said methoxy group is optionally substituted by three deuterium atoms.

[0018] In certain embodiments, R a is selected from hydrogen, a hydroxy group, fluorine, a cyano group, CH3O-, CD3O-, CH2FO- or CHF2O-.

[0019] In certain embodiments, R a is selected from hydrogen, fluorine, CH3O-, CD3O- or CHF2O-.

[0020] In certain embodiments, R b is hydrogen, C 1~4 Alkyl group or C 1~4 The alkoxy group is selected from the group consisting of alkoxy groups.

[0021] In certain embodiments, R b is C 1~6 In certain embodiments, R b is C 1~4 In certain embodiments, R b is C 1~3 In certain embodiments, R b is selected from methyl groups.

[0022] In certain embodiments, X is selected from CH, CF, C(CN) or N(CH), and Y is selected from N, CH, C(O), C(OH), C(OCH), C(OCHF), C(OCHF), CF, or C(OCD). In certain embodiments, X is selected from CH and Y is selected from C(OH), C(OCH), C(OCHF), C(OCHF), CF, or C(OCD). In certain embodiments, X is selected from CH and Y is selected from N. In certain embodiments, X is selected from N(CH) and Y is selected from C(O). In certain embodiments, X is selected from CF or C(CN) and Y is selected from CH or N.

[0023] In certain embodiments, [ka] is a double bond. In certain embodiments, [ka] is a single bond.

[0024] In certain embodiments, R 1 , R 2 are each independently C 1~6 Alkyl group, 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 to which it is attached form a 5- to 10-membered heterocyclyl group, provided that said 5- to 10-membered heterocyclyl group optionally contains one or more R c is replaced by

[0025] In certain embodiments, R 1 , R 2 are each independently C 1~6 alkyl groups, or R 1 , R 2together with the phosphorus atom to which it is attached form a 5- to 10-membered heterocyclyl group, provided that said 5- to 10-membered heterocyclyl group optionally contains one or more R c is replaced by

[0026] In certain embodiments, R 1 , R 2 are each independently C 1~3 Alkyl group, NH(R c )-C 1~3 Alkyl- or N(R c )(C 1~3 Alkyl)-C 1~3 alkyl-.

[0027] In certain embodiments, R 1 , R 2 are each independently C 1~3 It is selected from alkyl groups.

[0028] In certain embodiments, R 1 , R 2 are each independently selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[0029] In certain embodiments, R 1 , R 2 are each independently selected from a methyl group or an ethyl group.

[0030] In certain embodiments, R 1 , R 2 are each independently selected from methyl groups.

[0031] In certain embodiments, R 1 , R 2 together with the phosphorus atom attached thereto form a 5- to 10-membered heterocyclyl group, provided that the ring atoms of said 5- to 10-membered heterocyclyl group optionally contain one or more heteroatoms selected from N, O or S atoms, and said 5- to 10-membered heterocyclyl group optionally contains one or more R c is replaced by

[0032] In certain embodiments, R 1 , R 2 together with the phosphorus atom attached thereto form a 5- to 10-membered heterocyclyl group, provided that the ring atoms of said 5- to 10-membered heterocyclyl group optionally contain one or more heteroatoms selected from N, O or S atoms, and said 5- to 10-membered heterocyclyl group optionally contains one or more R c and the ring atom contains a N atom, N is R c is connected to.

[0033] In certain embodiments, R 1 , R 2 forms a 5- to 8-membered heterocyclyl group together with the phosphorus atom attached thereto, provided that the ring atoms of said 5- to 8-membered heterocyclyl group optionally contain one heteroatom selected from N or O atoms, and when the ring atom contains an N atom, N is not R c is connected to.

[0034] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 5- to 8-membered heterocycloalkyl group, provided that the ring atoms of said 5- to 8-membered heterocycloalkyl group contain at least one N atom, and N is not R c is connected to.

[0035] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered spiroheterocycloalkyl group, or a 9- or 10-membered fused heterocycloalkyl group, provided that said 5- or 6-membered heterocycloalkyl group, 9- or 10-membered spiroheterocycloalkyl group, or 9- or 10-membered fused heterocycloalkyl group may optionally be joined by one or more R c is replaced by

[0036] In certain embodiments, R 1 , R 2together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocyclyl group, provided that said 5- or 6-membered heterocyclyl group optionally contains one or more R c is replaced by

[0037] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocyclyl group, provided that the ring atoms of said 5- or 6-membered heterocyclyl group optionally contain one or more heteroatoms selected from N, O or S atoms, and if a ring atom contains an N atom, then N is not R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocyclyl group, provided that the ring atoms of said 5- or 6-membered heterocyclyl group optionally contain one heteroatom selected from N or O atoms, and if the ring atom contains an N atom, then N is not R c is connected to.

[0038] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocyclyl group, provided that the ring atoms of said 6-membered heterocyclyl group include at least one N atom, and N is R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocyclyl group, provided that the ring atoms of said 6-membered heterocyclyl group contain only one N atom and N is not R c is connected to.

[0039] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocyclyl group, with the proviso that the ring atoms of said 6-membered heterocyclyl group include only one O atom.

[0040] In certain embodiments, R 1 , R 2together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocyclyl group, and the ring atoms of said 5- or 6-membered heterocyclyl group consist of carbon atoms and phosphorus atoms.

[0041] In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocycloalkyl group, provided that the ring atoms of said 6-membered heterocycloalkyl group contain at least one N atom, and N is R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocycloalkyl group, provided that the ring atoms of said 6-membered heterocycloalkyl group contain only one N atom and N is not R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocycloalkyl group, with the proviso that the ring atoms of said 6-membered heterocycloalkyl group contain only one O atom. 1 , R 2 together with the phosphorus atom to which it is attached form a 5- or 6-membered heterocycloalkyl group, and the ring atoms of said 5- or 6-membered heterocycloalkyl group consist of carbon atoms and phosphorus atoms.

[0042] In certain embodiments, the structural unit [ka] is a structural unit [ka] may be selected from the following structural units: [ka] optionally one or more R c may be replaced by

[0043] In certain embodiments, the structural unit [ka] is a structural unit [ka] may be selected from

[0044] In certain embodiments, the structural unit [ka] is a structural unit [ka] may be selected from

[0045] In certain embodiments, the structural unit [ka] is a structural unit [ka] is.

[0046] In certain embodiments, R 1 , R 2 are each independently selected from a methyl group or an ethyl group, or a structural unit [ka] is a structural unit [ka] Selected from.

[0047] In certain embodiments, R 1 , R 2 are each independently selected from a methyl group or a structural unit [ka] is a structural unit [ka] is.

[0048] In certain embodiments, each R c are independently 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 C substituted by alkyl- or one or more hydroxy groups 1~6 alkyl-.

[0049] In certain embodiments, each R c are independently 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- to 6-membered cycloalkyl-S(O)2-, C1~3 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 by one or more hydroxy or cyano groups 1~3 alkyl-, provided that R c is optionally substituted by one or more halogens when not hydrogen or O=.

[0050] In certain embodiments, each R c are independently hydrogen, C 1~3 Alkyl-, C 1~3 Alkyl-C(O)-, C 1~3 Alkyl-S(O)2-, 3- to 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 1~3Alkyl-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 by one or more hydroxy or cyano groups 1~3 alkyl-, provided that R c is optionally substituted by one or more halogens when not hydrogen.

[0051] In certain embodiments, each R c are independently 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- to 5-membered cycloalkyl-, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, 3- to 5-membered heterocycloalkyl-, phenyl-CH2- or C substituted by one hydroxy group or cyano group 1~3 alkyl-, provided that R c is optionally substituted by 1, 2 or 3 halogens when not hydrogen.

[0052] In certain embodiments, each R c are independently 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 1~3 alkyl)amino-C(O)-CH2-, 3- to 5-membered cycloalkyl-, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, 3- to 5-membered heterocycloalkyl- or C(O) substituted by one hydroxy group or cyano group 1~3 alkyl-, provided that R c is optionally substituted by 1, 2 or 3 halogens when not hydrogen.

[0053] In certain embodiments, each R c are independently 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(C1~3 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 substituted by one hydroxy group 1~3 alkyl-.

[0054] In certain embodiments, each R c are each independently a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, [ka] , acetyl group, [ka] Selected from.

[0055] In certain embodiments, each R c are each independently a methyl group, an ethyl group, an isopropyl group, [ka] , acetyl group, [ka] Selected from.

[0056] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered benzocycloalkyl group, an 8- to 12-membered benzocycloalkenyl group, or an 8- to 12-membered benzoheterocyclyl group.

[0057] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered benzocycloalkyl group, an 8- to 12-membered benzocycloalkenyl group, an 8- to 12-membered benzoheterocycloalkyl group, or an 8- to 12-membered benzoheterocycloalkenyl group.

[0058] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered benzocycloalkyl group, or an 8- to 12-membered benzoheterocycloalkyl group.

[0059] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 10-membered fused ring, or an 8- to 10-membered fused heterocyclic ring.

[0060] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 10-membered benzocycloalkyl group, an 8- to 10-membered benzocycloalkenyl group, and an 8- to 10-membered benzoheterocyclyl group.

[0061] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 10-membered benzocycloalkyl group, an 8- to 10-membered benzocycloalkenyl group, an 8- to 10-membered benzoheterocycloalkyl group, or an 8- to 10-membered benzoheterocycloalkenyl group.

[0062] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, an 8- to 10-membered benzocycloalkyl group, or an 8- to 10-membered benzoheterocycloalkyl group.

[0063] In certain embodiments, ring A is selected from a phenyl group, a thienyl group, a 2,3-dihydro-1H-indenyl group, a 2,3-dihydrobenzofuryl group, or a benzofuryl group.

[0064] In certain embodiments, ring A is selected from a phenyl group, a thienyl group, or a 2,3-dihydro-1H-indenyl group.

[0065] In certain embodiments, n is 0, 1, or 2; or n is 1, 2, or 3.

[0066] In certain embodiments, n is 0 or 1, or n is 0 or 2, or n is 0 or 3, or n is 1 or 2, or n is 1 or 3, or n is 2 or 3. In certain embodiments, n is 2.

[0067] In certain embodiments, each R 3 are each independently an amino group, a nitro group, a halogen, or C 1~6 alkyl- or phenyl groups, provided that the C 1~6 The alkyl- or phenyl group may optionally be one or more R d is replaced by

[0068] In certain embodiments, each R 3 are each independently an amino group, a halogen, or C 1~6 alkyl- or phenyl groups, provided that the C 1~6 The alkyl- or phenyl group may optionally be one or more R d is replaced by

[0069] In certain embodiments, each R 3 are each independently an amino group, a nitro group, a halogen, or C 1~4 alkyl- or phenyl groups, provided that the C 1~4 The alkyl- or phenyl group may optionally be one or more R d is replaced by

[0070] In certain embodiments, each R 3 are each independently an amino group, a nitro group, a halogen, or C 1~4 alkyl- or phenyl groups, provided that the C 1~4 The alkyl- or phenyl group may optionally be one, two or three R d is replaced by

[0071] In certain embodiments, R d is a hydroxy group, a halogen or C1~3 Alkyl-NH-C 1~3 alkyl-.

[0072] In certain embodiments, R d is selected from a hydroxy group, fluorine or methyl -NH-methyl-.

[0073] In certain embodiments, each R 3 are each independently an amino group, a nitro group, fluorine, a methyl group, a trifluoromethyl group, -CF2CH2OH, -CHF2, -CF2CH3, -CF2C(CH3)2OH, or [ka] Selected from.

[0074] In certain embodiments, each R 3 are each independently an amino group, a fluorine atom, a methyl group, a trifluoromethyl group, -CF2CH2OH, -CHF2, -CF2CH3, -CF2C(CH3)2OH, or [ka] Selected from.

[0075] In certain embodiments, each R 3 are each independently selected from an amino group, a nitro group, a fluorine group, a methyl group, or a trifluoromethyl group.

[0076] In certain embodiments, the structural unit [ka] teeth, [ka] Selected from, and [ka] Selected from.

[0077] In certain embodiments, R 4 , R 5 are each independently hydrogen, deuterium, or C 1~3 alkyl groups, provided that the C 1~3 The alkyl group is optionally substituted with one or more halogens.

[0078] In certain embodiments, R 4 is C 1~3 alkyl groups, R 5 is selected from hydrogen or deuterium, provided that 1~3 The alkyl group is optionally substituted with one or more halogens. In certain embodiments, R 4 is selected from a methyl group, and R 5 is selected from hydrogen or deuterium, with the proviso that said methyl groups are optionally substituted by one or more fluorines. 4 is selected from a methyl group or -CHF, and R 5 is selected from hydrogen or deuterium. 4 is selected from a methyl group, and R 5 is selected from hydrogen.

[0079] In certain embodiments, R 5 is C 1~3 alkyl groups, R 4 is selected from hydrogen or deuterium, provided that 1~3 The alkyl group is optionally substituted with one or more halogens. In certain embodiments, R 5 is selected from a methyl group, and R 4 is selected from hydrogen or deuterium, with the proviso that said methyl groups are optionally substituted by one or more fluorines. 5 is selected from a methyl group or -CHF, and R 4 is selected from hydrogen or deuterium. 5 is selected from a methyl group, and R 4 is selected from hydrogen.

[0080] In certain embodiments, R 6 is hydrogen, halogen or C 1~3 alkyl groups, provided that the C 1~3 The alkyl group is optionally substituted with one or more halogens.

[0081] In certain embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl groups are optionally substituted with one or more halogens. 6 is selected from hydrogen, fluorine, chlorine or a methyl group, wherein said methyl group is optionally substituted by one, two or three fluorines. In certain embodiments, R 6 is selected from hydrogen, chlorine, a methyl group, or —CHF. In certain embodiments, R 6 is selected from methyl groups.

[0082] In certain embodiments, the heteroatoms of a heterocyclyl group, heteroaryl group, or heterocycloalkyl group described herein are selected from N, O, S, and P. In certain embodiments, the heteroatoms of a heterocyclyl group, heteroaryl group, or heterocycloalkyl group described herein are selected from N, O, and P. In certain embodiments, the heteroatoms of a heterocyclyl group, heteroaryl group, or heterocycloalkyl group described herein are selected from N and P.

[0083] In another aspect of the present application, there is provided a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X and Y are independent of each other. a , C(O), N or NR b Selected from [ka] represents a single bond or a double bond by X and Y, R a is hydrogen, hydroxyl group, halogen, C 1~6 Alkyl group or C 1~6 alkoxy groups, provided that the C 1~6 The alkyl group is optionally substituted with one or more halogens, and 1~6 the alkoxy group is optionally substituted with one or more deuterium or halogen atoms; R b is hydrogen, C 1~6 Alkyl group or C 1~6 selected from alkoxy groups, R 1 , R 2 are each independently C 1~6 Alkyl group, 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 attached thereto form a 5- to 8-membered heterocyclyl group, provided that the ring atoms of said 5- to 8-membered heterocyclyl group contain at least one N atom, and N is R c connected to Each R c are independently hydrogen, C 1~6 Alkyl group, 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 1~6Alkyl-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 group, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1~6 Alkyl-, C 6~10 Aryl-C 1~6 C substituted by alkyl- or one or more hydroxy groups 1~6 alkyl groups, provided that R c is optionally substituted by one or more halogens when not hydrogen; Ring A is C 6~10 an aryl group, a 5- to 10-membered heteroaryl group, or an 8- to 12-membered fused ring; n is 0, 1, 2 or 3; Each R 3 are each independently an amino group, a nitro group, a halogen, or C 1~8 alkyl group or 3- to 6-membered cycloalkyl group, provided that the C 1~8 The alkyl group and the 3- to 6-membered cycloalkyl group may optionally be one or more R d is replaced by R d is selected from a hydroxy group or a halogen.

[0084] In certain embodiments, in the compound of formula (II), R 1 , R 2 , R 3 ,X,Y,n,ring A, [ka] The definition of is as described above.

[0085] In certain embodiments, X is CR a Y is selected from CR a , C(O), N or NR b In certain embodiments, X is selected from CRa Y is selected from CR a , C(O) or N. In certain embodiments, X is selected from CR a and Y is selected from N.

[0086] In certain embodiments, X and Y are both CR a In certain embodiments, X is selected from CH and Y is CR a Selected from.

[0087] In certain embodiments, R a is hydrogen, halogen or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with one or more deuterium or halogen. In certain embodiments, R a is hydrogen, halogen or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with three deuterium atoms or one or more fluorines. a is hydrogen, halogen or C 1~4 alkoxy groups, provided that the C 1~4 The alkoxy group is optionally substituted with three deuterium or two fluorine atoms.

[0088] In certain embodiments, R a is selected from hydrogen, fluorine, a methoxy group, or a difluoromethoxy group, with the proviso that the methoxy group is optionally substituted by three deuterium atoms.

[0089] In certain embodiments, R a is selected from hydrogen, fluorine, CH3O-, CD3O- or CHF2O-.

[0090] In certain embodiments, R b is C 1~6 In certain embodiments, R b is C 1~4In certain embodiments, R b is C 1~3 In certain embodiments, R b is selected from methyl groups.

[0091] In certain embodiments, X is selected from CH, N(CH3) and Y is selected from N, C(O), C(OCH3), CF, or C(OCD3). In certain embodiments, X is selected from CH and Y is selected from C(OCH3), CF, or C(OCD3). In certain embodiments, X is selected from CH and Y is selected from N. In certain embodiments, X is selected from N(CH3) and Y is selected from C(O).

[0092] In certain embodiments, R 1 , R 2 are each independently C 1~3 Alkyl group, NH(R c )-C 1~3 Alkyl- or N(R c )(C 1~3 Alkyl)-C 1~3 alkyl-.

[0093] In certain embodiments, R 1 , R 2 are each independently C 1~3 It is selected from alkyl groups.

[0094] In certain embodiments, R 1 , R 2 are each independently selected from methyl groups.

[0095] In certain embodiments, R 1 , R 2 together with the phosphorus atom attached thereto form a 6-membered heterocyclyl group, the ring atoms of which include at least one N atom, and N is R c In certain embodiments, R 1 , R 2together with the phosphorus atom attached thereto form a 6-membered heterocyclyl group, the ring atoms of which contain only one N atom, and N is R c is connected to.

[0096] In certain embodiments, R 1 , R 2 together with the phosphorus atom attached thereto form a 5- to 8-membered heterocycloalkyl group, the ring atoms of which contain at least one N atom, and N is R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocycloalkyl group, the ring atoms of which contain at least one N atom, and N is R c In certain embodiments, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocycloalkyl group, the ring atoms of which contain only one N atom, and N is R c is connected to.

[0097] In certain embodiments, the structural unit [ka] is a structural unit [ka] Selected from.

[0098] In certain embodiments, R 1 , R 2 are each independently selected from a methyl group or a structural unit [ka] is a structural unit [ka] Selected from.

[0099] In certain embodiments, each R c are independently hydrogen, C 1~3 Alkyl group, 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 group, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1~3 Alkyl-, phenyl-C 1~3 C substituted by alkyl- or one or more hydroxy groups 1~3 It is selected from alkyl groups.

[0100] In certain embodiments, each R c are independently hydrogen, C 1~3 Alkyl group, 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 1~3alkyl)amino-C(O)-CH2-, 3- to 5-membered cycloalkyl group, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH2-, phenyl-CH2- or C substituted by one hydroxy group 1~3 It is selected from alkyl groups.

[0101] In certain embodiments, each R c are each independently a methyl group, an ethyl group, an isopropyl group, an acetyl group, [ka] Selected from.

[0102] In certain embodiments, ring A is C 6~10 It is selected from an aryl group, a 5- to 6-membered heteroaryl group, or an 8- to 10-membered fused ring.

[0103] In certain embodiments, ring A is selected from a phenyl group, a thienyl group, or a 2,3-dihydro-1H-indenyl group.

[0104] In certain embodiments, n is 0, 1, or 2; or n is 1, 2, or 3.

[0105] In certain embodiments, n is 0 or 1, or n is 0 or 2, or n is 0 or 3, or n is 1 or 2, or n is 1 or 3, or n is 2 or 3. In certain embodiments, n is 2.

[0106] In certain embodiments, each R 3 are each independently an amino group, a nitro group, a halogen atom, or C 1~4 alkyl groups, 1~4 The alkyl group may optionally be one, two, or three R d is replaced by

[0107] In certain embodiments, R dis selected from a hydroxy group or fluorine.

[0108] In certain embodiments, each R 3 are each independently selected from an amino group, a nitro group, fluorine, a methyl group, a trifluoromethyl group, -CF2CH2OH, -CHF2, -CF2CH3, or -CF2C(CH3)2OH.

[0109] In certain embodiments, the structural unit [ka] teeth, [ka] Selected from, and [ka] Selected from.

[0110] In certain embodiments, the compound of formula (I) or formula (II), its stereoisomer, or pharmaceutically acceptable salt thereof of the present application is selected from the compound of formula (III), its stereoisomer, or pharmaceutically acceptable salt thereof: [ka] where R 1 , R 2 , R 3 ,X,Y,n,ring A, [ka] The definition of is as described above.

[0111] In certain embodiments, a compound of formula (I) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, X and Y are independent of each other. a , N, for example, X and Y are both selected from CR a or X is selected from CR a and Y is N; R a is hydrogen or C 1~4 alkoxy groups, preferably R a is selected from hydrogen or a methoxy group; [ka] represents a double bond, R 1 , R 2 together with the phosphorus atom attached thereto form a 6-membered heterocyclyl group, provided that the ring atoms of said 6-membered heterocyclyl group contain at least one N atom or O atom, and if a ring atom contains an N atom, then N is not R c (preferably containing one N atom and N being connected to R c connected to R c is C 1~4 Alkyl-S(O)2- (preferably a methylsulfonyl group), C 3~6 cycloalkyl-S(O)2- (preferably cyclopropylsulfonyl group), Ring A is C 6~10 aryl groups, preferably C6 aryl groups (i.e., phenyl groups); n is 0, 1, 2 or 3, preferably 2; Each R 3 are each independently a halogen (preferably F), C 1~8 Alkyl groups (preferably C 1~4 alkyl group, more preferably a methyl group or an ethyl group), provided that the C 1~8 the alkyl group is optionally substituted with one or more halogens (preferably F); R 4 , R 5 are each independently hydrogen or C 1~3 alkyl groups, provided that the C 1~3 The alkyl group is optionally substituted by one or more fluorines (preferably, R4 is selected from hydrogen and R5 is selected from methyl groups, or R4 is selected from methyl groups and R 5 is selected from hydrogen), R6 is hydrogen, halogen or C 1~6 alkyl groups, provided that the C 1~6 The alkyl group is optionally substituted with one or more halogens, e.g., R 6 may be selected from hydrogen, a methyl group, or a methyl group optionally substituted with one or more halogens (e.g., —CH 2 F).

[0112] In certain embodiments, the compound of formula (II) of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, X and Y are independent of each other. a , N, for example, X and Y are both selected from CR a or X is selected from CR a and Y is N; R a is hydrogen or C 1~4 alkoxy groups, preferably R a is selected from hydrogen or a methoxy group, and more preferably, R a is selected from hydrogen, [ka] represents a double bond, R 1 , R 2 together with the phosphorus atom to which it is attached form a 6-membered heterocyclyl group, provided that the ring atoms of said 6-membered heterocyclyl group contain at least one N atom (preferably one N atom), and N is R c connected to R c is C 1~4 Alkyl-S(O)2- (preferably a methylsulfonyl group), C 3~6 cycloalkyl-S(O)2- (preferably cyclopropylsulfonyl group), Ring A is C 6~10 aryl groups, preferably C6 aryl groups (i.e., phenyl groups); n is 0, 1, 2 or 3, preferably 2; Each R 3are each independently a halogen (preferably F), C 1~8 Alkyl groups (preferably C 1~4 , more preferably a methyl group or an ethyl group), provided that the C 1~8 The alkyl group is optionally substituted with one or more halogens (preferably F).

[0113] In certain embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomer, or pharmaceutically acceptable salt thereof is selected from compounds of formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), and (III-9), its stereoisomer, or pharmaceutically acceptable salt thereof; [ka] where R 1 , R 2 , R 3 , Y, n, ring A, R a , R b , R c The definition of is as described above.

[0114] In certain embodiments, the compound of formula (I) or formula (II), its stereoisomer, or pharmaceutically acceptable salt thereof of the present application is selected from compounds of formula (IV), compounds of formula (V), and compounds of formula (VI), its stereoisomer, or pharmaceutically acceptable salt thereof; [ka] where R 3 , Y, n, R b , R c The definition of is as described above.

[0115] In certain embodiments, the present application includes the above-defined variables and embodiments thereof, and any combination thereof.

[0116] In certain embodiments, the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0117] In certain embodiments, the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka]

[0118] In another aspect of the present application, there is provided 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), [ka] where: Rx is selected from chlorine, bromine or iodine; R 6 is a C optionally substituted by one or more halogens 1~6 alkyl groups, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, n, and ring A are defined as above.

[0119] In another aspect of the present application, Step (i) of reacting a compound of formula M1 with a compound of formula N1 under acidic conditions to prepare a compound of formula M2; and (ii) reacting a compound of formula M2 with a compound of formula N2 to prepare a compound of formula M3; [ka] where: Rx is selected from chlorine, bromine or iodine; R 6 is a C optionally substituted by one or more halogens 1~6 alkyl groups, R 3 , R 4 , R 5 , X, Y, n, and ring A are defined as above.

[0120] In another aspect of the present application, [ka] Step (a) of reacting a compound of formula M2 with thionyl chloride to prepare a compound of formula M2-1; and (b) a substitution reaction of a compound of formula M2-1 with a compound of formula N2 under basic conditions to prepare a compound of formula M3; where: Rx is selected from chlorine, bromine or iodine; R 6 is a C optionally substituted by one or more halogens 1~6 alkyl groups, R 3 , R 4 , R 5 , X, Y, n, and ring A are defined as above.

[0121] In certain embodiments, in the method for preparing a compound of Formula (I), a compound of Formula M3 is prepared from said method.

[0122] In another aspect of the present application, a method for preparing a compound of formula (III-8), which comprises reacting a compound of formula M3-1 with 1-benzyl-1,4-azaphospholane-4-oxide to prepare a compound of formula M3-2, followed by debenzylation to obtain a compound of formula M3-3, and finally preparing a compound of formula (III-8) by a substitution reaction; [ka] wherein Rx is selected from chlorine, bromine, or iodine; R 3 , R c , n, and ring A are defined as above.

[0123] In certain embodiments, the present application provides a method for preparing a compound of formula (III-8): Step (1) of reacting a compound of formula M3-1 with 1-benzyl-1,4-azaphospholane-4-oxide to prepare a compound of formula M3-2; Step (2) of reacting a compound of formula M3-2 to obtain a compound of formula M3-3; and step (3) reacting a compound of formula M3-3 to obtain a compound of formula (III-8), Optionally, step (2) comprises: [ka] is carried out in the presence of where: Rx is selected from chlorine, bromine or iodine; R 6 is a C optionally substituted by one or more halogens 1~6 alkyl groups, R 3 , R c , n, and ring A are defined as above.

[0124] In another aspect, the present application further provides the following intermediate compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [ka]

[0125] In another aspect of the present application, there is provided a pharmaceutical composition comprising a compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0126] In another aspect of the present application, there is provided a method for treating or preventing diseases and / or conditions associated with or regulated by SOS1 in a mammal, said method comprising administering to a mammal, preferably a human, in need of such treatment or prevention a therapeutically or prophylactically effective amount of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0127] In another aspect of the present application, there is provided the use of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing diseases and / or conditions associated with or modulated by SOS1.

[0128] In another aspect of the present application, there is provided the use of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment or prevention of diseases and / or conditions associated with or modulated by SOS1.

[0129] In another aspect of the present application, there is provided the compound, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing diseases and / or conditions associated with or regulated by SOS1.

[0130] In a particular embodiment, said diseases and / or conditions associated with or modulated by SOS1 are selected from diseases and / or conditions in which SOS1 interacts with proteins of the RAS family.

[0131] In certain embodiments, said disease and / or condition associated with or modulated by SOS1 is selected from cancer, for example non-small cell lung cancer. [Effects of the Invention]

[0132] The compounds of the present application have good KRAS-G12C / SOS1 protein binding inhibitory activity, K562 cell proliferation inhibitory activity, in vitro and in vivo drug activity, and good pharmacokinetic properties.

[0133] "Definition" Unless otherwise specified, the following terms used herein have the following meanings: Certain terms are to be understood in their ordinary sense in the art, and not as open or unclear, unless otherwise defined. When trade names are mentioned herein, they refer to the corresponding product or its active ingredient.

[0134] chemical bond [ka] represents a single bond or a double bond depending on the groups connected to both ends. For example, if X and Y connected to both ends of the chemical bond are CR a or N, chemical bond [ka] is a double bond, and one of X and Y attached to both ends of the chemical bond is CO or NR a If [ka] is a single bond. Those skilled in the art will recognize that the selection of X and Y is consistent with valence bond rules.

[0135] The term "substituted" means that any or more hydrogen atoms on a particular atom may be replaced by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxygen (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur on aryl groups.

[0136] The term "any" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (-CHCH), monosubstituted (e.g., -CHCHF), polysubstituted (e.g., -CHFCHF, -CHCHF, etc.), or fully substituted (e.g., -CFCF). As will be understood by those skilled in the art, groups containing one or more substituents do not allow for substitution or forms of substitution that are spatially incompatible and / or synthetically impossible.

[0137] As used herein, "C m~n " means that the moiety has an integer number of carbon atoms in the specified range. For example, "C 1~6 " means that the subject group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and "C 1~3 " means that the group in question may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0138] When a particular variable (e.g., R) occurs more than one time in a compound composition or structure, it is independently defined at each occurrence. Thus, for example, if a subject group is substituted with two R, each R is independently selected.

[0139] When the number of a particular connecting group is 0, for example, -(CH2)0-, this indicates that the connecting group is a covalent bond.

[0140] When a bond of a substituent crosses and connects two atoms of a ring, the substituent can be bonded to any atom of the ring. For example, the structural unit [ka] or [ka] indicates that substitution can occur at any position on the cyclohexyl group or cyclohexadiene.

[0141] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0142] The term "hydroxy" refers to an -OH group.

[0143] The term "amino group" refers to the group -NH2.

[0144] The term "nitro" refers to the -NO2 group.

[0145] The term "cyano" refers to the group -CN.

[0146] The term "alkyl group" refers to a group having the general formula C n H 2n+1 The alkyl group may be linear or branched. For example, the term "C 1~6 "Alkyl group" 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 above definitions apply to the alkyl (alkyl) portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups.

[0147] The term "alkoxy" refers to an --O-alkyl group.

[0148] The term "alkylamino" or "monoalkylamino" refers to an -NH-alkyl group.

[0149] The term "dialkylamino" refers to an -N(alkyl)2 group.

[0150] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, such carbocyclic rings generally have 3 to 10 members. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, and the like.

[0151] The term "heterocyclyl group" 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 specified, such heterocyclyl groups are generally 3- to 12-membered rings containing 1-3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Non-limiting examples of heterocyclyl groups include oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, or the like. [ka] Including, but not limited to, the following:

[0152] The term "heterocycloalkyl group" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycloalkyl group is generally a 3- to 12-membered, 3- to 7-membered, or 5- to 8-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; and examples of 6-membered heterocycloalkyl groups 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 [ka] Examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

[0153] The term "aryl group" refers to an aromatic ring group having an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0154] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system having at least one ring atom selected from N, O, or S, the remaining ring atoms being C, and at least one aromatic ring. Preferred heteroaryl groups have a single 5-8 membered ring or multiple fused rings containing 6-14, and especially 6-10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0155] The term "fused ring" refers to a 7-20 member all-carbon polycyclic ring system in which two rings share two adjacent carbon atoms, at least one of which has a completely conjugated π-electron system, but which is not aromatic as a whole. Depending on the number of constituent rings, fused rings can be classified as bicyclic, tricyclic, tetracyclic or polycyclic rings, preferably bicyclic or tricyclic rings, and more preferably 6-membered / 6-membered or 5-membered / 6-membered bicyclic rings. Non-limiting examples of fused rings are: [ka] Includes.

[0156] The term "spiroheterocycloalkyl group" refers to a fully saturated 5- to 20-membered polycyclic ring system in which one carbon atom (called a spiro atom) is shared between the monocyclic rings, and one or more ring atoms of the polycyclic ring system are heteroatoms selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen (preferably one or two heteroatoms), with the remaining ring atoms being carbon atoms. Preferably, the polycyclic ring system has 6 to 14 members, more preferably 6 to 10 members. Depending on the number of spiro atoms shared between the rings, spiroheterocycles can be classified as monospiroheterocycles, bisspiroheterocycles, or polyspiroheterocycles. Preferably, the spiroheterocycles are monospiroheterocycles or bisspiroheterocycles, and more preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycles. Non-limiting examples of spiroheterocycles are: [ka] Includes.

[0157] The term "fused heterocycloalkyl group" refers to a fully saturated polycyclic ring system having 5 to 20 ring atoms and two ring atoms shared by two rings, in which one or more ring atoms of the polycyclic ring system are heteroatoms selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen (preferably one or two heteroatoms), and the remaining ring atoms are carbon atoms. Preferably, the polycyclic ring system has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms. Depending on the number of constituent rings, the heterocyclic ring can be classified as a bicyclic, tricyclic, or polycyclic bridged heterocycle, and preferably a bicyclic ring. Non-limiting examples of fused heterocycles are: [ka] Includes.

[0158] The term "benzocycloalkyl group" refers to a fused benzene ring and cycloalkyl group (i.e., the benzene ring and the cycloalkyl group share two adjacent carbon atoms). Non-limiting examples of benzocycloalkyl groups are: [ka] Includes:

[0159] The term "cycloalkenyl" refers to an unsaturated carbocyclic ring containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, and which can exist as a monocyclic, bridged, or spirocyclic ring. Non-limiting examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0160] The term "benzocycloalkenyl group" refers to a fused benzene ring and cycloalkenyl group (i.e., the benzene ring and the cycloalkenyl group share two adjacent carbon atoms). Non-limiting examples of benzocycloalkenyl groups are: [ka] Includes.

[0161] The term "benzoheterocyclyl group" refers to a fused benzene ring and heterocyclyl group (i.e., the benzene ring and heterocyclyl group share two adjacent carbon atoms). Non-limiting examples of benzoheterocyclyl groups are: [ka] Includes.

[0162] The term "benzoheterocycloalkyl group" refers to a fused benzene ring and heterocycloalkyl group (i.e., the benzene ring and the heterocycloalkyl group share two adjacent carbon atoms). Non-limiting examples of benzoheterocycloalkyl groups are: [ka] Includes.

[0163] The term "heterocycloalkenyl group" refers to an unsaturated cyclic group containing at least one carbon-carbon double bond or carbon-nitrogen double bond and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, such heterocyclic rings typically contain 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Non-limiting examples of heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 3-pyrrolinyl, 3,4-dihydro-2H-pyran, dihydrofuryl, dihydrothienyl, and dihydrothiopyranyl.

[0164] The term "benzoheterocycloalkenyl group" refers to a fused benzene ring and heterocycloalkenyl group (i.e., the benzene ring and heterocycloalkenyl group share two adjacent carbon atoms). Non-limiting examples of benzoheterocycloalkenyl groups are: [ka] Includes.

[0165] The term "fused heterocycle" refers to a 7-20 membered polycyclic ring system in which two rings share two adjacent atoms, at least one ring atom is selected from N, O, and S, the remaining ring atoms are C, and at least one ring has a completely conjugated π-electron system, but is not aromatic as a whole. Depending on the number of constituent rings, fused rings can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic, and more preferably 6-membered / 6-membered or 5-membered / 6-membered bicyclic. Non-limiting examples of fused heterocycles are: [ka] Includes.

[0166] The term "treatment" means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) inhibiting the disease or disease state, i.e., reducing its progression; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to disappear.

[0167] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state.

[0168] The term "therapeutically or prophylactically effective amount" refers to an amount of a compound of the present application that (i) treats or prevents a specific disease, condition, or disorder described herein, (ii) reduces, 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 "therapeutically effective amount" of a compound of the present application will vary depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of ordinary skill in the art based on their knowledge and the contents of this disclosure.

[0169] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and for which the benefit-risk ratio is reasonable.

[0170] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0171] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof with pharmaceutically acceptable excipients, which facilitates administration of the compounds of the present application to a living body.

[0172] The term "pharmaceutically acceptable additive" refers to an additive that does not cause obvious irritation to the living body and does not impair the biological activity and properties of the active compound. Suitable additives include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc., and are known to those skilled in the art.

[0173] The term "comprise" and similar terms, such as the English expressions "comprises" or "comprising," are to be understood as open and non-exclusive expressions, such as "including, but not limited to."

[0174] Unless otherwise stated, the singular forms of terms cover the plural and the plural forms cover the singular. Unless otherwise stated, the terms "a" or "one" mean "at least one" or "at least one." Unless otherwise stated, "or" is used in the sense of "and / or."

[0175] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. These compounds of the present invention include cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic and other mixtures, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Substituents such as alkyl groups may also have other asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0176] Unless otherwise specified, "(D)" or "(+)" represents dextrorotatory, "(L)" or "(-)" represents levorotatory, and "(DL)" or "(±)" represents racemic.

[0177] Solid wedge bonds unless otherwise stated [ka] and wedge-shaped dashed bond [ka] represents the absolute configuration of the chiral center, and a linear solid bond [ka] and linear dashed bonds [ka] represents the relative configuration of the chiral center.

[0178] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared using asymmetric synthesis, chiral reagents, or other conventional techniques. To obtain enantiomers of specific compounds of the present invention, asymmetric synthesis or derivatization with chiral auxiliaries can be used. Separation of the diastereomeric mixture and removal of the auxiliary groups can provide the desired pure enantiomers. Alternatively, if the molecule contains basic (e.g., amino) or acidic (e.g., carboxy) functional groups, formation of diastereomeric salts with an appropriate optically active acid or base can be followed by separation and subsequent recovery of the diastereomers to obtain the pure enantiomers using conventional methods well known in the art. Separation of enantiomers and diastereomers is also commonly accomplished by chromatography, which utilizes chiral stationary phases, optionally combined with chemical derivatization (e.g., carbamate formation from amines).

[0179] The present application further includes compounds of the present application that are identical to the compounds described herein, but in which one or more atoms have been replaced by an atom whose atomic mass or mass number is different from the normal atomic mass or mass number occurring in nature, i.e., isotopically labeled. Examples of isotopes that can be attached to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example: 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, 36 Cl, etc.

[0180] Certain isotopes (e.g., 3 H, 14 The compounds of the present application labeled with isotopes of deuterium (C) can be used for compound and / or substrate tissue distribution analysis. 3 H), carbon-14( 14 C) is particularly preferred because it is easily obtainable and detectable. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C. 18 F can be used to measure substrate occupancy in positron emission tomography (PET) studies. In general, isotopically labeled compounds of the present application can be prepared by procedures analogous to the techniques and / or examples disclosed below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0181] Also, isotopes with larger mass numbers (e.g., deuterium (i.e., 2 Substitution with H or D) may be preferred in some cases due to the therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced doses), however, deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0182] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable additives, and can be prepared, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

[0183] Typical routes of administration of the compounds of the present application, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous.

[0184] The pharmaceutical compositions of the present application can be manufactured by conventional methods well known in the art, for example, mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing, or the like.

[0185] In certain embodiments, the pharmaceutical composition is for oral administration. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable additives well known in the art. With such additives, the compound of the present application can be formulated as a tablet, pill, dragee, capsule, liquid, gel, syrup, suspension, etc., for oral administration to a patient.

[0186] Oral solid compositions can be prepared by conventional methods such as blending, filling, and tableting. For example, they can be prepared by blending an active compound with a solid additive, and optionally pulverizing the mixture. If necessary, other suitable additives can be added, and the mixture can then be granulated to obtain tablets or dragee cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents, etc.

[0187] The pharmaceutical compositions are also suitable for parenteral administration, for example as appropriate unit dose sterile solutions, suspensions or lyophilized products.

[0188] In all administration methods of the compound of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, administered singly or in divided doses.

[0189] The compounds of the present application can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments made in combination with other chemical synthetic methods, and alternative forms familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0190] The chemical reactions of certain embodiments of the present application are carried out in suitable solvents, which must be compatible with the chemical transformations of the present application and the reagents and raw materials used. In order to obtain the compounds of the present application, those skilled in the art may need to select or modify synthetic steps or reaction processes based on existing embodiments.

[0191] In this field, one major factor to consider when planning a synthetic route is the selection of an appropriate protecting group for a reactive functional group (e.g., an amino group in this application). In this regard, see, for example, Greene's Protective Groups in Organic Synthesis (4th Ed.). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited herein are incorporated herein in their entirety.

[0192] Any patents, patent applications, or existing publications are expressly incorporated by reference herein for purposes of explanation and disclosure. These publications are provided because they were published prior to the filing date of the present application. Any statement as to the disclosure date of such documents or representation of their contents is based on the information known to the applicant and does not constitute an admission that the disclosure date of such documents or their contents are correct. Furthermore, the incorporation of such publications into this specification does not constitute an admission that such publications constitute common general knowledge in the art in all applicable countries.

[0193] In certain embodiments, the compounds of the present application can be prepared by one skilled in the art of organic synthesis by reference to the following routes. Route 1: [ka] where: Ring A, R c , R 3 , n are defined as above.

[0194] Route 2: [ka] where: Ring A, R 3 , n are defined as above.

[0195] Route 3: [ka] where: Ring A, R 3 , n are defined as above.

[0196] The following abbreviations are used in this application: PBS represents fetal bovine serum, PBS represents phosphate-buffered saline, PBST represents phosphate-buffered saline with polysorbate, BSA represents bovine serum albumin, GAPDH represents glyceraldehyde-3-phosphate dehydrogenase, DMSO represents dimethyl sulfoxide, DTT represents dithiothreitol, and HTRF represents homogeneous time-resolved fluorescence. DETAILED DESCRIPTION OF THE INVENTION

[0197] The present invention will be further described below using examples to make the present invention clearer, but the scope of the present application is not limited to these examples. It will be obvious to those skilled in the art that various modifications and improvements may 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 products and can be used without purification.

[0198] Example 1: Preparation of Compound 1 [ka]

[0199] Step A: Preparation of Compound 1-1 A 250 mL three-neck flask was charged with methyl 2-amino-4-methoxybenzoate (4 g) and absolute ethanol (16 mL). Water (28 mL) and concentrated hydrochloric acid (7 mL) were added at room temperature with stirring. The mixture was cooled to 0°C in an ice bath with mechanical stirring, and a solution of iodine monochloride (3.58 g) in concentrated hydrochloric acid (2 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature and react overnight with continued stirring. Water (100 mL) was added to the reaction mixture, and the mixture was stirred vigorously for 5 minutes. The mixture was then suction filtered, the cake washed with water (20 mL), and the solid was collected and pulped with petroleum ether (50 mL) to give 6.45 g of compound 1-1. MS (ESI, [M+H] + ): m / z=307.81. 1 H NMR(500MHz,DMSO-d6)δ 7.99(s,1H),6.38(s,1H),3.78(s,3H),3.75(s,3H).

[0200] Step B: Preparation of Compound 1-2 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 flask in this order, and the reaction flask was placed in an oil bath at 120 °C and reacted for 6 hours with stirring. 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 2.5 M aqueous sodium hydroxide solution, and the mixture was suction filtered. The cake was washed with a large amount of water, and the solid was collected, dried by heating, and then subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain 5.9 g of compound 1-2. MS (ESI, [M+H] + ): m / z=316.79. 1 H NMR(500MHz,DMSO-d6)δ 12.19(s,1H),8.37(s,1H),7.05(s,1H),3.95(s,3H),2.32(s,3H).

[0201] Step C: Preparation of Compounds 1-3 Compound 1-2 (1 g) obtained in Step B and chloroform (10 mL) were added to a 25 mL three-neck flask. Thionyl chloride (2.94 g) and two drops of N,N-dimethylformamide were added in that order with stirring at room temperature. The reaction mixture was heated to 70 °C and stirred for 3 hours. The reaction mixture was concentrated to dryness, and water (40 mL) and dichloromethane (50 mL) were added to the residue. Saturated aqueous sodium bicarbonate solution was added dropwise with vigorous stirring to adjust the pH to slightly alkaline. The mixture was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The residue was concentrated and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 0.41 g of compound 1-3. MS (ESI, [M+H] + ): m / z=334.77. 1 H NMR(500MHz,DMSO-d6)δ 8.42(s,1H),7.18(s,1H),3.98(s,3H),2.50(s,3H).

[0202] Step D: Preparation of Compounds 1-4 Compound 1-3 (200 mg) obtained in Step C, (R)-1-(m-tolyl)ethan-1-amine (98 mg), N,N-diisopropylethylamine (129 mg), and 1,4-dioxane (2 mL) were added to a 25 mL one-neck flask, and the mixture was heated to 100 °C under nitrogen protection and stirred for 5 hours. The reaction was stopped, and the reaction solution was concentrated to dryness. The residue was dissolved in dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate, 1 M hydrochloric acid, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 160 mg of compound 1-4. MS (ESI, [M+H] + ): m / z=434.00. 1H NMR(500MHz,DMSO-d6)δ 8.88(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).

[0203] Step E: Preparation of Compound 1 Compound 1-4 (0.09 g), dimethylphosphine oxide (0.017 g), triethylamine (0.032 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.13 mg), tris(dibenzylideneacetone)dipalladium(0) (4.85 mg), and 1,4-dioxane (2 mL) were added to a 15 mL pressure tube and stirred for 2 hours at 120 °C in an oil bath under nitrogen protection. The reaction mixture was cooled to room temperature, filtered under suction, and the filtrate was concentrated to dryness. The residue was purified by C18 column (120 g) chromatography (40% acetonitrile + 60% water) to give 58.5 mg of compound 1. HRMS (ESI, [M+H] + ): m / z=384.1855. 1 H NMR(500MHz,DMSO-d6)δ 8.80(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),2.43(s,3H),2.33(s,3H),1.75(s,3H),1.72(s,3H),1.60(d,J=7.1Hz,3H).

[0204] Example 2: Preparation of Compound 2 [ka]

[0205] Step A: Preparation of Compound 2-1 Referring to the method of Step D of Example 1, compound 2-1 was prepared by reacting compound 1-3 with (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine. MS (ESI, [M+H] + ): m / z=487.94. 1 H NMR(500MHz,DMSO-d6)δ 8.86(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).

[0206] Step B: Preparation of Compound 2 Compound 2 was prepared with reference to the method of Step E of Example 1. HRMS (ESI, [M+H] + ): m / z=438.1599. 1 H NMR(500MHz,DMSO-d6)δ 8.88(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).

[0207] Example 3: Preparation of Compound 3 [ka]

[0208] Step A: Preparation of Compound 3-1 Referring to the method of Step D of Example 1, compound 1-3 was reacted with (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethan-1-ol to prepare compound 3-1. MS (ESI, [M+H] + ): m / z=499.95. 1 H 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,J=7.7Hz,1 H),7.03(s,1H),4.05-4.01(m,1H),3.92(s,3H),3.84(td,J=14.2,6.3Hz,2H),2.36(s,3H),1.58(d,J=7.0Hz,3H).

[0209] Step B: Preparation of Compound 3 Compound 3 was prepared according to the method of Step E of Example 1. HRMS (ESI, [M+H] + ): m / z=450.1728. 1 H NMR(500MHz,DMSO-d6)δ 8.88(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).

[0210] Example 4: Preparation of Compound 4 [ka]

[0211] Step A: Preparation of Compound 4-1 Referring to the method of Step D of Example 1, compound 1-3 was reacted with (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine to prepare compound 4-1. MS (ESI, [M+H] + ): m / z=484.4. 1 H NMR(500MHz,DMSO-d6)δ 8.90(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).

[0212] Step B: Preparation of Compound 4 Compound 4 was prepared with reference to the method of Step E of Example 1. MS (ESI, [M+H] + ): m / z=434.17. 1 H NMR(500MHz,CDCl3)δ 8.41(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=55.5Hz,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).

[0213] Example 5: Preparation of Compound 5 [ka]

[0214] Step A: Preparation of Compound 5-1 Referring to the method of Step D of Example 1, compound 1-3 was reacted with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethan-1-amine to prepare compound 5-1. MS (ESI, [M+H] + ): m / z=502.25. 1 H NMR(500MHz,CDCl3)δ 8.14(s,1H),7.50-7.41(m,2H),7.14(t,J=7.7Hz,1H),7.06(s,1H),5.88-5.6 8(m,2H),3.96(s,3H),2.52(s,3H),2.02(td,J=1.1,18.6Hz,3H),1.70(s,3H).

[0215] Step B: Preparation of Compound 5 Compound 5 was prepared with reference to the method of Step E of Example 1. MS (ESI, [M+H] + ): m / z=452.5. 1 H NMR(500MHz,CDCl3)δ 8.48(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).

[0216] Example 6: Preparation of Compound 6 [ka]

[0217] Step A: Preparation of Compound 6-1 [ka]

[0218] Step a: Preparation of Compound 6-1-1 A 250 mL three-neck flask was charged with ethyl 2-(3-bromophenyl)acetate (10 g) and anhydrous tetrahydrofuran (100 mL) and cooled to -78 °C under nitrogen protection. [Bis(trimethylsilyl)amino]lithium (103 mL, 1 mol / L) was added dropwise to the reaction mixture, and the mixture was allowed to react for 30 minutes while maintaining the temperature at -78 °C. A solution of N-fluoro-N-(benzenesulfonyl)benzenesulfonamide (25.9 g) in anhydrous tetrahydrofuran (50 mL) was then slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 hours with continued stirring. Upon completion of the reaction, water (100 mL) was added to the reaction mixture and vigorously stirred. The mixture was then extracted twice with ethyl acetate (100 mL), spin-dried, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 97:3) to obtain 10.1 g of compound 6-1-1. 19 F NMR(471MHz,MeOH-d4)δ 105.17-105.60(m). 1 H NMR(500MHz,MeOH-d4)δ 7.76-7.69(m,2H),7.57(m,1H),7.44(m,1H),4.31(m,2H),1.28(t,J=7.1Hz,3H).

[0219] Step b: Preparation of compound 6-1-2 A 500 mL three-neck flask was charged with compound 6-1-1 (9 g) obtained in step a and anhydrous tetrahydrofuran (200 mL) and cooled to -78 °C under nitrogen protection. Methylmagnesium bromide (22 mL, 3 mol / L) was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was returned to 0 °C and the reaction was continued with stirring for 1 hour. Upon completion of the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture and stirred vigorously. The mixture was then extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with water (100 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain 7.0 g of compound 6-1-2.

[0220] Step c: Preparation of compound 6-1-3 Compound 6-1-2 (6.8 g) obtained in step b, 1,4-dioxane (150 mL), tributyl(1-ethoxyethylene)tin (18.53 g), bis(triphenylphosphine)palladium(II) dichloride (1.811 g), and triethylamine (7.77 g) were added to a 250 mL three-neck flask, and the mixture was heated to 100 °C in an oil bath under nitrogen protection for 3 hours. After cooling and spin drying, 20.0 g of compound 6-1-3 was obtained. MS (ESI, [M+H] + ): m / z=257.1.

[0221] Step d: Preparation of compound 6-1-4 Compound 6-1-3 (20 g), tetrahydrofuran (20 mL), and dilute hydrochloric acid (19 mL, 4 mol / L) were added to a 250 mL single-neck flask and reacted at room temperature for 2.5 hours. After the reaction was completed, water (200 mL) was added to the reaction mixture and vigorously stirred. The mixture was then extracted once with ethyl acetate (100 mL), spin-dried, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3.3 g of compound 6-1-4. MS (ESI, [M+H] + ): m / z=229.1. 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).

[0222] Step e: Preparation of Compound 6-1-5 Compound 6-1-4 (3 g) obtained in step d, tetrahydrofuran (30 mL), (S)-2-methylpropane-2-sulfinamide (2.390 g), and tetraethyl titanate (8.99 g) were added to a 100 mL three-neck flask and heated to 80 °C in an oil bath under nitrogen protection for 4.5 hours. Upon completion of the reaction, water (50 mL) was added to the reaction mixture, stirred vigorously, filtered, and the cake was washed three times with ethyl acetate (20 mL). The organic phase was separated, spin-dried, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain 4.2 g of compound 6-1-5. MS (ESI, [M+H] + ): m / z=332.2. 1 H NMR(500MHz,MeOH-d4)δ 8.13(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).

[0223] Step f: Preparation of compound 6-1-6 Compound 6-1-5 (4.2 g) obtained in step e and anhydrous tetrahydrofuran (40 mL) were added to a 100 mL three-neck flask and cooled to -78 ° C. Lithium tri-sec-butylborohydride (28.4 mL, 1 mol / L) was added dropwise to the reaction system, and the mixture was stirred at -78 ° C. for 2 hours. Upon completion of the reaction, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution and stirred vigorously for 2 minutes. The mixture was then warmed to room temperature and allowed to stand for separation. The organic phase was collected, spin-dried, and subjected to silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 2.5 g of compound 6-1-6. MS (ESI, [M+H] + ): m / z=334.0. 1H NMR(500MHz,MeOH-d4)δ 7.53(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).

[0224] Step g: Preparation of Compound 6-1 Compound 6-1-6 (2.3 g) obtained in step e and 1,4-dioxane hydrochloric acid solution (8 mL, 4 mol / L) were added to a 100 mL single-neck flask and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was spin-dried to obtain 2.0 g of compound 6-1. 1 H NMR(500MHz,MeOH-d4)δ 7.63(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).

[0225] Step B: Preparation of Compound 6-2 Referring to the method of Step D in Example 1, compound 1-3 was reacted with compound 6-1 obtained in Step A to prepare compound 6-2. MS (ESI, [M+H] + ): m / z=527.98.

[0226] Step C: Preparation of Compound 6 Compound 6 was prepared with reference to the method of Step E of Example 1. MS (ESI, [M+H] + ): m / z=478.09. 1 H NMR(500MHz,MeOH-d4)δ 8.58(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).

[0227] Example 7: Preparation of Compound 7 [ka]

[0228] Step A: Preparation of Compound 7-1 Referring to the method of Step D of Example 1, compound 1-3 was reacted with (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine to prepare compound 7-1. MS (ESI, [M+H] + ): m / z=532.89. 1 H NMR(500MHz,DMSO-d6)δ 8.82(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).

[0229] Step B: Preparation of Compound 7-2 Compound 7-2 was prepared following the method of Step E of Example 1. MS (ESI, [M+H] + ): m / z=483.08. 1 H NMR(500MHz,DMSO-d6)δ 8.92(d,J=7.6Hz,1H),8.76-8.73(m,2H),8.41-8.39(m,2H),7.16(d,J=4.7Hz,1 H),5.72(p,J=7.1Hz,1H),3.98(d,J=9.8Hz,3H),2.41(s,3H),1.79-1.70(m,9H).

[0230] Step C: Preparation of Compound 7 Compound 7-2 (100 mg), tetrahydrofuran (15 mL), and water (5.00 mL) were added to a 50 mL three-neck flask. Ammonium chloride (444 mg) and zinc powder (203 mg) were added while stirring at room temperature. The reaction flask was placed in an oil bath at 70 °C and reacted for 5 hours with stirring. The reaction was stopped, the reaction solution was cooled to room temperature, saturated brine (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column (methanol:dichloromethane = 7:93) to obtain 32 mg of compound 7. HRMS (ESI, [M+H] + ): m / z=453.1675. 1 H NMR(500MHz,CDCl3)δ 8.55(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).

[0231] Example 8: Preparation of Compound 8 [ka]

[0232] Step A: Preparation of Compound 8-1 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)ethan-1-amine to prepare compound 8-1. MS (ESI, [M+H] + ): m / z=546.88. 1H NMR(500MHz,CD3OD)δ 8.77(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).

[0233] Step B: Preparation of Compound 8-2 Compound 8-2 was prepared with reference to the method of Step E of Example 1. MS (ESI, [M+H] + ): m / z=497.08. 1 H NMR(500MHz,CD3OD)δ 8.65(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,1 H),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).

[0234] Step C: Preparation of Compound 8 Compound 8-2 (0.16 g), methanol (10 mL), water (2 mL), and tetrahydroxydiborane (0.231 g) were added to a 25 mL single-neck flask in this order and stirred for 10 minutes. A solution of sodium hydroxide (0.129 g) in water (2 mL) was added and stirred overnight at room temperature. The reaction mixture was poured into water (20 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and ethyl acetate (10 mL) was added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 120 mg of compound 8. MS (ESI, [M+H] + ): m / z=467.16. 1H NMR(500MHz,CD3OD)δ 8.61(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).

[0235] Example 9: Preparation of Compound 9 [ka]

[0236] Step A: Preparation of Compound 9-1 A 500 mL pressure flask was charged with 5-amino-2-chloroisonicotinic acid (15 g), ammonium acetate (67.0 g), triethyl orthoacetate (141 g), and methanol (100 mL), and the mixture was stirred in an oil bath at 125° C. for 9 hours. The reaction was stopped, the reaction solution was cooled to room temperature, and suction filtered. The cake was washed with ethyl acetate (50 mL). The solid was collected and dried by heating to obtain 8.1 g of compound 9-1. MS(ESI, [MH] - ): m / z=194.1. 1 H NMR(500MHz,DMSO-d6)δ 8.79(s,1H),7.90(s,1H),2.38(s,3H).

[0237] Step B: Preparation of Compound 9-2 Compound 9-1 (10 g), 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-neck flask and allowed to react overnight at room temperature with stirring. The reaction was stopped, and the reaction mixture was poured into water (50 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 9.7 g of compound 9-2.

[0238] Step C: Preparation of Compound 9-3 Compound 9-2 (3 g) obtained in Step B, (R)-1-(3-(trifluoromethyl)phenyl)ethan-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-neck flask and stirred at room temperature for 2 hours under nitrogen protection. The reaction was stopped, and the reaction mixture was poured into water (100 mL). Dichloromethane (30 mL × 3) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 2.2 g of compound 9-3. MS (ESI, [M+H] + ): m / z=367.26. 1 H NMR(500MHz,DMSO-d6)δ 8.87-8.80(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).

[0239] Step D: Preparation of Compound 9 Compound 9 was prepared with reference to the method of Step E of Example 1. MS (ESI, [M+H] +): m / z=409.4. 1 H NMR(500MHz,DMSO-d6)δ 9.25(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,1H),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).

[0240] Example 10: Preparation of Compound 10 [ka]

[0241] Step A: Preparation of Compound 10-1 Compound 7-1 (1.1 g) obtained in Step A of Example 7, 1-benzyl-1,4-azaphospholane 4-oxide (0.441 g), triethylamine (0.294 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.113 g), tris(dibenzylideneacetone)dipalladium(0) (0.090 g), and 1,4-dioxane (10 mL) were added to a 25 mL three-neck flask and reacted with stirring under nitrogen protection at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and suction filtered. The filtrate was concentrated to dryness, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=95:5) to obtain 0.94 g of compound 10-1. MS (ESI, [M+H] + ): m / z=614.40. 1H NMR(500MHz,DMSO-d6)δ 8.86(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,1 H),3.99(s,3H),3.69(s,2H),3.04-2.96(m,2H),2.88-2.82(m,2H),2. 48-2.45(m,2H),2.37(s,3H),1.83-1.76(m,2H),1.67(d,J=7.1Hz,3H).

[0242] Step B: Preparation of Compound 10-2 Compound 10-1 (0.699 g) obtained in Step A and 1,2-dichloroethane (10 mL) were added to a 25 mL three-neck flask and stirred in an ice-water bath. 1-Chloroethyl chloroformate (0.195 g) was added, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated to dryness, and methanol (5 mL) was added to the residue. The mixture was heated to reflux and stirred for 15 minutes. The reaction mixture was concentrated to dryness, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol = 94:6) to obtain 348 mg of compound 10-2. MS (ESI, [M+H] + ): m / z=524.07. 1 H NMR(500MHz,DMSO-d6)δ 8.85(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=7.1 Hz,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).

[0243] Step C: Preparation of Compound 10-3 Compound 10-2 (150 mg), tetrahydrofuran (1 mL), triethylamine (87 mg), and acetic anhydride (32.2 mg) were added to a 10 mL single-neck flask and stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, which was then stirred at room temperature for 5 minutes. The mixture was extracted with dichloromethane (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column (dichloromethane:methanol = 96:4) to obtain 144 mg of compound 10-3. MS (ESI, [M+H] + ): m / z=566.03. 1 H NMR (500 MHz, DMSO-d6) δ 8.91(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=25.9,13.2 Hz,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).

[0244] Step D: Preparation of Compound 10 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-neck flask, and stannous chloride dihydrate (182 mg) was added while stirring at room temperature. The reaction flask was placed in an oil bath at 50°C and reacted with stirring for 1 hour. The reaction was stopped, and the reaction solution was concentrated to dryness. The mixture was separated and purified using a silica gel column (dichloromethane:methanol = 94:6) to obtain 89 mg of compound 10. HRMS (ESI, [M+H] + ): m / z=536.2073. 1H NMR(500MHz,DMSO-d6)δ 8.76(d,J=7.5Hz,1H),8.68(d,J=13.8Hz,1H),7.12(d,J=4.8Hz,1H),6.9 1(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).

[0245] Example 11: Preparation of Compound 11 [ka]

[0246] Step A: Preparation of Compound 11-1 Compound 11-1 was prepared using compound 2-1 obtained in step A of Example 2, with reference to the method of step A of Example 10. HRMS (ESI, [M+H] + ): m / z=569.2283. 1 H NMR(500MHz,DMSO-d6)δ 8.78(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=4.6Hz,1H),5.6 6(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).

[0247] Step B: Preparation of Compound 11-2 Compound 11-2 was prepared following the method of Step B of Example 10. HRMS(ESI,[M+H] + ):m / z=479.1814. 1 H NMR(500MHz,DMSO-d6)δ 8.80(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).

[0248] Structural C: Preparation of compound 11 In Example 10, the method of the chemical compound C is the reference and the compound 11 is the preparation. HRMS(ESI,[M+H] + ):m / z=521.1961. 1 H NMR(500MHz,DMSO-d6)δ 8.83(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).

[0249] Example 12: Production of Compound 12

change

[0250] ステップA: Preparation of compound 12-1 Compound 12-1 was prepared using compound 4-1 obtained in step A of Example 4, with reference to the method of step A of Example 10. MS (ESI, [M+H] + ): m / z=565.55. 1 H NMR(500MHz,DMSO-d6)δ 8.95(s,1H),8.73(d,J=13.6Hz,1H),7.70(d,J=7.8Hz,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).

[0251] Step B: Preparation of Compound 12-2 Compound 12-2 was prepared following the method of Step B of Example 10. MS (ESI, [M+H] + ): m / z=475.18. 1 H NMR(500MHz,DMSO-d6)δ 8.86(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,1H),5.76(p, J=6.9Hz,1H),3.95(s,3H),3.17-3.06(m,4H),2.55(s,3H),2.43-2.36(m,2H),2.35(s,3H),1.77(d,J=18.6Hz,2H),1.54(d,J=7.0Hz,3H).

[0252] Step C: Preparation of Compound 12 Compound 12 was prepared following the method of Step C of Example 10. MS (ESI, [M+H] + ): m / z=517.12. 1H NMR(500MHz,CDCl3)δ 8.47(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).

[0253] Example 13: Preparation of Compound 13 [ka] Compound 13 was prepared by reacting compound 12-2 with N,N-dimethylglycine according to the method of Step C of Example 10. MS (ESI, [M+H] + ): m / z=560.11. 1 H NMR(500MHz,CDCl3)δ 8.53(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).

[0254] Example 14: Preparation of Compound 14 [ka] Following the method of Step C of Example 10, compound 14 was prepared by reacting compound 12-2 with cyclopropanecarboxylic acid. MS (ESI, [M+H] + ): m / z=543.10. 1 H NMR(500MHz,CDCl3)δ 8.47(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,1H),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).

[0255] Example 15: Preparation of Compound 15 [ka]

[0256] Step A: Preparation of Compound 15-1 Compound 15-1 was prepared following the method of Step A of Example 10. MS (ESI, [M+H] + ): m / z=583.1. 1H NMR(500MHz,CDCl3)δ 8.57(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=6.0,12.7,13.2H z,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).

[0257] Step B: Preparation of Compound 15-2 Compound 15-2 was prepared following the method of Step B of Example 10. MS (ESI, [M+H] + ): m / z=493.08. 1 H NMR(500MHz,CDCl3)δ 8.56(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,3H),3.40(d dd,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).

[0258] Step C: Preparation of Compound 15 Compound 15 was prepared following the method of Example 10, Step C. MS (ESI, [M+H] + ): m / z=535.13. 1H NMR(500MHz,CDCl3)δ 8.55(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),2.45(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).

[0259] Example 16: Preparation of Compound 16 [ka] Compound 16 was prepared by reacting compound 15-2 with N,N-dimethylglycine according to the method of Step C of Example 10. MS (ESI, [M+H] + ): m / z=578.14. 1 H NMR(500MHz,CDCl3)δ 8.55(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),6.5 6(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=14.0,27.4 Hz,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).

[0260] Example 17: Preparation of Compound 17 [ka] Compound 17 was prepared by reacting compound 15-2 with cyclopropanecarboxylic acid according to the method of Step C of Example 10. MS (ESI, [M+H] + ): m / z=561.11. 1 H NMR(500MHz,CDCl3)δ 8.56(d,J=14.2Hz,1H),7.58-7.38(m,2H),7.18-7.06(m,2H),6.63(d,J=7.0Hz,1H),5.8 5(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=4.5,7.9Hz,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).

[0261] Example 18: Preparation of Compound 18 [ka]

[0262] Step A: Preparation of Compound 18-1 Compound 18-1 was prepared using compound 8-1 obtained in step A of Example 8, with reference to the method of step A of Example 10. MS (ESI, [M+H] + ): m / z=628.18. 1H NMR(500MHz,CD3OD):δ 8.65(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,2H),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).

[0263] Step B: Preparation of Compound 18-2 Compound 18-2 was prepared following the method of Step B of Example 10. MS (ESI, [M+H] + ): m / z=538.09.

[0264] Step C: Preparation of Compound 18-3 Compound 18-3 was prepared following the method of Example 10, Step C. MS (ESI, [M+H] + ): m / z=580.07.

[0265] Step D: Preparation of Compound 18 Compound 18 was prepared following the method of Step C of Example 8. MS (ESI, [M+H] + ): m / z=550.09. 1H NMR(500MHz,CD3OD):δ 8.62(d,J=14.3Hz,1H),7.08(d,J=5.0Hz,1H),7.03(s,1H),6.90(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,3 H),3.87(dd,J=23.5,11.3Hz,1H),3.50(dd,J=23.2,12.5Hz,1H),2.65-2.52(m,2 H),2.44(d,J=5.8Hz,6H),2.23(s,3H),2.16-1.99(m,2H),1.59(d,J=7.0Hz,3H).

[0266] Example 19: Preparation of Compound 19 [ka]

[0267] Step A: Preparation of Compound 19-1 Compound 9-1 (0.13 g), N,N-dimethylformamide (1.3 mL), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (0.45 g), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.152 g) were added in this order to a 25 mL single-neck flask, and a mixed solution of (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (0.178 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.152 g) dissolved in N,N-dimethylformamide (1.3 mL) was added dropwise to the mixture while stirring at room temperature. After the dropwise addition was completed, the mixture was stirred at 50° C. overnight. After the reaction was completed, the reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate=70:30) to obtain 0.14 g of compound 19-1. MS (ESI, [M+H] + ) m / z = 385.06. 1H NMR(500MHz,DMSO-d6)δ 8.91(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).

[0268] Step B: Preparation of Compound 19-2 Compound 19-1 (0.14 g) obtained in Step A, 1-benzyl-1,4-azaphospholane-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) (0.017 g, 0.018 mmol), and N,N-dimethylformamide (3 mL) were added to a 10 mL microwave tube. After replacing the atmosphere with nitrogen, the mixture was heated to 165°C at 150 watts in a microwave reactor and reacted for 50 minutes. After suction filtration, the filtrate was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column (dichloromethane:methanol = 97:3) to obtain 0.15 g of compound 19-2. MS (ESI, [M+H] + ) m / z = 558.16. 1 H NMR(500MHz,DMSO-d6)δ 9.31(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=12.0Hz ,2H),2.45-2.32(m,5H),1.92(t,J=14.6Hz,2H),1.64(d,J=7.1Hz,3H).

[0269] Step C: Preparation of Compound 19-3 Compound 19-2 (0.15 g) obtained in Step B and 1,2-dichloroethane (14 mL) were added to a 50 mL single-neck flask, and 1-chloroethyl 1-chloroformate (0.077 g) was added dropwise in an ice bath. The mixture was heated to reflux and reacted for 2.5 hours. The reaction mixture was concentrated to dryness, and methanol (5 mL) was added to the residue. The mixture was then refluxed for 30 minutes. The reaction mixture was concentrated to dryness to obtain 0.16 g of compound 19-3. MS (ESI, [M+H] + ) m / z = 468.13. 1 H NMR(500MHz,DMSO-d6)δ 11.11(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).

[0270] Step D: Preparation of Compound 19 In an ice-water bath, methanesulfonyl chloride (0.043 g) was added dropwise to a solution of compound 19-3 (0.16 g) obtained in step C and triethylamine (0.104 g) in tetrahydrofuran (3.2 mL). After the addition was complete, the temperature was maintained and the reaction was allowed to proceed for 2 hours. The reaction mixture was concentrated to dryness, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by C18 column chromatography (acetonitrile:water = 40:60) to obtain 86 mg of compound 19. HRMS (ESI, [M+H] + )m / z=546.13611. 1H NMR(500MHz,CD3OD)δ 9.11(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). 31 P NMR (202 MHz, CD3OD) δ 31.1.

[0271] Example 20: Preparation of Compound 20 [ka]

[0272] Step A: Preparation of Compound 20-1 Compound 20-1 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ) m / z = 369.09. 1 H NMR(500MHz,DMSO-d6)δ 12.80(s,1H),9.14(s,1H),8.42(d,J=5.6Hz,1H),7.37-7.29(m,5H),3.63(s,2) H),2.95-2.76(m,4H),2.44(s,3H),2.41-2.31(m,2H),1.94(t,J=15.5Hz,2H).

[0273] Step B: Preparation of Compound 20-2 Referring to the method of Example 19, Step A, compound 20-1 was reacted with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to prepare compound 20-2. MS (ESI, [M+H] + ) m / z = 540.16. 1H NMR(500MHz,CDCl3)δ 9.18(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=55.0 Hz,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).

[0274] Step C: Preparation of Compound 20-3 Compound 20-3 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ) m / z = 450.16.

[0275] Step D: Preparation of Compound 20 Compound 20 was prepared following the method of Step D of Example 19. HRMS (ESI, [M+H] + )m / z=528.1443. 1 H NMR(500MHz,DMSO-d6)δ 9.40(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).

[0276] Example 21: Preparation of Compound 21 [ka] In 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). After the addition, the temperature was maintained and the reaction was allowed to proceed for 20 minutes. Upon completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (15 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by C18 column chromatography (acetonitrile:water = 40:60) to obtain 49 mg of compound 21. HRMS (ESI, [M+H] + ) m / z=554.1635. 1 H NMR(500MHz,CD3OD)δ 9.11(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).

[0277] Example 22: Preparation of Compound 22 [ka]

[0278] Step A: Preparation of Compound 22-1 Referring to the method of Example 19, Step A, compound 9-1 was reacted with (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethan-1-amine hydrochloride to prepare compound 22-1. MS (ESI, [M+H] + ) m / z = 377.10. 1H NMR(500MHz,acetone-d6)δ 8.81(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).

[0279] Step B: Preparation of Compound 22-2 Compound 22-2 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ) m / z = 550.13. 1 H NMR(500MHz,DMSO-d6)δ 9.17(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,1H),7.09(dd ,J=7.6Hz,1H),5.74(m,1H),4.87(t,J=16.6Hz,2H),3.65(s,3H),2.99-2.79(m,4 H),2.44(s,3H),2.43-2.34(m,2H),1.93(t,J=10.5Hz,2H),1.60(d,J=7.0Hz,3H).

[0280] Step C: Preparation of Compound 22-3 Compound 22-3 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ) m / z = 460.17.

[0281] Step D: Preparation of Compound 22 Compound 22 was prepared following the method of Step D of Example 19. HRMS (ESI, [M+H] + ) m / z=538.1596. 1H NMR(500MHz,CD3OD)δ 9.10(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). 31 P NMR (202 MHz, CD3OD) δ 31.22.

[0282] Example 23: Preparation of Compound 23 [ka] Compound 23 was synthesized by following the preparation method of Example 19, except that (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was replaced with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethan-1-amine hydrochloride. HRMS (ESI, [M+H] + )m / z=542.1608. 1 H NMR(500MHz,DMSO-d6)δ 9.18(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).

[0283] Example 24: Preparation of Compound 24 [ka]

[0284] Step A: Preparation of Compound 24-1 To a 50 mL single-neck flask, 5-amino-2-chloropyridine-4-carboxylic acid (3 g) and methanol (11.14 g) were added in this order, and the mixture was stirred in an ice-salt bath while thionyl chloride (4.14 g) and 2 drops of N,N-dimethylformamide were added dropwise. After the addition was completed, the mixture was heated to 65 °C and reacted for 12 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1.8 g of compound 24-1. MS (ESI, [M+H] + ): m / z=186.97.

[0285] Step B: Preparation of Compound 24-2 Compound 24-1 (1.7 g) obtained in step A, fluoroacetonitrile (2.69 g), and methanesulfonic acid (7.0 g) were added to a 15 mL pressure flask in this order, and the reaction system was heated to 105 °C and reacted with stirring for 4 hours. Upon completion of the reaction, 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 aqueous sodium hydroxide solution. The reaction solution was extracted with dichloromethane (20 mL × 5), the organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness. The residue was separated and purified using a silica gel column (dichloromethane:methanol = 97:3) to obtain 0.43 g of compound 24-2. MS (ESI, [M+H] + ): m / z=214.02. 1 H NMR(500MHz,DMSO-d6)δ 12.90(br,1H),8.93(s,1H),7.99(s,1H),5.40(s,1H),5.31(s,1H).

[0286] Step C: Preparation of Compound 24-3 Compound 24-3 was prepared following the method of Example 19, Step A. MS (ESI, [M+H] +): m / z=403.06. 1 H NMR(500MHz,DMSO-d6)δ 9.13(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).

[0287] Step D: Preparation of Compound 24-4 Compound 24-4 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ): m / z=576.11. 1 H NMR(500MHz,CD3OD)δ 9.23(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,2 H),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).

[0288] Step E: Preparation of Compound 24-5 Compound 24-5 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ): m / z=486.11.

[0289] Step F: Preparation of Compound 24 Compound 24 was prepared by reacting compound 24-5 with methanesulfonyl chloride according to the method of Step D of Example 19. HRMS (ESI, [M+H] + ): m / z=564.1277. 1H NMR(500MHz,CD3OD)δ 9.24(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),5.3 0(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).

[0290] Example 25: Preparation of Compound 25 [ka]

[0291] Step A: Preparation of Compound 25-2 [ka]

[0292] Step a: Preparation of compound 25-2-1 In a 500 mL single-neck flask, 2-fluoro-3-trifluoromethylbenzoic acid (15 g), N,N-dimethylformamide (100 mL), dimethylhydroxylamine hydrochloride (7.17 g), N,N-diisopropylethylamine (37.3 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.9 g) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction was stopped, and the reaction solution was poured into water (500 mL), extracted with ethyl acetate (200 mL), and the organic phase was washed with water (200 mL) and then saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using silica gel (petroleum ether:ethyl acetate = 60:40) to obtain 17.4 g of compound 25-2-1. MS (ESI, [M+H] + ) m / z = 252.04. 1H NMR(500MHz,DMSO-d6)δ 7.93-7.83(m,2H),7.52(t,J=7.8Hz,1H),3.31(s,3H),2.70(s,3H).

[0293] Step b: Preparation of compound 25-2-2 Under nitrogen protection at 0°C, a 1M solution of methylmagnesium bromide in tetrahydrofuran (29.9 mL) was slowly added dropwise to a stirred solution of compound 25-2-1 (5 g) obtained in step a in ultra-dehydrated tetrahydrofuran (50 mL). After the addition was complete, the mixture was heated to 35°C and reacted for 2 hours with stirring. The reaction was stopped, and saturated aqueous ammonium chloride solution (150 mL) was slowly added to the reaction solution. The mixture was stirred at room temperature for 10 minutes, and the mixture was allowed to stand for liquid separation. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to give 4 g of compound 25-2-2. 1 H 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).

[0294] Step c: Preparation of compound 25-2-3 Compound 25-2-2 (4 g) obtained in step b, dry tetrahydrofuran (40 mL), (R)-(+)-tert-butylsulfinamide (2.352 g), and tetraethyl titanate (11.07 g) were added to a 100 mL single-neck flask, and the mixture was heated to 80 ° C. and reacted for 3 hours. The reaction was stopped, and ice water (150 mL) and ethyl acetate (150 mL) were added to the reaction solution while stirring at room temperature. The mixture was stirred for 5 minutes, and then suction filtered. The filtrate was separated, and 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. MS (ESI, [M+H] + ) m / z = 309.97.

[0295] Step d: Preparation of compound 25-2-4 Compound 25-2-3 (3 g) obtained in step c and tetrahydrofuran (30 mL) were added to a 250 mL three-neck flask in this order, and the mixture was cooled to -50 °C under nitrogen protection. Sodium borodeuteride (0.731 g) was added in several portions, and the reaction was continued for 3 hours while maintaining the temperature and stirring. The reaction solution was quenched by adding deuterium oxide (20 mL) dropwise, and 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 purified using a silica gel column (petroleum ether:ethyl acetate = 60:40) to obtain 0.62 g of compound 25-2-4. MS (ESI, [M+H] + ) m / z = 313.00. 1 H NMR(500MHz,DMSO-d6)δ 7.89(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).

[0296] Step e: Preparation of compound 25-2 Compound 25-2-4 (0.6 g) obtained in step d, 1,4-dioxane (2 mL), and 4 M hydrochloric acid dioxane solution (2.5 mL) were added to a 100 mL single-neck flask in this order, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was pulped with methyl tert-butyl ether (5 mL) to obtain 0.38 g of compound 25-2. MS (ESI, [M-HCl + H] + ) m / z = 209.04. 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).

[0297] Step B: Preparation of Compound 25-3 Compound 25-3 was prepared from compound 25-2 prepared in Step A of Example 19 and compound 20-1. MS (ESI, [M+H] + ) m / z = 559.14. 1 H NMR(500MHz,DMSO-d6)δ 9.30(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,5H),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).

[0298] Step C: Preparation of Compound 25-4 Compound 25-4 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ): m / z=469.28.

[0299] Step D: Preparation of Compound 25 Compound 25 was prepared by reacting compound 25-4 with methanesulfonyl chloride according to the method of Step D of Example 19. HRMS (ESI, [M+H] + ): m / z=547.1432. 1 H NMR(500MHz,CD3OD)δ 9.11(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).

[0300] Example 26: Preparation of Compound 26 [ka]

[0301] Step A: Preparation of Compound 26-1 [ka]

[0302] Step a: Preparation of compound 26-1-1 Compound 26-1-1 was prepared by following the procedure of step a of Example 25, substituting 2-methyl-3-trifluoromethylbenzoic acid for 2-fluoro-3-trifluoromethylbenzoic acid. MS (ESI, [M+H] + ) m / z = 248.07. 1 H NMR(500MHz,CD3OD)δ 7.73(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).

[0303] Step b: Preparation of compound 26-1-2 Compound 26-1-2 was prepared with reference to the method in step b of Example 25. GCMS:[M] + =202. 1 H NMR(500MHz,CD3OD)δ 7.83(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).

[0304] Step c: Preparation of compound 26-1-3 A 100 mL three-neck flask was charged with 1 M [bis(trimethylsilyl)amino]lithium in tetrahydrofuran (17.68 mL) and dry tetrahydrofuran (50 mL), in that order. Under nitrogen protection at -74 °C, a solution of compound 26-1-2 (2.75 g) obtained in step b in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at -74 °C for 10 minutes. Chlorotrimethylsilane (1.921 g) was slowly added to the reaction mixture, and after 2 minutes, the dropwise addition was completed. The reaction was continued with stirring for 1 hour at -74 °C, and then the temperature was raised to room temperature and continued for 20 minutes. Upon completion of the reaction, saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was stirred vigorously for 5 minutes. Extraction with ethyl acetate (10 mL x 3) was performed. The combined organic phases were dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was dissolved in acetonitrile (50 mL), stirred at 0 °C, and a selective fluorination reagent (5.30 g) was added. The mixture was allowed to react for 5 hours while warming to room temperature and continuing to stir. Upon completion of the reaction, the reaction solution was concentrated to dryness. Water (20 mL) was added to the residue, and extraction with ethyl acetate (40 mL x 3) was performed. The combined organic phases were dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was separated and purified using a silica gel column (petroleum ether: ethyl acetate = 91:10) to obtain 1.34 g of compound 26-1-3. 1 H NMR(500MHz,CD3OD)δ 7.84(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).

[0305] Step d: Preparation of compound 26-1-4 Referring to the method of step c of Example 25, compound 26-1-3 obtained in step c above was reacted with S-tert-butylsulfinamide to prepare compound 26-1-4. MS (ESI, [M+H] + ) m / z = 324.10.

[0306] Step e: Preparation of compound 26-1 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-neck flask in this order. 1 M lithium tri-sec-butylborohydride in tetrahydrofuran (51.0 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. After the reaction was complete, saturated ammonium chloride solution (30 mL) was added dropwise to the reaction mixture, and the mixture was stirred vigorously for 10 minutes. The mixture was then warmed to room temperature and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue that was purified using a silica gel column (dichloromethane:methanol = 98:2) to obtain 360 mg of a yellow oily liquid. The yellow oil, 1,4-dioxane (20 mL), and 4 M hydrogen chloride in 1,4-dioxane (0.857 mL) were added to a 100 mL single-neck flask in this order, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness, and the residue was purified with methyl tert-butyl ether (10 mL) to give 250 mg of compound 26-1. MS (ESI, [M+H] + ) m / z=221.99. 1 H NMR(500MHz,D2O)δ 7.83(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).

[0307] Step B: Preparation of Compound 26-2 Compound 26-2 was prepared by following the procedure of Step A of Example 19, substituting 6-bromo-2-methylquinazolin-4(3H)-one for compound 9-1. MS(ESI, [M+H+2] + ) m / z = 444.04.

[0308] Step C: Preparation of Compound 26-3 Compound 26-3 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ) m / z = 571.78.

[0309] Step D: Preparation of Compound 26-4 Compound 26-4 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ) m / z = 481.31.

[0310] Step E: Preparation of Compound 26 Compound 26 was prepared following the method of Step D of Example 19. HRMS (ESI, [M+H] + )m / z=559.1558. 1 H NMR(500MHz,CD3OD)δ 8.72(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). 31 P NMR (202 MHz, CD3OD) δ 32.62.

[0311] Example 27: Preparation of Compound 27 [ka]

[0312] Step A: Preparation of Compound 27-1 Compound 27-1 was prepared by following the procedure of Step A of Example 19, substituting 6-bromo-2-methylquinazolin-4(3H)-one for compound 9-1. MS (ESI, [M+H] + ) m / z = 410.05.

[0313] Step B: Preparation of Compound 27-2 Compound 27-2 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ) m / z = 539.15.

[0314] Step C: Preparation of Compound 27-3 Compound 27-3 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ) m / z = 449.15.

[0315] Step D: Preparation of Compound 27 Following the method of Step D of Example 19, compound 27 was prepared by reacting compound 27-3 with methanesulfonyl chloride. HRMS (ESI, [M+H] + )m / z=527.1489. 1 H NMR(500MHz,CD3OD)δ 8.80(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,1 H),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).

[0316] Example 28: Preparation of Compound 28 [ka]

[0317] Step A: Preparation of Compound 28-1 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-neck flask in this order and reacted at room temperature for 3 hours with stirring. The reaction was stopped, and saturated sodium chloride solution (100 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (100 mL x 2). 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. MS(ESI, [MH] - ) m / z = 291.79. 1 H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),6.35(s,1H),3.78(s,3H),2.57(s,2H).

[0318] Step B: Preparation of Compound 28-2 Compound 28-1 (1.3 g) obtained in Step A, 2-methoxyethanol (13 mL), and formamidine acetate (0.924 g) were added to a 50 mL single-neck flask in this order, and the mixture was reacted at 120°C with stirring for 2 hours. The reaction was then stopped, cooled to room temperature, and filtered with suction. The cake was washed with methanol (10 mL). The cake was collected and pulped with methanol (30 mL). The cake was collected and dried with suction filtration to obtain 0.95 g of compound 28-2. MS (ESI, [M+H] + ) m / z = 302.81.

[0319] Step C: Preparation of Compound 28-3 Compound 28-2 (0.5 g) obtained in step B above, N,N-dimethylformamide (10 mL), and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (1.723 g) were added to a 50 mL single-neck flask in this order, and while stirring at room temperature, a solution of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.756 g) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (0.344 g) in N,N-dimethylformamide (10 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight to allow the reaction to proceed. The reaction was stopped, purified water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). 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. MS (ESI, [M+H] + ) m / z = 473.97. 1 H NMR(500MHz,DMSO-d6)δ 9.01(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,1 H),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).

[0320] Step D: Preparation of Compound 28-4 Compound 28-4 was prepared using compound 28-3 according to the method of Step A of Example 10. MS (ESI, [M+H] + ) m / z = 555.14. 1H NMR(500MHz,DMSO-d6)δ 8.94(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),7.39-7.34(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).

[0321] Step E: Preparation of Compound 28-5 Acetonitrile (50 mL), cerium ammonium nitrate (2.471 g), and water (10 mL) were added to a 100 mL single-neck flask in this order, and after stirring for 2 minutes to completely dissolve, compound 28-4 (0.5 g) obtained in step D above was added and allowed to react at room temperature for 1 hour with stirring. The reaction was stopped, and saturated aqueous sodium bicarbonate 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 then saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 0.208 g of compound 28-5. MS (ESI, [M+H] + ) m / z = 465.2. 1 H NMR(500MHz,DMSO-d6)δ 8.93(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).

[0322] Step F: Preparation of Compound 28 Compound 28 was prepared by reacting compound 28-5 with acetic anhydride according to the method of Step C of Example 10. HRMS (ESI, [M+H] + ) m / z=507.1772. 1 H NMR (500 MHz, DMSO-d6) δ 8.97(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),4.47-4.3 7(m,1H),4.09-3.99(m,1H),3.94(s,3H),3.81-3.69(m,1H),3.41-3.31(m,1 H),2.49-2.30(m,2H),2.13(s,3H),2.03-1.84(m,2H),1.61(d,J=7.1Hz,3H).

[0323] Example 29: Preparation of Compound 29 [ka]

[0324] Step A: Preparation of Compound 29 Following the method of Step D of Example 19, compound 29 was prepared by reacting compound 28-5 with methanesulfonyl chloride. HRMS (ESI, [M+H] + )m / z=543.1441. 1 H NMR(500MHz,DMSO-d6)δ 8.98(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),3.04(s,3H),2.55(d,J=13.7Hz,2H),2.09-1.96(m,2H),1.61(d,J=7.1Hz,3H).

[0325] Example 30: Preparation of Compound 30 [ka]

[0326] Step A: Preparation of Compound 30-1 Compound 1-1 (1 g), fluoroacetonitrile (1.923 g), and methanesulfonic acid (2.504 g) were added to a 15 mL pressure flask in this order, and the reaction flask was placed in a 120 °C oil bath and stirred for 4 hours. The reaction was stopped, and the reaction solution was allowed to cool to room temperature. The reaction solution was concentrated, and the pH was adjusted to alkaline directly with 4 M aqueous sodium hydroxide. The reaction solution was then suction filtered, the cake was washed with a large amount of water, and the solid was collected and dried by heating to obtain 0.68 g of compound 30-1. MS (ESI, [M+H] + ) m / z = 334.74.

[0327] Step B: Preparation of Compound 30-2 Compound 30-2 was prepared by following the procedure of Step A of Example 19, substituting (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride. MS (ESI, [M+H] + ) m / z = 505.99. 1 H NMR(500MHz,DMSO-d6)δ 8.99(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=7.7Hz,1H),7.2 3(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).

[0328] Step C: Preparation of Compound 30-3 Compound 30-3 was prepared following the method of Example 10, Step A. MS (ESI, [M+H] + ) m / z = 587.20. 1 H NMR(500MHz,DMSO-d6)δ 9.06(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).

[0329] Step D: Preparation of Compound 30-4 Compound 30-4 was prepared following the method of Step B of Example 10. MS (ESI, [M+H] + ) m / z = 497.16.

[0330] Step E: Preparation of Compound 30 Compound 30 was prepared by reacting compound 30-4 with acetic anhydride following the method of Step C of Example 10. HRMS (ESI, [M+H] + ) m / z=539.1835. 1H NMR (500 MHz, CD3OD) δ 8.69(d,J=14.3Hz,1H),7.63(t,J=7.4Hz,1H),7.47(t,J=7.0Hz,1H),7.26-7.2 4(m,2H),7.00(m,1H),5.83(q,J=7.0Hz,1H),5.24(dt,J=48.0,13.5Hz,2H),4.6 7-4.59(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).

[0331] Example 31: Preparation of Compound 31 [ka]

[0332] Step A: Preparation of Compound 31-1 Compound 31-1 was prepared by following the method of Step B of Example 24, substituting methyl 2-amino-5-bromobenzoate for compound 24-1. MS (ESI, [M+H] + ) m / z=256.94. 1 H NMR(500MHz,DMSO-d6)δ 12.74(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).

[0333] Step B: Preparation of Compound 31-2 Compound 31-2 was prepared following the method of Example 19, Step A. MS (ESI, [M+H] + ) m / z = 428.03. 1H NMR(500MHz,DMSO-d6)δ 8.79(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).

[0334] Step C: Preparation of Compound 31-3 Compound 31-3 was prepared following the method of Step B of Example 19. MS (ESI, [M+H] + ) m / z = 557.13. 1 H NMR(500MHz,DMSO-d6)δ 9.08(d,J=7.2Hz,1H),8.90(d,J=12.2Hz,1H),8.14(t,J=9.0Hz,1H),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).

[0335] Step D: Preparation of Compound 31-4 Compound 31-4 was prepared following the method of Step B of Example 10. MS (ESI, [M+H] + ) m / z = 467.20.

[0336] Step E: Preparation of Compound 31 Compound 31 was prepared by reacting compound 31-4 with acetic anhydride following the method of Step E of Example 30. HRMS (ESI, [M+H] +) m / z=509.1730. 1 H NMR(500MHz,CD3OD)δ 8.81(d,J=13.1Hz,1H),8.22-8.11(m,1H),7.91(dd,J=8.6,2.4Hz,1H),7.64(t,J=7.3Hz,1 H),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,1 H),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). 31 P NMR (202 MHz, CD3OD) δ 34.37.

[0337] Example 32: Preparation of Compound 32 [ka]

[0338] Step A: Preparation of Compound 32-1 Compound 32-1 was prepared by following the method of Example 24, Step A, substituting 2-amino-5-bromo-4-fluorobenzoic acid for 5-amino-2-chloropyridine-4-carboxylic acid. MS (ESI, [M+H] + ) m / z = 249.05. 1 H NMR(500MHz,DMSO-d6)δ 7.90(d,J=8.1Hz,1H),7.01(s,2H),6.72(d,J=11.5Hz,1H),3.79(s,3H).

[0339] Step B: Preparation of Compound 32-2 Compound 32-2 was prepared following the method of Step B of Example 24. 1H NMR(500MHz,DMSO-d6)δ 12.78(s,1H),8.35(d,J=7.6Hz,1H),7.69(d,J=9.7Hz,1H),5.36(s,1H),5.27(s,1H).

[0340] Step C: Preparation of Compound 32-3 Compound 32-3 was prepared following the method of Example 19, Step A. MS(ESI, [M+H+2] + ) m / z = 448.02. 1 H NMR(500MHz,DMSO-d6)δ 8.98(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(d d,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).

[0341] Step D: Preparation of Compound 32-4 Compound 32-4 was prepared following the method of Example 19, Step B. MS (ESI, [M+H] + ) m / z = 575.11. 1 H NMR(500MHz,CD3OD)δ 8.70-8.64(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),2.10(m,2H),1.60(d,J=7.1Hz,3H).

[0342] Step E: Preparation of Compound 32-5 Compound 32-5 was prepared following the method of Example 19, Step C. MS (ESI, [M+H] + ) m / z = 485.15.

[0343] Step F: Compound 32 was prepared following the method of Example 10, Step C. HRMS (ESI, [M+H] + )m / z=527.1646. 1 H NMR(500MHz,CD3OD)δ 8.80(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),2.59-2.43(m,2H),2.38-2.24(m,2H),2.22(s,3H),1.72(d,J=7.2Hz.3H). 31 P NMR (202 MHz, CD3OD) δ 31.37.

[0344] Example 33: Preparation of Compound 33 [ka]

[0345] Step A: Preparation of Compound 33-1 6-Bromo-2,4-dichloroquinazoline (0.5 g), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (0.447 g), N,N-diisopropylethylamine (0.689 g), and acetonitrile (3 mL) were added to a 25 mL single-neck flask, and the reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated to dryness, and the residue was purified using a silica gel column (petroleum ether:ethyl acetate = 80:20) to obtain 0.7 g of compound 33-1. MS(ESI, [M+H+2] + ) m / z = 432.00. 1H NMR(500MHz,DMSO-d6)δ 9.10(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).

[0346] Step B: Preparation of Compound 33-2 A 25 mL single-neck flask was charged with compound 33-1 (0.5 g) obtained in Step A, 1-benzyl-1,4-azaphospholane 4-oxide (0.267 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.134 g), tris(dibenzylideneacetone)dipalladium(0) (0.106 g), N,N-diisopropylethylamine (0.225 g), and 1,4-dioxane (10 mL). Under nitrogen protection, the mixture was heated to 70 °C in an oil bath and stirred for 2 h. The reaction mixture was cooled to room temperature, suction filtered, and the filtrate was concentrated to dryness. The residue was purified using a silica gel column (dichloromethane:methanol = 95:5) to obtain 0.5 g of compound 33-2. MS (ESI, [M+H] + ) m / z = 559.09. 1 H NMR(500MHz,DMSO-d6)δ 9.41(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),7.29(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).

[0347] Step C: Preparation of Compound 33-3 Compound 33-2 (0.18 g) obtained in Step B, cerium ammonium nitrate (0.883 g), acetonitrile (20 mL), and water (4 mL) were added to a 100 mL one-neck flask and stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30 mL × 3), the organic phase was washed with water and then saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated to dryness to give 0.3 g of crude compound 33-3, which was directly used in the next step. MS (ESI, [M+H] + ) m / z = 469.12.

[0348] Step D: Preparation of Compound 33 Following the method of Step C of Example 10, compound 33 was prepared by reacting compound 33-3 with acetic anhydride. HRMS (ESI, [M+H] + ) m / z=511.1277. 1 H NMR(500MHz,CDCl3)δ 8.79(d,J=13.0Hz,1H),7.81(q,J=6.2,5.6Hz,2H),7.65-7.41(m,3H),7.17(q,J=7.5Hz,1H),6.88(td,J=55.0,3.0Hz,1H),5.79(t,J=7.1Hz,1 H),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). 31 P NMR (202 MHz, CDCl3) δ 29.70.

[0349] Example 34: Preparation of Compound 34 [ka]

[0350] Step A: Preparation of Compound 34-1 Compound 34-1 was prepared by reacting compound 1-2 with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride in accordance with the method of Step A of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with compound 1-2. MS (ESI, [M+H] + ) m / z = 488.02.

[0351] Step B: Preparation of Compound 34 A 5 mL microwave tube was charged with compound 34-1 (0.075 g), diethylphosphine oxide (0.016 g), N,N-diisopropylethylamine (0.04 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.9 mg), tris(dibenzylideneacetone)dipalladium(0) (7.05 mg), and N,N-dimethylformamide (3 mL). After the addition was complete, the atmosphere was purged with nitrogen and the reaction mixture was heated to 170 °C at 150 watts in a microwave reactor for 35 minutes. The reaction mixture was then suction filtered through diatomaceous earth. The filtrate was poured into water (30 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column (dichloromethane:methanol = 97:3) to give 29 mg of compound 34. HRMS (ESI, [M+H] + )m / z=466.1886. 1 H NMR(500MHz,CD3OD)δ 8.59(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). 31 P NMR (202 MHz, CD3OD) δ 49.9.

[0352] Example 35: Preparation of Compound 35 [ka]

[0353] Step A: Preparation of Compound 35-1 Compound 35-1 was prepared by reacting compound 9-1 with compound 9-1 following the procedure of Step A of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride. MS (ESI, [M+H] + ) m / z = 367.05. 1 H NMR(500MHz,CD3OD)δ 8.76(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).

[0354] Step B: Preparation of Compound 35-2 [ka]

[0355] Step a: Preparation of compound 35-2-1 Ammonium phosphinate (28 g, 337 mmol) was added to a 500 mL three-neck flask, and hexamethyldisilazane (109 g) was added dropwise. After the addition was complete, the reaction mixture was heated to 120 °C under nitrogen protection and stirred for 4 hours. Bis(2-bromoethyl) ether (78 g) was added dropwise to the reaction flask, and the temperature was maintained while the reaction continued for another 4 hours. The reaction mixture was cooled with stirring in an ice-water bath, and absolute ethanol (150 mL) was added dropwise. After the addition was complete, the reaction mixture was heated to reflux and reacted for 1 hour. The reaction was stopped, cooled to room temperature, and suction filtered. The cake was washed with dichloromethane, and the filtrate was concentrated to obtain 42.4 g of crude compound 35-2-1. GCMS:[M] + =136.

[0356] Step b: Preparation of compound 35-2-2 A 25 mL three-neck flask was charged with compound 35-2-1 (1 g) obtained in step a and dichloromethane (20 mL). Under nitrogen protection, the mixture was cooled to below 0 °C in an ice-salt bath, and oxalyl chloride (1.578 g) was added dropwise. After the addition was complete, the mixture was allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated to dryness, and the residue was dissolved in toluene (10 mL) and concentrated to dryness to obtain 1.8 g of crude compound 35-2-2, which was used directly in the next step without further purification.

[0357] Step c: Preparation of compound 35-2 Under nitrogen protection at -70 °C, 1 M diisobutylaluminum hydride toluene solution (6.48 mL) was slowly added to a stirred solution of compound 35-2-2 (1.8 g) obtained in step b in dichloromethane (15 mL), and the mixture was reacted with stirring at -70 °C for 2 hours. Upon completion of the reaction, methanol (3 mL) was added to the reaction solution at -70 °C and the reaction was continued with stirring for 5 minutes. The reaction solution was transferred to an ice-water bath and continued to stir. When the reaction solution warmed to 0 °C, 10 vol% aqueous acetic acid (10 mL) was added and stirred at room temperature for 10 minutes. The solution was separated, and the aqueous phase was extracted with dichloromethane (20 mL × 5). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give 1.7 g of crude compound 35-2, which was used directly in the next step without further purification.

[0358] Step C: Preparation of Compound 35 Compound 35 was prepared by reacting compound 35-1 with compound 35-2 according to the method of Step B of Example 19. HRMS (ESI, [M+H] + )m / z=451.1510. 1 H NMR(500MHz,CD3OD)δ 9.12(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=54.9Hz,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). 31 P NMR (202 MHz, CD3OD) δ 30.08.

[0359] Example 36: Preparation of Compound 36 [ka]

[0360] Step A: Preparation of Compound 36-1 Compound 36-1 was prepared by following the procedure of Step A of Example 19, substituting (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride. MS (ESI, [M+H] + ) m / z = 411.96. 1H NMR(500MHz,DMSO-d6)δ 9.50(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).

[0361] Step B: Preparation of Compound 36 Compound 36 was prepared by following the method of Step B of Example 19. HRMS (ESI, [M+H] + ) m / z=450.1552. 1 H NMR(500MHz,CD3OD)δ 8.69(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,1 H),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). 31 P NMR (202 MHz, CD3OD) δ 31.65.

[0362] Example 37: Preparation of Compound 37 [ka]

[0363] Step A: Preparation of Compound 37-1 Referring to the method of Example 19, Step A, compound 37-1 was prepared by reacting (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with 6-bromo-2-methylquinazolin-4(3H)-one. MS (ESI, [M+H] +) m / z = 428.08.

[0364] Step B: Preparation of Compound 37 Compound 37 was prepared by reacting compound 37-1 with compound 35-2 according to the method of Step B of Example 19. HRMS (ESI, [M+H] + )m / z=468.1479. 1 H NMR(500MHz,CD3OD)δ 8.80(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). 31 P NMR (202 MHz, CD3OD) δ 31.62.

[0365] Example 38: Preparation of Compound 38 [ka]

[0366] Step A: Preparation of Compound 38-1 Referring to the method of Step A of Example 19, compound 38-1 was prepared by reacting (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with 6-bromo-7-fluoro-2-methylquinazolin-4(3H)-one. MS (ESI, [M+H] + ) m / z = 428.05. 1H NMR(500MHz,DMSO-d6) δ 8.91(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).

[0367] Step B: Preparation of Compound 38 Compound 38 was prepared by following the method of Example 19, Step B. HRMS (ESI, [M+H] + )m / z=468.1463. 1 H NMR(500MHz,CD3OD)δ 8.66(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). 31 P NMR (202 MHz, CD3OD) δ 28.87.

[0368] Example 39: Preparation of Compound 39 [ka]

[0369] Step A: Preparation of Compound 39-1 2-Amino-3-fluorobenzoic acid (10 g) and dichloromethane (170 mL) were added to a 500 mL single-neck flask in this order, and N-iodosuccinimide (14.50 g) was added while stirring at room temperature. After the dropwise addition was completed, the mixture was stirred overnight at room temperature. Upon completion of the reaction, the mixture was filtered with suction, and the cake was pulped with dichloromethane (50 mL), filtered with suction, and dried to obtain 12.9 g of compound 39-1. 1 H NMR(500MHz,DMSO-d6)δ 7.81-7.80(m,1H),7.57(dd,J=10.8,2.0Hz,1H).

[0370] Step B: Preparation of Compound 39-2 Compound 39-2 was prepared following the method of Example 24, Step A. 1 H NMR(500MHz,DMSO-d6)δ 7.84-7.79(m,1H),7.61-7.59(m,1H),6.69(s,2H),3.82(s,3H).

[0371] Step C: Preparation of Compound 39-3 Compound 39-3 was prepared following the method of Step B in Example 1. MS (ESI, [M+H] + ) m / z = 304.75.

[0372] Step D: Preparation of Compound 39-4 Compound 39-4 was prepared following the method of Step E of Example 1. MS (ESI, [M+H] + ) m / z = 297.04. 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).

[0373] Step E: Preparation of Compound 39 Compound 39 was prepared by following the method of Step A of Example 19. HRMS (ESI, [M+H] + )m / z=468.1466. 1H NMR(500MHz,CD3OD)δ 8.50(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). 31 P NMR (202 MHz, CD3OD) δ 31.53.

[0374] Example 40: Preparation of Compound 40 [ka]

[0375] Step A: Preparation of Compound 40-1 4,6-Dichloro-2-methylpyrimidine (16.3 g) and ammonium hydroxide (80 mL) were added to a 350 mL pressure-resistant reaction flask in this order, and the mixture was sealed and heated to 90° C. for overnight reaction. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The cake was collected and dried under reduced pressure to obtain 14 g of compound 40-1. MS (ESI, [M+H] + ) m / z = 143.93.

[0376] Step B: Preparation of Compound 40-2 Compound 40-1 (2 g) obtained in step A and methanol (20 mL) were added to a 100 mL three-neck flask in this order. The mixture was cooled to 0 °C in an ice-salt bath, and then a solution of iodine monochloride (15.58 g) in methanol (20 mL) was added dropwise. After the addition was complete, the mixture was cooled to room temperature and stirred overnight. Upon completion of the reaction, the reaction mixture was poured into water (100 mL), saturated sodium sulfite solution (200 mL) was added, and the pH was adjusted to 6-7 with 2 M sodium hydroxide solution. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3.3 g of compound 40-2. MS (ESI, [M+H] + ) m / z = 269.86. 1 H NMR(500MHz,DMSO-d6)δ 7.28(d,2H),2.29(s,3H).

[0377] Step C: Preparation of Compound 40-3 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 tris(o-tolyl)phosphine (0.158 g) were added to a 250 mL single-neck flask in this order. The atmosphere was purged with nitrogen three times. Under nitrogen protection, the mixture was heated to 100 °C for 8 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified using a silica gel column (petroleum ether:ethyl acetate = 70:30) to obtain 1.7 g of compound 40-3. MS (ESI, [M+H] + ) m / z = 270.38. 1 H NMR(500MHz,DMSO-d6)δ 7.45-7.40(m,3H),6.34(d,J=16.4Hz,1H),2.31(s,3H),1.48(s,9H).

[0378] Step D: Preparation of Compound 40-4 To a 25 mL reaction flask, compound 40-3 (0.4 g) obtained in Step C and acetonitrile (8 mL) were added in that order, and the reaction flask was placed under a 365 nm light and stirred at room temperature for 4 hours. The reaction was stopped, filtered, and the cake was collected to give 0.22 g of compound 40-4. MS (ESI, [M+H] + ) m / z = 270.08. 1 H NMR(500MHz,DMSO-d6)δ 6.88(s,2H),6.70(d,J=11.6Hz,1H),6.05(d,J=11.6Hz,1H),2.30(s,3H),1.29(s,9H).

[0379] Step E: Preparation of Compound 40-5 Compound 40-4 (2.8 g) obtained in step D, trifluoroethanol (1.038 g), and potassium tert-butoxide (2.56 g) were added to a 250 mL reaction flask in this order, and the mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Methyl tert-butyl ether (20 mL) was added to the residue, and the mixture was pulped to give 2.2 g of compound 40-5. MS (ESI, [M+H] + ) m / z = 260.05. 1 H NMR(500MHz,DMSO-d6)δ 12.46(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).

[0380] Step F: Preparation of Compound 40-6 Compound 40-5 (2 g) obtained in step E and N,N-dimethylformamide (20 mL) were added to a 250 mL single-neck flask in this order, cooled to below 5 °C in an ice-water bath, sodium hydride (0.370 g) was added, and the mixture was stirred at room temperature for 5 minutes. Next, iodomethane (1.314 g) was added dropwise to the reaction flask in an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 hours. Upon completion of the reaction, the reaction mixture was poured into ice-water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified using a silica gel column (petroleum ether:ethyl acetate = 70:30) to obtain 1.7 g of compound 40-6. MS (ESI, [M+H] + ) m / z = 274.03. 1 H NMR(500MHz,DMSO-d6)δ 7.90(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).

[0381] Step G: Preparation of Compound 40-7 Compound 40-6 (0.65 g) obtained in step F and 48% aqueous hydrobromic acid (8 mL) were added to a 100 mL single-neck flask in this order. Sodium bromate (1.077 g) was added in several portions while stirring at room temperature. After the dropwise addition was completed, the reaction flask was transferred to a 60 °C oil bath and stirred for 2 h. Upon completion of the reaction, the reaction solution was poured into ice water (10 mL), saturated sodium sulfite solution (30 mL) was added, and the mixture was stirred vigorously for 5 min. The pH was adjusted to 6-7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 0.7 g of compound 40-7 was obtained by separation and purification using a silica gel column (petroleum ether:ethyl acetate = 80:20). MS (ESI, [M+H] + ) m / z = 351.92. 1H NMR(500MHz,DMSO-d6)δ 8.31(s,1H),5.23(q,J=8.9Hz,2H),3.68(s,3H),2.62(s,3H).

[0382] Step H: Preparation of Compound 40-8 Compound 40-7 (0.7 g) obtained in step G and 48% aqueous hydrobromic acid (7 mL) were added to a 100 mL single-neck flask in this order. After the dropwise addition was completed, the mixture was heated to 100 °C and reacted for 2.5 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water (100 mL), and the pH was adjusted to 6-7 with saturated sodium bicarbonate solution. The mixture was then filtered to collect the cake, which was then dried to give 0.537 g of compound 40-8. MS(ESI, [M+H+2] + ) m / z = 271.96. 1 H NMR(500MHz,DMSO-d6)δ 12.90(s,1H),8.24(s,1H),3.63(s,3H),2.41(s,3H).

[0383] Step I: Preparation of compound 40-9 Compound 40-9 was prepared following the method of Example 19, Step A. 1 H NMR(500MHz,DMSO-d6)δ 8.93(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).

[0384] Step J: Preparation of Compound 40 Following the method of Step B of Example 19, compound 40 was prepared by reacting compound 40-9 with compound 35-2 obtained in Step c of Example 35. HRMS (ESI, [M+H] + ) m / z=495.1768. 1H NMR(500MHz,CD3OD)δ 8.78(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).

[0385] Example 41: Preparation of Compound 41 [ka]

[0386] Step A: Preparation of Compound 41-1 Methyl 5-amino-2-chloroisonicotinate (2 g), N,N-dimethylformamide (20 mL), and N-bromosuccinimide (1.9 g) were added to a 100 mL single-neck flask in this order, and the reaction mixture was heated to 80°C for 3 hours. Upon completion of the reaction, the reaction mixture was poured into water (200 mL) and extracted with methyl tert-butyl ether (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified using a silica gel column (petroleum ether:ethyl acetate = 80:20) to obtain 2.6 g of compound 41-1. MS(ESI, [M+H+2] + ) m / z = 266.87. 1 H NMR(500MHz,DMSO-d6)δ 7.63(s,1H),6.78(s,2H),3.88(s,3H).

[0387] Step B: Preparation of Compound 41-2 Compound 41-1 (1.1 g) obtained in step A, acetonitrile (3.40 g), and methanesulfonic acid (3.98 g) were added to a 35 mL microwave tube in this order and stirred at room temperature for 10 minutes. The mixture was then placed in a microwave reactor and heated to 120 °C at 50 watts for 2 hours. Upon completion of the reaction, the 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. The mixture was then suction filtered to obtain 0.8 g of compound 41-2. MS(ESI, [MH] - ) m / z=273.89. 1 H NMR(500MHz,CD3OD)δ 7.94(s,1H),2.48(s,3H).

[0388] Step C: Preparation of Compound 41-3 Compound 41-2 (0.2 g) obtained in step B and N,N-dimethylformamide (2 mL) were added to a 5 mL microwave tube in this order, followed by zinc cyanide (39.4 mg) and tetrakis(triphenylphosphine)palladium(0) (78 mg). The atmosphere was purged with nitrogen three times, and the tube was placed in a microwave reactor. The tube was heated to 110 °C at 50 watts for 1 hour. Upon completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 80:20) to obtain 136 mg of compound 41-3. MS(ESI, [MH] - ) m / z=218.95. 1 H NMR(500MHz,CD3OD)δ 7.97(s,J=7.2Hz,1H),2.51(s,3H).

[0389] Step D: Preparation of Compound 41-4 Compound 41-4 was prepared following the method of Example 19, Step A. MS (ESI, [M+H] + ) m / z = 410.12.

[0390] Step E: Preparation of Compound 41 Referring to the method of Step B of Example 19, compound 41 was prepared by reacting compound 41-1 prepared in Step D above with compound 35-2. HRMS (ESI, [M+H] + ) m / z=494.1365. 1 H NMR(500MHz,CD3OD)δ 8.97(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). 31 P NMR (202 MHz, CD3OD) δ 29.64.

[0391] Example 42: Preparation of Compound 42 [ka]

[0392] Step A: Preparation of Compound 42 Compound 42 was prepared by reacting compound 19-1 with phosphorinane 1-oxide according to the method of Step B of Example 19. HRMS (ESI, [M+H] + ): m / z=467.1620. 1 H NMR(500MHz,CD3OD)δ 9.10(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).

[0393] Example 43: Preparation of Compound 43 [ka]

[0394] Step A: Preparation of Compound 43 Compound 43 was prepared by reacting compound 19-1 with phosphorane-1-oxide according to the method of Step B of Example 19. HRMS (ESI, [M+H] + ): m / z=453.1594. 1 H NMR(500MHz,CD3OD)δ 9.09(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=7.8Hz,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).

[0395] In the following Examples 44 to 47 (Table 1), methyl 2-amino-4-methoxybenzoate is replaced with the following fragment 1-1, and (R)-1-(m-tolyl)ethan-1-amine is replaced with the following fragment 1-2, respectively, by referring to the method of Example 1, and finally, compounds 44 to 47 can be produced by referring to the method of Step C of Example 7. [Table A-1] [Table A-2]

[0396] The following intermediates (Table 2-1) can be prepared by replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the corresponding fragment b in accordance with the method of Example 19, to give intermediate compounds 2a-1 to 2a-6. [Table B]

[0397] In Examples 48 to 60 (Table 2), compound 7-1 is replaced with intermediates 2a-1 to 2a-6 prepared above by referring to the method of Example 10, and acetic anhydride is replaced with fragment 2 shown below, respectively, to prepare compounds 48 to 60 by substitution, reductive amination, or condensation reaction. [Table C-1] [Table C-2] [Table C-3] [Table C-4] [Table C-5] [Table C-6]

[0398] The following intermediates (Table 3-1) can be prepared by replacing 5-amino-2-chloroisonicotinic acid with the following fragment 2a, respectively, following the method of Step A in Example 9, to give the following intermediate compounds 3a-1 and 3a-2. [Table D]

[0399] In the following Examples 61 to 64 (Table 3), compounds 61 to 64 can be produced by referring to the method of Example 19, by replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the following fragment 3-1, and by replacing compound 9-1 with the intermediate compound prepared above. [Table E-1] [Table E-2]

[0400] In the following Example 65 (Table 4), compound 9-1 is replaced with intermediate 3a-2 by referring to the method of Example 35, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride is replaced with the corresponding fragment 4-1, compound 35-2 is replaced with the corresponding fragment 4-2, and the reaction is carried out. Finally, compound 65 can be produced by referring to the method of Step C of Example 7. In the following Examples 66 to 71 (Table 4), compound 9-1 is replaced with intermediate 3a-2 by referring to the method of Example 35, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride is replaced with the following fragment 4-1, and compound 35-2 is replaced with the following fragment 4-2, and compounds 66 to 71 can be produced. [Table F-1] [Table F-2] [Table F-3] [Table F-4]

[0401] Test Example 1: Phosphorylation activity inhibition test at the in vitro cellular level 1.1 Test Reagents and Equipment 1.1.1 Test Reagents [Table G]

[0402] 1.1.2 Equipment [Table H]

[0403] 1.2 Procedure for phosphorylation activity inhibition test at the in vitro cellular level One petri dish of H358 human non-small cell lung cancer cells (Nanjing Kebai Biotechnology Co., Ltd.) in good condition and in the exponential growth phase was used. The cells were collected in a centrifuge tube and centrifuged at 1000 rpm for 5 minutes in a benchtop low-speed centrifuge. The supernatant was discarded, and 5 mL of 5% FBS-containing seeding medium was added with a pipette to resuspend the cells. The cells were counted using a cell counter, and the seeding medium was diluted to a cell density of 1.5 x 10 5The concentration was adjusted to cells / mL. 40 μL of the solution was seeded into a 384-well, black-bottomed plate using a multichannel pipette. After overnight incubation in a 37°C, 5% CO2, and humidity-saturated cell incubator, compounds were loaded using a Tecan D300e microdispenser. After 1 hour, the medium was discarded, and 40 μL of 4% paraformaldehyde was added to each well. The wells were incubated for 20 minutes at room temperature and washed with PBS. 40 μL of methanol was added to each well, incubated for 10 minutes at room temperature, and washed with PBST. 20 μL of 5% BSA blocking buffer was added to each well for 1 hour at room temperature. After discarding the blocking buffer, 20 μL of a primary antibody mixture (rabbit anti-pERK diluted 1:1000 (final concentration) and mouse anti-GAPDH diluted 1:5000 (final concentration)) was added to each well. The mixture was incubated overnight at 4°C and washed with PBST. 20 μL of secondary antibody mixture was added to each well, except for goat anti-rabbit 800 and goat anti-mouse 647, which were both diluted 1:1000 (final concentration). The mixture was incubated at room temperature in the dark for 45 minutes and then washed with PBST. The results were scanned using Azure Biosystems, and the EC values ​​were calculated using a four-parameter logistic model with the logarithm of compound concentration on the horizontal axis and the phosphorylation inhibition rate on the vertical axis. 50 The values ​​were calculated and analyzed, and the results are shown in Table 5. [Table I]

[0404] Test Example 2: Guanine nucleotide exchange test In this study, we quantitatively examined the ability of SOS1 to mediate KRAS activation. His-tagged KRAS G12C was added to the reaction system, which was then bound by a lanthanide Eu-labeled anti-His antibody. The accessory protein SOS1cat and the fluorescent GTP analog EDA-GTP-DY-647P1 were then added. The fluorescent GTP analog was loaded onto KRAS G12C via the accessory protein, resulting in resonance energy transfer between anti-6His-cryptate (FRET donor) and EDA-GTP-DY-647P1 (FRET acceptor). Prior treatment with an SOS1 inhibitor compound attenuated SOS1's ability to bind and mediate KRAS activation, and reduced FRET activity between the donor and acceptor.

[0405] 2.1 Test Reagents and Equipment 2.1.1 Test Reagents [Table J]

[0406] 2.1.2 Equipment [Table K]

[0407] 2.2 Nucleotide exchange test procedure Preparation of His-KRAS G12C: The K-Ras4B-G12C sequence (UniProt P01116-2, amino acids 1–169) was codon-optimized and gene-synthesized. Finally, it was subcloned into the pET-30a(+) vector and transformed into BL21(DE3) competent cells. A suitable clone was selected and cultured in TB medium with IPTG low-temperature induction. The cells were then harvested. The cells were disrupted using an ultrasonicator, centrifuged, and filtered to obtain the supernatant. The protein was purified using Ni Sepharose HP and Superdex 200 pg (16 / 60) to obtain a protein with a purity of over 90%. The activity was then assayed for further use.

[0408] Preparation of SOS1cat: Human SOS1 (UniProt Q07889, amino acids 564-1049) was codon-optimized and gene synthesized. Finally, the gene was subcloned into the pET-30a(+) vector and transformed into BL21(DE3) competent cells. A suitable clone was selected and cultured in TB medium. IPTG low-temperature induction was performed for expression, and the cells were harvested. The cells were disrupted using an ultrasonicator, centrifuged, and filtered to collect the supernatant. The protein was purified using Ni Sepharose HP, Superdex 200 pg (16 / 60), and Superdex 200 pg (16 / 60) to obtain a protein with a purity of over 90%. The activity was assayed for further use.

[0409] A test buffer was prepared and the components were: HEPES pH 7.4: 20 mM, NaCl: 150 mM, MgCl2: 0.5 mM, DTT: 2 mM, BSA: 0.05%, Igepal: 0.0025%.

[0410] A KRAS G12C working solution, an SOS1cat working solution, and a blank control solution were prepared in test buffer. The KRAS G12C working solution contained 100 nM His-KRAS G12C and 2 nM anti-His-terbium. The SOS1cat working solution contained 20 nM SOS1cat and 200 nM EDA-GTP-DY-647P1. The blank control solution contained 100 nM EDA-GTP-DY-647P1.

[0411] The entire test procedure was performed at 20°C. 5 μL of SOS1cat working solution was added to each well in the test group, and 5 μL of blank control working solution was added to each well in the control group, followed by incubation at 20°C for 10 minutes. Compounds were then added using a Tecan D300e microdispenser. The compound was serially diluted 2-fold to set up eight concentration gradients, with the highest final concentration being 10 μM. The incubation was then continued for 30 minutes at 20°C. Finally, 5 μL of KRAS G12C working solution was added to each well, followed by incubation at 20°C for 15 minutes. The 665 nm / 620 nm fluorescence ratio was measured using an Envision microplate reader to reflect the degree of nucleotide conversion. The inhibition rate was calculated as follows: (mean value of negative control group - mean value of test group) / (mean value of negative control group - mean value of blank group) × 100%. The negative control group did not contain any compound, and all other conditions were the same as those of the test group. The IC was calculated using a four-parameter logistic model with the logarithm of the compound concentration on the horizontal axis and the inhibition rate on the vertical axis. 50 The values ​​were calculated and analyzed and the results are shown in Table 6.

[0412] Test Example 3: KRAS / SOS1 protein binding test This test can be used not only to detect the inhibitory ability of compounds against the protein interaction between SOS1 and KRAS G12C, but also to verify the molecular mechanism of action of the compounds. 50 A low value indicates that the SOS1 inhibitor compound can efficiently inhibit protein interactions.

[0413] 3.1 Test Reagents and Buffers 3.1.1 Reagents: GST-SOS1 (564-1049), provided by our company: Human SOS1 (UniProt Q07889, amino acids 564-1049) was codon-optimized and gene synthesized. Finally, the gene was subcloned into the pGEX-4T-1 vector and transformed into BL21 (DE3) competent cells. A suitable clone was selected and cultured in TB medium for IPTG-induced low-temperature expression. The cells were harvested. The cells were disrupted using an ultrasonicator, centrifuged, and filtered to collect the supernatant. The protein was purified using Ni Sepharose HP and Superdex 200 pg (16 / 60) to obtain a protein with a purity of over 90%. The activity was assayed for further use. Kras-G12C-6xHis(1-169), provided by our company: K-Ras4B-G12C (UniProt P01116-2, amino acids 1-169) was codon-optimized and gene-synthesized. Finally, it was subcloned into the pET-30a(+) vector and transformed into BL21(DE3) competent cells. A suitable clone was selected and cultured in TB medium with IPTG low-temperature induction. The cells were then harvested. The cells were disrupted using an ultrasonicator, centrifuged, and filtered to collect the supernatant. The protein was purified using Ni Sepharose HP and Superdex 200 pg (16 / 60) to obtain a protein with a purity of over 90%. The activity was then assayed for further use. GDP (Sigma, catalog number G7127), MAb anti-GST-XL665 (Cisbio, catalog no. 61GSTXLA); MAb anti-6His-Tb cryptate Gold (Cisbio, catalog no. 61HI2TLA).

[0414] 3.1.2 Buffers: Dilution buffer (Cisbio, Cat. No. 62DLBDDF), Detection buffer (Cisbio, catalog number 62DB2FDG), GST-SOS1 working solution: prepared in dilution buffer, concentration 92 nM. GDP-Kras-G12C-His working solution: prepared in dilution buffer, the final concentration of GDP was 40 μM and the final concentration of Kras-G12C-His was 100 nM. Antibody working solution: Prepared in detection buffer, MAb anti-GST-XL665 and MAb anti-6His-Tb cryptate Gold had concentrations of 4x and were mixed 1:1.

[0415] 3.2 Test Procedure: 5 μL of GST-SOS1 working solution was added to each well of the test and negative groups, and 5 μL of dilution buffer was added to each well of the control group. Compounds were then added to the test group using a Tecan D300e microdispenser, diluted 3-fold to create seven concentration gradients up to 5000 nM, and incubated at room temperature for 30 minutes. Next, 5 μL of pre-prepared GDP-Kras-G12C-His working solution (GDP and Kras-G12C-His were incubated at room temperature for 10 minutes) was added to each well and incubated at room temperature for 15 minutes. Finally, 10 μL of antibody working solution was added to each well and incubated at room temperature for 50 minutes. The 665 nm / 620 nm fluorescence ratio was measured using an Envision microplate reader. The inhibition rate was calculated as follows: Inhibition rate (%) = (mean value of negative control group - mean value of test group) / (mean value of negative control group - mean value of blank group) x 100%. The negative control group did not contain the compound, but 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 on the horizontal axis and the inhibition rate on the vertical axis. 50 The values ​​were calculated and the results are shown in Table 6.

[0416] Test Example 4: Measurement of K562 cell proliferation inhibitory activity The K562 cell line can be purchased from the American Type Culture Collection (ATCC).

[0417] K562 cells in good growth condition were collected in a centrifuge tube and the cell density was adjusted to 3 x 10 4The cells were adjusted to a concentration of 10000 nM / mL and seeded into a 96-well plate (100 μL / well). The cells were cultured overnight in a cell incubator. Compounds were loaded using a nanoliter dispenser to final compound concentrations of 10,000 nM to 4.6 nM. Two replicate wells were used for control. After 72 hours of culture in the cell incubator, detection reagent CCK-8 (Cell Counting Kit-8, Dojindo Laboratories, 10 μL / well) was added. After 1 hour of incubation in the cell incubator, absorbance values ​​were measured at 450 nm using an Envision microplate reader. A dose-response curve was fitted using a four-parameter analysis, and IC values ​​were calculated. 50 was calculated and the results are shown in Table 6. [Table L-1] [Table L-2]

[0418] Test Case 5: Pharmacodynamic evaluation of SOS1 inhibitors in the MIA PaCa-2 human pancreatic cancer nude mouse xenograft tumor model 1 × 10 mice were placed under the right armpit of an SPF female BALB / C nude mouse (provided by Changzhou Kawensi Experimental Animal Co., Ltd.). 7 MIA PaCa-2 cells (Kras G12C mutant tumor cells, Nanjing Kebai Biotechnology Co., Ltd.) were subcutaneously inoculated. The average tumor volume was approximately 200 mm. 3 The animals were then divided into treatment and control groups, with eight animals per group. The day of grouping was designated day 0, and oral gavage administration began on day 1, with administration twice daily. The dose for the treatment group was 10 mL / kg. The control group served as a solvent control. Continuous administration was performed, and tumor volumes were measured two to three times a week. At the same time, the mice were weighed and the data were recorded. The general behavior of the mice was observed and recorded daily. After the experiment, the tumors were removed, weighed, and photographed.

[0419] Tumor volume calculation formula: Tumor volume (mm 3 )=1 / 2×(a×b 2) (where a represents the major axis and b represents the minor axis). Relative tumor growth rate (T / C%) was the percentage of tumor volume in the treatment group relative to the control group at the time point of interest. The calculation formula for relative tumor inhibition rate (TGI, %) was TGI% = (1 - tumor weight in treatment group / tumor weight in control group) × 100%. The formula for calculating the weight change rate (WCR, %) is WCR = (Wt t -Wt0) / Wt0 × 100%, where Wt0 is the body weight of the animals at the time of grouping (i.e., day d0), and Wt t was the animal weight at each measurement.

[0420] The compounds of the present application have good in vivo pharmacodynamic activity.

Claims

1. A compound of formula (I) 【Chemistry A1】 During the ceremony, X and Y are both selected from CR a , or X is selected from CH and Y is selected from N, or X is selected from NR b and Y is selected from C(O), or X is selected from CF or C(CN) and Y is selected from N; [Chemistry A2] represents a single bond or a double bond by X and Y; R ａ is hydrogen, a hydroxy group, a halogen, a cyano group, C １～６ Alkyl group or C １～６ alkoxy groups, provided that the C １～６ Alkyl group or C １～６ the alkoxy group is optionally substituted with one or more deuterium or halogen atoms; R ｂ is C １～６ alkyl groups, R １ , R ２ are each independently C １～６ alkyl group, 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 attached thereto form a 5- to 10-membered heterocyclyl group, provided that said C １～６ The alkyl group or the 5- to 10-membered heterocyclyl group may optionally be one or more R ｃ is replaced by Each R ｃ are each independently 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- to 6-membered cycloalkyl-S(O) ２ -, C １～６ Alkyl OC(O)-, C １～６ Alkyl-O-C １～６ Alkyl-, C １～６ Alkyl-O-C 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 by one or more hydroxy or cyano groups １～６ alkyl-, provided that R ｃ is optionally substituted by one or more halogens when not hydrogen or O=; Ring A is selected from a phenyl group, a thienyl group, a 2,3-dihydro-1H-indenyl group, a 2,3-dihydrobenzofuryl group, and a benzofuryl group; n is 0, 1, 2 or 3; Each R ３ are each independently an amino group, a nitro group, a halogen, or C １～８ alkyl- or phenyl groups, provided that １～８ The alkyl or phenyl group may optionally be one or more R ｄ is replaced by R ｄ is a hydroxy group, a halogen, or C １～６ Alkyl-NH-C １～６ alkyl-, R ４ , R ５ are each independently hydrogen, deuterium, or C １～６ alkyl groups, provided that the C １～６ the alkyl group is optionally substituted with one or more halogens; R ６ is hydrogen, halogen or C １～６ alkyl groups, provided that the C １～６ A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is optionally substituted by one or more halogens.

2. X is selected from CH and Y is CR ａ or X is selected from CH and Y is C(OH), C(OCH ３ ), C(OCHF ２ ), C(OCH ２ F), CF or C (OCD ３ ) or X is selected from N(CH ３ 2. The compound of formula (I) according to claim 1, wherein Y is selected from C(O), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. R ａ is hydrogen, a hydroxy group, a halogen, a cyano group, C １～４ Alkyl group or C １～４ alkoxy groups, provided that the C １～４ Alkyl group and C １～４ The alkoxy group is optionally substituted with one or more deuterium or halogen, or R ａ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or C １～４ alkoxy groups, provided that the C １～４ The alkoxy group is optionally substituted with three deuterium atoms or one or more fluorines, or R ａ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or C １～４ alkoxy groups, provided that the C １～４ The alkoxy group is optionally substituted with three deuterium atoms, one or two fluorine atoms, or R ａ is selected from hydrogen, hydroxy, fluorine, cyano, methoxy, monofluoromethoxy or difluoromethoxy, with the proviso that said methoxy is optionally substituted by three deuterium atoms, or R ａ represents hydrogen, hydroxyl group, fluorine, cyano group, CH ３ O-, CD ３ O-, CH ２ FO- or CHF ２ 3. The compound of formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from: O-.

4. Rb is C １～４ alkyl groups or R ｂ is C １～３ alkyl groups or R ｂ The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of methyl and methyl.

5. R １ , R ２ are each independently C １～３ alkyl group, NH(R ｃ )-C １～３ Alkyl- or N(R ｃ ) (C １～３ alkyl)-C １～３ alkyl- or R １ , R ２ are each independently C １～３ alkyl groups or R １ , R ２ are each independently selected from a methyl group or an ethyl group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

6. R １ , R ２ together with the phosphorus atom to which it is attached form a 5- to 10-membered heterocyclyl group, provided that the ring atoms of said 5- to 10-membered heterocyclyl group optionally contain one or more heteroatoms selected from N, O or S atoms, and said 5- to 10-membered heterocyclyl group optionally contains one or more R ｃ and when the ring atom contains a N atom, N is replaced by R ｃ or R １ , R ２ together with the phosphorus atom attached thereto form a 5- to 8-membered heterocyclyl group, provided that the ring atoms of said 5- to 8-membered heterocyclyl group optionally contain one heteroatom selected from N or O atoms, and when the ring atom contains an N atom, N is not R ｃ or R １ , R ２ together with the phosphorus atom attached thereto form a 5- or 6-membered heterocyclyl group, provided that the ring atoms of said 5- or 6-membered heterocyclyl group optionally contain one heteroatom selected from N or O atoms, and when the ring atom contains an N atom, N is not R ｃ connected to or as a structural unit [Chemistry A3] is a structural unit [Chemistry A4] Selected from Or, structural unit 【Chemical A5】 is a structural unit 【Chemical A6】 The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof,

7. Each R ｃ are each independently 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-O-C １～３ Alkyl-, C １～３ Alkyl-O-CH ２ -C(O)-, di(C １～３ alkyl)amino-C(O)-, di(C １～３ alkyl)amino-CH ２ -C(O)-, di(C １～３ alkyl)amino-C(O)-CH ２ -, 3- to 5-membered cycloalkyl-, 3- to 5-membered cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH ２ -, 3- to 5-membered heterocycloalkyl-, phenyl-CH ２ - or C substituted by one hydroxy or cyano group １～３ alkyl groups, provided that R ｃ is optionally substituted by 1, 2 or 3 halogens when not hydrogen, or each R ｃ are each independently a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, 【Chemical A7】 , acetyl group, 【Chemical A8】 The compound of formula (I) according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

8. The compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein n is 0, 1, or 2, or n is 1, 2, or 3, or n is 2.

9. R ３ are each independently an amino group, a nitro group, a halogen, or C １～４ alkyl group or phenyl group, provided that １～４ The alkyl or phenyl group may optionally be one or more R ｄ and R ｄ is a hydroxy group, a halogen, or C １～３ Alkyl-NH-C １～３ alkyl- or R ３ are each independently an amino group, a nitro group, a halogen, or C １～４ alkyl group or phenyl group, provided that １～４ The alkyl or phenyl group may optionally be one, two, or three R ｄ and Rd is selected from a hydroxy group, fluorine or methyl-NH-methyl-, or R ３ each independently represents an amino group, a nitro group, a fluorine atom, a methyl group, a trifluoromethyl group, or —CF ２ CH ２ OH, -CHF ２ , -CF ２ CH ３ , -CF ２ C(CH ３ ) ２ OH, or 【Chemical A9】 or R ３ are each independently an amino group, a fluorine atom, a methyl group, a trifluoromethyl group, or —CF ２ CH ２ OH, -CHF ２ , -CF ２ CH ３ , -CF ２ C(CH ３ ) ２ OH, or 【Chemical A10】 The compound of formula (I) according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

10. Structural Unit 【Chemical A11】 teeth, 【Chemical A12】 Selected from, and 【Chemistry A13】 The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

11. R ４ , R ５ are each independently hydrogen, deuterium, or C １～３ alkyl groups, provided that the C １～３ The alkyl group is optionally substituted with one or more halogens or R ４ is selected from a methyl group, and R ５ is selected from hydrogen or deuterium, with the proviso that said methyl group is optionally substituted by one or more fluorines, or R ４ is a methyl group or -CH ２ Selected from F, R ５ is selected from hydrogen or deuterium, or R ５ is C １～３ alkyl groups, R ４ is selected from hydrogen or deuterium, provided that １～３ The alkyl group is optionally substituted with one or more halogens or R ５ is a methyl group or -CH ２ Selected from F, R ４ The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein is selected from hydrogen or deuterium.

12. R ６ is hydrogen, halogen or C １～３ alkyl groups, provided that the C １～３ The alkyl group is optionally substituted with one or more halogens or R ６ is selected from hydrogen, fluorine, chlorine or a methyl group, wherein said methyl group is optionally substituted by one, two or three fluorines, or R ６ is hydrogen, chlorine, a methyl group or -CH ２ F or R ６ The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein is selected from a methyl group.

13. X and Y are each independently CR ａ , N, R ａ is hydrogen or C １～４ selected from alkoxy groups, 【Chemical A14】 represents a double bond, R １ , R ２ together with the phosphorus atom attached thereto form a 6-membered heterocyclyl group, provided that the ring atoms of said 6-membered heterocyclyl group contain at least one N atom or O atom, and if a ring atom contains an N atom, then N is not R ｃ connected to R ｃ is C １～４ Alkyl-S(O) ２ -, C ３～６ Cycloalkyl-S(O) ２ Selected from - Ring A is selected from phenyl groups; n is 0, 1, 2 or 3; Each R ３ are each independently a halogen, C １～８ alkyl groups, provided that the C １～８ the alkyl group is optionally substituted with one or more halogens; R ４ , R ５ are each independently hydrogen or C １～３ alkyl groups, provided that the C １～３ the alkyl group is optionally substituted with one or more fluorines; R ６ is hydrogen, halogen or C １～６ alkyl groups, provided that the C １～６ 13. The compound of formula (I) according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the alkyl group is optionally substituted with one or more halogens.

14. A compound of formula (II), 【Chemical A15】 During the ceremony, X and Y are both selected from CR a , or X is selected from CH and Y is selected from N, or X is selected from NR b and Y is selected from C(O), or X is selected from CF or C(CN) and Y is selected from N; 【Chemical A16】 represents a single bond or a double bond by X and Y; R ａ is hydrogen, a hydroxy group, a halogen, C １～６ Alkyl group or C １～６ alkoxy groups, provided that the C １～６ The alkyl group is optionally substituted with one or more halogens, and １～６ the alkoxy group is optionally substituted with one or more deuterium or halogen atoms; R ｂ is C １～６ alkyl groups, R １ , R ２ are each independently C １～６ alkyl group, 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 to which it is attached form a 5- to 8-membered heterocyclyl group, provided that the ring atoms of said 5- to 8-membered heterocyclyl group contain at least one N atom, and N is R ｃ connected to Each R ｃ are each independently hydrogen, C １～６ Alkyl group, C １～６ Alkyl-C(O)-, C １～６ Alkyl OC(O)-, C １～６ Alkyl-O-C １～６ Alkyl-, C １～６ Alkyl-O-C 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 group, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C １～６ Alkyl-, C ６～１０ Aryl-C １～６ C substituted by alkyl- or one or more hydroxy groups １～６ alkyl groups, provided that R ｃ is optionally substituted by one or more halogens when not hydrogen; Ring A is selected from a phenyl group, a thienyl group, a 2,3-dihydro-1H-indenyl group, a 2,3-dihydrobenzofuryl group, and a benzofuryl group; n is 0, 1, 2 or 3; Each R ３ are each independently an amino group, a nitro group, a halogen, or C １～８ alkyl groups, provided that the C １～８ The alkyl group may optionally be one or more R ｄ is replaced by R ｄ is selected from a hydroxy group or a halogen, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

15. A compound of formula (III): 【Chemical A17】 where: R １ 、R ２ 、R ３ 、X, Y, n, ring A 【Chemical A18】 is as defined in any one of claims 1 to 13, or the structural unit 【Chemical A19】 is as defined in claim 6, or the structural unit 【Chemical A20】 11. A compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as defined in claim 10.

16. The compound of formula (III), its stereoisomer or pharmaceutically acceptable salt thereof is selected from compounds of formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8) and (III-9), their stereoisomers or pharmaceutically acceptable salts; 【Chemical A21】 where: R １ , R ２ , R ３ , Y, n, ring A, R ａ , R ｂ , R ｃ is as defined in any one of claims 1 to 14, or the structural unit 【Chemical A22】 is as defined in claim 6, or the structural unit 【Chemistry A23】 16. The compound of formula (III) according to claim 15, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: is as defined in claim 10.

17. A compound selected from the group consisting of a compound of formula (IV), a compound of formula (V), and a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical A24】 where: R ３ , Y, n, R ｂ , R ｃ is as defined in any one of claims 1 to 13, or the structural unit 【Chemical A25】 The compound of formula (I) according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

18. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry A26-1】 【Chemistry A26-2】 【Chemistry A26-3】 【Chemistry A26-4】 【Chemistry A26-5】 【Chemistry A26-6】 【Chemistry A26-7】 【Chemistry A26-8】 【Chemistry A26-9】 【Chemistry A26-10】

19. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemical A27】

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof.

21. A compound according to any one of claims 1 to 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 for treating a disease and / or condition associated with or modulated by SOS1.

22. The compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claims 1 to 18, wherein the disease and / or condition associated with or regulated by SOS1 is selected from cancer, and optionally the cancer is selected from non-small cell lung cancer.

Images