Phosphorus-containing SOS1 inhibitors

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a phosphorus-containing SOS1 inhibitor, namely a compound shown as a formula (I), a preparation method of the phosphorus-containing SOS1 inhibitor, a pharmaceutical composition containing the compound, and application of the phosphorus-containing SOS1 inhibitor in preparation of drugs for treating diseases and / or symptoms related to SOS1 or regulated by SOS1. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of May 10, 2021, an application number of 202180030884.3, and an invention title of "Phosphorus-Containing SOS1 Inhibitor".

[0002] Citation of Related Applications

[0003] This application claims the priority and benefits of Chinese Patent Application No. 202010387620.0 filed with the State Intellectual Property Office of the People's Republic of China on May 9, 2020 and the priority and benefits of Chinese Patent Application No. 202110450032.1 filed with the State Intellectual Property Office of the People's Republic of China on April 25, 2021, the entire contents of which are hereby incorporated by reference in their entirety into the text. Technical Field

[0004] This application relates to phosphorus-containing SOS1 inhibitors, methods for preparing the same, pharmaceutical compositions containing the inhibitors, and their use in the treatment of diseases and / or disorders related to or regulated by SOS1. Background Art

[0005] RAS is the most frequently mutated oncogene in human cancers, and KRAS is the most frequently occurring subtype in the RAS family. KRAS gene mutations account for 86% of the total number of RAS gene mutations.

[0006] Binding of a guanine nucleotide exchange factor (GEF) for Son of Sevenless 1 (SOS1) promotes the release of GDP from RAS family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in the GTP-bound state, RAS family proteins are active and recruit effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to 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 (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathways affect diverse cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth (Young et al., Adv. Cancer Res., 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).

[0007] Selective inhibition of the binding of the catalytic site of SOS1 to RAS family proteins can prevent the SOS1-mediated activation of RAS family proteins into the GTP-bound form. Thus, SOS1 inhibitor compounds can inhibit signal transduction in cells downstream of RAS family proteins (e.g., ERK phosphorylation). An ideal SOS1 inhibitor compound should be able to selectively and potently inhibit the binding of SOS1:RAS-family proteins and ERK phosphorylation in cells.

[0008] Recently, researchers at Bayer reported the discovery of a class of selective SOS1 inhibitors containing a quinazoline core structure (Proc Natl Acad Sci. 2019;116(7):2551-2560), with the representative compound BAY-293, which can block RAS activation by interfering with the RAS-SOS1 interaction.

[0009]

[0010] In this article, we provide novel SOS1 inhibitor compounds that can inhibit ERK phosphorylation in cells by interfering with the RAS-SOS1 interaction. DETAILED DESCRIPTION OF THE INVENTION

[0012] On the one hand, the present application provides a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts,

[0013]

[0014] wherein,

[0015] X and Y are each independently selected from CR a , C(O), N or NR b ;

[0016] Depending on the difference between X and Y, it represents a single bond or a double bond respectively;

[0017] R a is selected from hydrogen, hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more deuteriums or halogens;

[0018] R b is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy;

[0019] R 1 , R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl)-C 1-6 alkyl-, or R 1 , R 2 and the phosphorus atom to which they are attached together form a 5- to 10-membered heterocyclic group, wherein the C 1-6 alkyl or 5- to 10-membered heterocyclic group is optionally substituted by one or more R c ;

[0020] Each R c is independently selected from hydrogen, O=, HN=, C 1-6 alkyl-N=, C 1-6 alkyl-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O) 2 -, 3- to 6-membered cycloalkyl-S(O) 2 -, C 1-6 alkylOC(O)-, C 1-6 alkyl-O-C 1-6 alkyl-, C 1-6 alkyl-O-C1-6 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 1-6 alkyl- substituted by one or more hydroxyl or cyano groups, wherein said R c is optionally substituted by one or more halogens when not hydrogen and O=;

[0021] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring or 8- to 12-membered fused heterocycle;

[0022] n is 0, 1, 2 or 3;

[0023] Each R 3 is independently selected from amino, nitro, halogen, C 1-8 alkyl-, 3- to 6-membered cycloalkyl- or phenyl, wherein said C 1-8 alkyl-, 3- to 6-membered cycloalkyl- or phenyl is optionally substituted by one or more R d substituents;

[0024] R d is selected from hydroxyl, halogen or C 1-6 alkyl-NH-C 1-6 alkyl-;

[0025] R 4 and R 5 are independently selected from hydrogen, deuterium or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one or more halogens;

[0026] R 6 is selected from hydrogen, a halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogens.

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

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

[0029] In some embodiments, X is selected from NR b , Y is selected from CR a , C(O), N or NR b . In some embodiments, X is selected from NR b , Y is selected from CR a , C(O) or N. In some embodiments, X is selected from NR b , Y is selected from C(O).

[0030] In some embodiments, both X and Y are selected from CR a . In some embodiments, X is selected from CH, Y is selected from CR a .

[0031] In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with one or more deuteriums or halogens.

[0032] In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4The alkyl group is optionally substituted with one or more halogens, and the C 1-4 alkoxy group is optionally substituted with one or more deuteriums or halogens. In some embodiments, R a is selected from hydrogen, hydroxyl, halogen, cyano, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with one or more halogens, and the C 1-3 alkoxy is optionally substituted with one or more deuteriums or halogens.

[0033] In some embodiments, R a is selected from hydrogen, hydroxyl, halogen, cyano, or C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with one or more deuteriums or halogens.

[0034] In some embodiments, R a is selected from hydrogen, hydroxyl, halogen, cyano, or C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted with one or more deuteriums or halogens. In some embodiments, R a is selected from hydrogen, hydroxyl, halogen, cyano, or C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted with 3 deuteriums or one or more fluorines. In some embodiments, R a is selected from hydrogen, hydroxyl, halogen, cyano, or C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted with 3 deuteriums, or 1 or 2 fluorines.

[0035] In some embodiments, R a is selected from hydrogen, hydroxyl, fluorine, cyano, methoxy, monofluoromethoxy, or difluoromethoxy, wherein the methoxy is optionally substituted with 3 deuteriums.

[0036] In some embodiments, R a is selected from hydrogen, hydroxyl, fluorine, cyano, CH 3 O-, CD 3 O-, CH 2 FO-, or CHF 2 O-.

[0037] In some embodiments, R a is selected from hydrogen, fluorine, CH 3 O-, CD 3 O-, or CHF 2 O-.

[0038] In some embodiments, R bSelected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy.

[0039] In some embodiments, R b is selected from C 1-6 alkyl. In some embodiments, R b is selected from C 1-4 alkyl. In some embodiments, R b is selected from C 1-3 alkyl. In some embodiments, R b is selected from methyl.

[0040] In some embodiments, X is selected from CH, CF, C(CN) or N(CH 3 ), Y is selected from N, CH, C(O), C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF or C(OCD 3 ). In some embodiments, X is selected from CH, Y is selected from C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF or C(OCD 3 ). In some embodiments, X is selected from CH, Y is selected from N. In some embodiments, X is selected from N(CH 3 ), Y is selected from C(O). In some embodiments, X is selected from CF or C(CN), Y is selected from CH or N.

[0041] In some embodiments, is a double bond. In some embodiments, is a single bond.

[0042] In some embodiments, R 1 , R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl)-C 1-6 alkyl-, or R 1 , R 2 and the phosphorus atom to which they are attached together form a 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c .

[0043] In some embodiments, R 1 , R 2independently selected from C 1-6 alkyl, or R 1 , R 2 and the phosphorus atom to which it is attached together form a 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c .

[0044] In some embodiments, R 1 , R 2 are independently selected from C 1-3 alkyl, NH(R c )-C 1-3 alkyl- or N(R c )(C 1-3 alkyl)-C 1-3 alkyl-.

[0045] In some embodiments, R 1 , R 2 are independently selected from C 1-3 alkyl.

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

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

[0048] In some embodiments, R 1 , R 2 are independently selected from methyl.

[0049] In some embodiments, R 1 , R 2 and the phosphorus atom to which it is attached together form a 5- to 10-membered heterocyclic group, wherein the ring atoms of the 5- to 10-membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, and the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c .

[0050] In some embodiments, R 1 , R 2 and the phosphorus atom to which it is attached together form a 5- to 10-membered heterocyclic group, wherein the ring atoms of the 5- to 10-membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c , and when the ring atoms contain an N atom, the N is connected to R c .

[0051] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- to 8-membered heterocyclic group, wherein the ring atoms of the 5- to 8-membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain an N atom, N is connected to R c .

[0052] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- to 8-membered heterocycloalkyl group, wherein the ring atoms of the 5- to 8-membered heterocycloalkyl group contain at least one N atom, and N is connected to R c .

[0053] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- or 6-membered heterocycloalkyl group, a 9- or 10-membered spiroheterocyclic group, or a 9- or 10-membered fused heterocyclic group, wherein the 5- or 6-membered heterocycloalkyl group, 9- or 10-membered spiroheterocyclic group, or 9- or 10-membered fused heterocyclic group is optionally substituted by one or more R c .

[0054] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally substituted by one or more R c .

[0055] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- or 6-membered heterocyclic group, wherein the ring atoms of the 5- or 6-membered heterocyclic group optionally contain one or more heteroatoms selected from N, O or S atoms, and when the ring atoms contain an N atom, N is connected to R c . In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- or 6-membered heterocyclic group, wherein the ring atoms of the 5- or 6-membered heterocyclic group optionally contain a heteroatom selected from N or O atoms, and when the ring atoms contain an N atom, N is connected to R c .

[0056] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 6-membered heterocyclic group, wherein the ring atoms of the 6-membered heterocyclic group contain at least one N atom, and N is connected to R c . In some embodiments, R 1 and R2 together with the connected phosphorus atom form a 6-membered heterocyclic group, wherein only one N atom is contained in the ring atoms of the 6-membered heterocyclic group, and N is connected to R c connected.

[0057] In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 6-membered heterocyclic group, wherein only one O atom is contained in the ring atoms of the 6-membered heterocyclic group.

[0058] In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 5-membered or 6-membered heterocyclic group, and the ring atoms of the 5-membered or 6-membered heterocyclic group are composed of carbon atoms and phosphorus atoms.

[0059] In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 6-membered heterocycloalkyl group, wherein at least one N atom is contained in the ring atoms of the 6-membered heterocycloalkyl group, and N is connected to R c connected. In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 6-membered heterocycloalkyl group, wherein only one N atom is contained in the ring atoms of the 6-membered heterocycloalkyl group, and N is connected to R c connected. In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 6-membered heterocycloalkyl group, wherein only one O atom is contained in the ring atoms of the 6-membered heterocycloalkyl group. In some embodiments, R 1 , R 2 together with the connected phosphorus atom form a 5-membered or 6-membered heterocycloalkyl group, and the ring atoms of the 5-membered or 6-membered heterocycloalkyl group are composed of carbon atoms and phosphorus atoms.

[0060] In some embodiments, the structural unit is optionally selected from the structural unit wherein the structural unit

[0061] may optionally be substituted by one or more R c substituted.

[0062] In some embodiments, the structural unit is optionally selected from the structural unit

[0063] In some embodiments, the structural unit may be selected from structural units

[0064] In some embodiments, the structural unit is the structural unit

[0065] In some embodiments, R 1 and R 2 are each independently selected from methyl or ethyl, or the structural unit is selected from structural units

[0066]

[0067] In some embodiments, R 1 and R 2 are each independently selected from methyl, or the structural unit is the structural unit

[0068] In some embodiments, each R c is independently selected from hydrogen, C 1-6 alkyl-, C 1-6 alkyl-C(O)-, C 1-6 alkylOC(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-, C 6-10 aryl-C 1-6 alkyl- or C 1-6 alkyl- substituted with one or more hydroxyl groups.

[0069] In some embodiments, each R c is independently selected from hydrogen, O═, HN═, C 1-6 alkyl-N═, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3- to 6-membered cycloalkyl-S(O) 2 -, C 1-3 alkylOC(O)-, C 1-3 alkyl-O-C 1-3 alkyl-, C 1-3 alkyl-O-C 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 1-3 alkyl- substituted with one or more hydroxyl or cyano groups, where the R c is optionally substituted with one or more halogens when it is not hydrogen and O═.

[0070] In some embodiments, each R c is independently selected from 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 alkylOC(O)-, C 1-3 alkyl-O-C 1-3 alkyl-, C 1-3alkyl-O-C 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 1-3 alkyl- substituted with one or more hydroxy or cyano groups, wherein said R c when not hydrogen is optionally substituted with one or more halogens.

[0071] In some embodiments, each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3- to 5-membered cycloalkyl-S(O) 2 -, C 1-3 alkylOC(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 1-3alkyl-, wherein said R c when not hydrogen is optionally substituted with one, two or three halogens.

[0072] In some embodiments, each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3- to 5-membered cycloalkyl-S(O) 2 -, C 1-3 alkylOC(O)-, C 1-3 alkyl-O-C 1-3 alkyl-, C 1-3 alkyl-O-CH 2 -C(O)-, bis(C 1-3 alkyl)amino-C(O)-, bis(C 1-3 alkyl)amino-CH 2 -C(O)-, bis(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- or C 1-3 alkyl- substituted with one hydroxyl or cyano group, wherein said R c when not hydrogen is optionally substituted with one, two or three halogens.

[0073] In some embodiments, each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkylOC(O)-, C 1-3 alkyl-O-C 1-3 alkyl-, C 1-3 alkyl-O-CH 2 -C(O)-, bis(C 1-3 alkyl)amino-C(O)-, bis(C 1-3 alkyl)amino-CH 2 -C(O)-, bis(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 -, phenyl-CH 2 - or C 1-3 alkyl- substituted with one hydroxyl group.

[0074] In some embodiments, each R c is independently selected from hydrogen, methyl, ethyl, isopropyl, acetyl,

[0075] In some embodiments, each R c is independently selected from methyl, ethyl, isopropyl, acetyl,

[0076] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl, 8- to 12-membered benzocycloalkenyl or 8- to 12-membered benzheterocyclic group.

[0077] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl, 8- to 12-membered benzocycloalkenyl, 8- to 12-membered benzheterocycloalkyl or 8- to 12-membered benzheterocycloalkenyl.

[0078] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 12-membered benzocycloalkyl or 8- to 12-membered benzheterocycloalkyl.

[0079] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 10-membered fused ring or 8- to 10-membered fused heterocycle.

[0080] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl, 8- to 10-membered benzocycloalkenyl or 8- to 10-membered benzheterocyclic group.

[0081] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl, 8- to 10-membered benzocycloalkenyl, 8- to 10-membered benzheterocycloalkyl or 8- to 10-membered benzheterocycloalkenyl.

[0082] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 10-membered benzocycloalkyl or 8- to 10-membered benzheterocycloalkyl.

[0083] In some embodiments, ring A is selected from phenyl, thienyl, 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl or benzofuranyl.

[0084] In some embodiments, ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.

[0085] In some embodiments, n is 0, 1, or 2; alternatively, n is 1, 2, or 3.

[0086] In some embodiments, n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.

[0087] In some embodiments, each R 3 is independently selected from amino, nitro, halogen, C 1-6 alkyl-, or phenyl, wherein the C 1-6 alkyl- or phenyl is optionally substituted with one or more R d .

[0088] In some embodiments, each R 3 is independently selected from amino, halogen, C 1-6 alkyl-, or phenyl, wherein the C 1-6 alkyl- or phenyl is optionally substituted with one or more R d .

[0089] In some embodiments, each R 3 is independently selected from amino, nitro, halogen, C 1-4 alkyl-, or phenyl, wherein the C 1-4 alkyl- or phenyl is optionally substituted with one or more R d .

[0090] In some embodiments, each R 3 is independently selected from amino, nitro, halogen, C 1-4 alkyl-, or phenyl, wherein the C 1-4 alkyl- or phenyl is optionally substituted with 1, 2, or 3 R d .

[0091] In some embodiments, R d is selected from hydroxy, halogen, or C 1-3 alkyl-NH-C 1-3 alkyl-.

[0092] In some embodiments, R d is selected from hydroxy, fluoro, or methyl-NH-methyl-.

[0093] In some embodiments, each R 3 is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF 2 CH2 OH, -CHF 2 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 2 OH or

[0094] In some embodiments, each R 3 is independently selected from amino, fluorine, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 2 OH or

[0095] In some embodiments, each R 3 is independently selected from amino, nitro, fluorine, methyl or trifluoromethyl.

[0096] In some embodiments, the structural unit is selected from and is further selected from

[0097]

[0098] In some embodiments, R 4 , R 5 are independently selected from hydrogen, deuterium or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogens.

[0099] In some embodiments, R 4 is selected from C 1-3 alkyl, R 5 is selected from hydrogen or deuterium, wherein the C 1-3 alkyl is optionally substituted with one or more halogens. In some embodiments, R 4 is selected from methyl, R 5 is selected from hydrogen or deuterium, wherein the methyl is optionally substituted with one or more fluorines. In some embodiments, R 4 is selected from methyl or -CH 2 F, R 5 is selected from hydrogen or deuterium. In some embodiments, R 4 is selected from methyl, R5 Selected from hydrogen.

[0100] In some embodiments, R 5 is selected from C 1-3 alkyl, and R 4 is selected from hydrogen or deuterium, wherein the C 1-3 alkyl is optionally substituted with one or more halogens. In some embodiments, R 5 is selected from methyl, and R 4 is selected from hydrogen or deuterium, wherein the methyl is optionally substituted with one or more fluorines. In some embodiments, R 5 is selected from methyl or -CH 2 F, and R 4 is selected from hydrogen or deuterium. In some embodiments, R 5 is selected from methyl, and R 4 is selected from hydrogen.

[0101] In some embodiments, R 6 is selected from hydrogen, halogen, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogens.

[0102] In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, or isopropyl, wherein the methyl, ethyl, propyl, or isopropyl is optionally substituted with one or more halogens. In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, or methyl, wherein the methyl is optionally substituted with 1, 2, or 3 fluorines. In some embodiments, R 6 is selected from hydrogen, chlorine, methyl, or -CH 2 F. In some embodiments, R 6 is selected from methyl.

[0103] In some embodiments, the heteroatoms in the heterocyclic group, heteroaryl group, or heterocycloalkyl group described in the present application are selected from N, O, S, and P. In some embodiments, the heteroatoms in the heterocyclic group, heteroaryl group, or heterocycloalkyl group described in the present application are selected from N, O, and P. In some embodiments, the heteroatoms in the heterocyclic group, heteroaryl group, or heterocycloalkyl group described in the present application are selected from N and P.

[0104] On the other hand, the present application provides a compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts,

[0105]

[0106] wherein,

[0107] X and Y are each independently selected from CR a 、C(O), N, or NRb ;

[0108] Represents a single bond or a double bond depending on X and Y;

[0109] R a Selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted by one or more halogens, and the C 1-6 alkoxy is optionally substituted by one or more deuteriums or halogens;

[0110] R b Selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy;

[0111] R 1 、R 2 Are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl)-C 1-6 alkyl-, or R 1 、R 2 and the phosphorus atom to which it is attached together form a 5-8 membered heterocyclic group, wherein at least one of the ring atoms of the 5-8 membered heterocyclic group contains an N atom, and the N is connected to R c ;

[0112] Each R c Is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-C(O)-, C 1-6 alkylOC(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)-C1-6 alkyl-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl- or C 1-6 alkyl substituted with one or more hydroxyl groups, wherein said R c when not hydrogen is optionally substituted with one or more halogens;

[0113] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl or 8- to 12-membered fused ring;

[0114] n is 0, 1, 2 or 3;

[0115] Each R 3 is independently selected from amino, nitro, halogen, C 1-8 alkyl or 3- to 6-membered cycloalkyl, wherein said C 1-8 alkyl and 3- to 6-membered cycloalkyl are optionally substituted with one or more R d substituents;

[0116] R d is selected from hydroxyl or halogen.

[0117] In some embodiments, the compound of formula (II), wherein R 1 , R 2 , R 3 , X, Y, n, Ring A and are as defined above.

[0118] In some embodiments, X is selected from CR a , Y is selected from CR a , C(O), N or NR b . In some embodiments, X is selected from CR a , Y is selected from CR a , C(O) or N. In some embodiments, X is selected from CR a , Y is selected from N.

[0119] In some embodiments, both X and Y are selected from CR a . In some embodiments, X is selected from CH, Y is selected from CR a .

[0120] In some embodiments, R a is selected from hydrogen, halogen or C 1-4 alkoxy, wherein said C 1-4The alkoxy group is optionally substituted by one or more deuterium or halogen atoms. In some embodiments, R a is selected from hydrogen, halogen, or C 1-4 alkoxy, where the C 1-4 alkoxy is optionally substituted by 3 deuterium atoms or one or more fluorine atoms. In some embodiments, R a is selected from hydrogen, halogen, or C 1-4 alkoxy, where the C 1-4 alkoxy is optionally substituted by 3 deuterium atoms or 2 fluorine atoms.

[0121] In some embodiments, R a is selected from hydrogen, fluorine, methoxy, or difluoromethoxy, where the methoxy is optionally substituted by 3 deuterium atoms.

[0122] In some embodiments, R a is selected from hydrogen, fluorine, CH 3 O-, CD 3 O-, or CHF 2 O-.

[0123] In some embodiments, R b is selected from C 1-6 alkyl. In some embodiments, R b is selected from C 1-4 alkyl. In some embodiments, R b is selected from C 1-3 alkyl. In some embodiments, R b is selected from methyl.

[0124] In some embodiments, X is selected from CH and N(CH 3 ), Y is selected from N, C(O), C(OCH 3 ), CF, or C(OCD 3 ). In some embodiments, X is selected from CH, Y is selected from C(OCH 3 ), CF, or C(OCD 3 ). In some embodiments, X is selected from CH, Y is selected from N. In some embodiments, X is selected from N(CH 3 ), Y is selected from C(O).

[0125] In some embodiments, R 1 , R 2 are each independently selected from C 1-3 alkyl, NH(R c )-C 1-3 alkyl-, or N(R c )(C 1-3 alkyl)-C 1-3 alkyl-.

[0126] In some embodiments, R 1 and R 2 are each independently selected from C 1-3 alkyl.

[0127] In some embodiments, R 1 and R 2 are each independently selected from methyl.

[0128] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 6-membered heterocyclic group, the ring atoms of the 6-membered heterocyclic group containing at least one N atom, and the N is connected to R c . In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 6-membered heterocyclic group, the ring atoms of the 6-membered heterocyclic group containing only one N atom, and the N is connected to R c .

[0129] In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- to 8-membered heterocycloalkyl group, the ring atoms of the 5- to 8-membered heterocycloalkyl group containing at least one N atom, and the N is connected to R c . In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 6-membered heterocycloalkyl group, the ring atoms of the 6-membered heterocycloalkyl group containing at least one N atom, and the N is connected to R c . In some embodiments, R 1 and R 2 together with the phosphorus atom to which they are attached form a 6-membered heterocycloalkyl group, the ring atoms of the 6-membered heterocycloalkyl group containing only one N atom, and the N is connected to R c .

[0130] In some embodiments, the structural unit is selected from the structural units

[0131] In some embodiments, R 1 and R 2 are each independently selected from methyl, or the structural unit is selected from the structural units

[0132] In some embodiments, each R c is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkyl-C(O)-, C 1-3alkyl OC(O)-, C 1-3 alkyl-O-C 1-3 alkyl-, C 1-3 alkyl-O-C 1-3 alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino-C(O)-, amino-C 1-3 alkyl-C(O)-, mono(C 1-3 alkyl)amino-C 1-3 alkyl-C(O)-, di(C 1-3 alkyl)amino-C 1-3 alkyl-C(O)-, amino-C(O)-C 1-3 alkyl-, mono(C 1-3 alkyl)amino-C(O)-C 1-3 alkyl-, di(C 1-3 alkyl)amino-C(O)-C 1-3 alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-3 alkyl-, phenyl-C 1-3 alkyl- or C 1-3 alkyl substituted with one or more hydroxyl groups.

[0133] In some embodiments, each R c is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkyl-C(O)-, 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 -, phenyl-CH 2 - or C 1-3 alkyl substituted with one hydroxyl group.

[0134] In some embodiments, each R c is independently selected from methyl, ethyl, isopropyl, acetyl,

[0135] In some embodiments, ring A is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, or 8- to 10-membered fused ring.

[0136] In some embodiments, ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.

[0137] In some embodiments, n is 0, 1, or 2; alternatively, n is 1, 2, or 3.

[0138] In some embodiments, n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.

[0139] In some embodiments, each R 3 is independently selected from amino, nitro, halogen, or C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with 1, 2, or 3 R d groups.

[0140] In some embodiments, R d is selected from hydroxy or fluoro.

[0141] In some embodiments, each R 3 is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 or -CF 2 C(CH 3 ) 2 OH.

[0142] In some embodiments, the structural unit is selected from and further selected from

[0143]

[0144] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (III), its stereoisomer, or its pharmaceutically acceptable salt

[0145]

[0146] wherein, R 1 , R 2 , R3 、 X, Y, n, ring A and are as defined above.

[0147] In some embodiments, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts of the present invention,

[0148] X and Y are each independently selected from CR a and N. For example, both X and Y are selected from CR a , or X is CR a and Y is N;

[0149] R a is selected from hydrogen or C 1-4 alkoxy; preferably, R a is selected from hydrogen or methoxy;

[0150] represents a double bond;

[0151] R 1 , R 2 and the phosphorus atom to which it is attached together form a 6-membered heterocyclic group, wherein at least one of the ring atoms of the 6-membered heterocyclic group contains an N atom or an O atom, and when the ring atom contains an N atom, N is connected to R c (preferably containing one N atom, and N is connected to R c );

[0152] R c is selected from C 1-4 alkyl-S(O) 2 - (preferably mesyl), C 3-6 cycloalkyl-S(O) 2 - (preferably cyclopropylsulfonyl);

[0153] Ring A is selected from C 6-10 aryl, preferably C6 aryl (i.e., phenyl);

[0154] n is 0, 1, 2 or 3, preferably 2;

[0155] Each R 3 is independently selected from halogen (preferably F), C 1-8 alkyl (preferably C 1-4 alkyl, more preferably methyl or ethyl), wherein the C 1-8 alkyl is optionally substituted by one or more halogens (preferably F);

[0156] R 4 , R 5 are each independently selected from hydrogen or C 1-3 alkyl, wherein the C 1-3The alkyl group is optionally substituted by one or more fluorines (preferably R 4 is selected from hydrogen, R 5 is selected from methyl, or, R 4 is selected from methyl, R 5 is selected from hydrogen);

[0157] R 6 is selected from hydrogen, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more halogens, for example, R 6 may be selected from hydrogen, methyl or methyl optionally substituted by one or more halogens (for example, -CH 2 F).

[0158] In some embodiments, in the compound of formula (II), its stereoisomer or its pharmaceutically acceptable salt of the present invention,

[0159] X and Y are each independently selected from CR a and N, for example, both X and Y are selected from CR a , or X is CR a and Y is N;

[0160] R a is selected from hydrogen or C 1-4 alkoxy; preferably, R a is selected from hydrogen or methoxy; more preferably, R a is selected from hydrogen;

[0161] represents a double bond;

[0162] R 1 , R 2 and the phosphorus atom to which it is attached together form a 6-membered heterocyclic group, wherein at least one of the ring atoms of the 6-membered heterocyclic group contains an N atom (preferably contains one N atom), and N is connected to R c ;

[0163] R c is selected from C 1-4 alkyl-S(O) 2 -(preferably mesyl), C 3-6 cycloalkyl-S(O) 2 -(preferably cyclopropylsulfonyl);

[0164] Ring A is selected from C 6-10 aryl, preferably C6 aryl (i.e., phenyl);

[0165] n is 0, 1, 2 or 3, preferably 2;

[0166] Each R 3Independently selected from halogen (preferably F), C 1-8 alkyl (preferably C1-4, more preferably methyl or ethyl), wherein said C 1-8 alkyl is optionally substituted with one or more halogen (preferably F).

[0167] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or its pharmaceutically acceptable salts, which are selected from the compounds of formula (III-1), formula (III-2), formula (III-3), formula (III-4), formula (III-5), formula (III-6), formula (III-7), formula (III-8) and formula (III-9), their stereoisomers or their pharmaceutically acceptable salts,

[0168]

[0169]

[0170] wherein, R 1 , R 2 , R 3 , Y, n, ring A, R a , R b and R c are as defined above.

[0171] In some embodiments, the compound of formula (I) or formula (II) of the present application, its stereoisomers or its pharmaceutically acceptable salts, which are selected from the compounds of formula (IV), formula (V) and formula (VI), their stereoisomers or their pharmaceutically acceptable salts,

[0172]

[0173] wherein, R 3 , Y, n, R b and R c are as defined above.

[0174] In some embodiments, the present application includes the variables and their embodiments defined above, and any combination thereof.

[0175] In some embodiments, the compound of formula (I) of the present application is selected from the following compounds, their stereoisomers or their pharmaceutically acceptable salts:

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] In some embodiments, the compound of formula (I) of the present application is selected from the following compounds, their stereoisomers or their pharmaceutically acceptable salts:

[0184]

[0185]

[0186]

[0187] On the other hand, the present application provides a method for preparing the compound of formula (I), including: reacting a compound of formula M3 with a compound of formula N3 to prepare the compound of formula (I)

[0188]

[0189] Wherein,

[0190] Rx is selected from chlorine, bromine or iodine;

[0191] R 6 is selected from C 1-6 alkyl optionally substituted by one or more halogens;

[0192] R 1 , R 2 , R 3 , R 4 , R 5 X, Y, n and ring A are as defined above.

[0193] On the other hand, the present application provides a method for preparing the compound of formula M3, including:

[0194] Step (i): Reacting a compound of formula M1 with a compound of formula N1 under acidic conditions to prepare a compound of formula M2;

[0195] Step (ii): Reacting a compound of formula M2 with a compound of formula N2 to prepare a compound of formula M3;

[0196]

[0197] Wherein,

[0198] Rx is selected from chlorine, bromine or iodine;

[0199] R 6 selected from C alkyl optionally substituted by one or more halogens; 1-6 alkyl;

[0200] R 3 、R 4 、R 5 、X, Y, n and ring A are as defined above.

[0201] On the other hand, the present application provides a method for preparing a compound of formula M3, comprising:

[0202]

[0203] Step (a): Reacting a compound of formula M2 with thionyl chloride to prepare a compound of formula M2-1,

[0204] Step (b): Under basic conditions, subjecting the compound of formula M2-1 to a substitution reaction with a compound of formula N2 to prepare a compound of formula M3,

[0205] wherein,

[0206] Rx is selected from chlorine, bromine or iodine;

[0207] R 6 selected from C alkyl optionally substituted by one or more halogens; 1-6 alkyl;

[0208] R 3 、R 4 、R 5 、X, Y, n and ring A are as defined above.

[0209] In some embodiments, in the method for preparing a compound of formula (I), the compound of formula M3 is prepared by the method described above.

[0210] On the other hand, the present application provides a method for preparing a compound of formula (III-8), the method comprising:

[0211] Reacting a compound of formula M3-1 with 1-benzyl-1,4-azaphospholane-4-oxide to prepare a compound of formula M3-2, and then debenzylating to obtain a compound of formula M3-3, and finally subjecting to a substitution reaction to prepare a compound of formula (III-8),

[0212]

[0213] wherein, Rx is selected from chlorine, bromine or iodine;

[0214] R 3 、R c 、n and ring A are as defined above.

[0215] In some embodiments, the method for preparing the compound of formula (III-8) provided by the present application includes:

[0216] Step (1): Reacting the compound of formula M3-1 with 1-benzyl-1,4-azaphospholane-4-oxide to prepare the compound of formula M3-2; Step (2): Reacting the compound of formula M3-2 to obtain the compound of formula M3-3.

[0217] Step (3): Reacting the compound of formula M3-3 to obtain the compound of formula (III-8).

[0218] Optionally, step (2) is carried out in the presence of ...

[0219] wherein

[0220] Rx is selected from chlorine, bromine or iodine;

[0221] R 6 is selected from C 1-6 alkyl optionally substituted by one or more halogens;

[0222] R 3 、R c , n and the definition of ring A are as described above.

[0223] On the other hand, the present application also provides the following intermediate compounds, their stereoisomers or their pharmaceutically acceptable salts:

[0224]

[0225]

[0226] On the other hand, the present application provides a pharmaceutical composition comprising the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt of the present application. In some embodiments, the pharmaceutical composition of the present application further includes a pharmaceutically acceptable excipient.

[0227] On the other hand, the present application provides a method for treating or preventing diseases and / or disorders related to or regulated by SOS1 in mammals, said method comprising administering to a mammal in need of such treatment or prevention, preferably a human, a therapeutically or prophylactically effective amount of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition.

[0228] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating or preventing diseases and / or disorders related to or regulated by SOS1.

[0229] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment or prevention of diseases and / or disorders related to or regulated by SOS1.

[0230] On the other hand, the present application provides the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment or prevention of diseases and / or disorders related to or regulated by SOS1.

[0231] In some embodiments, the diseases and / or disorders related to or regulated by SOS1 are selected from the diseases and / or disorders in which SOS1 interacts with RAS family proteins.

[0232] In some embodiments, the diseases and / or disorders related to or regulated by SOS1 are selected from cancers, such as non-small cell lung cancer.

[0233] The compounds of the present application have good inhibitory activity against KRAS-G12C / SOS1 protein binding, inhibitory activity against K562 cell proliferation, in vitro and in vivo drug activities, and good pharmacokinetic properties.

[0234] Definitions

[0235] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0236] Chemical bond Depending on the groups connected at both ends, it represents a single bond or a double bond respectively. For example, when X and Y connected at both ends of the chemical bond are CR a or N, the chemical bond is a double bond; when one of X and Y connected at both ends of the chemical bond is CO or NR a the chemical bond is a single bond. Those skilled in the art can understand that the selection of X and Y does not violate the valence bond rules.

[0237] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, as long as the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0238] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by halogen for ethyl means that ethyl can be unsubstituted (-CH 2 CH 3 ), monosubstituted (such as -CH 2 CH 2 F), polysubstituted (such as -CHFCH 2 F, -CH 2 CHF 2 etc.) or fully substituted (-CF 2 CF 3 ). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized will be introduced.

[0239] In this article, C m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 " means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.

[0240] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 2 Rs, each R has independent options.

[0241] When the number of a connecting group is 0, such as -(CH 2 ) 0 -, it means that this connecting group is a covalent bond.

[0242] When a substituent's bond cross-connects between two atoms on a ring, this substituent can bond to any atom on this ring. For example, the structural unit means that its substitution can occur at any position on cyclohexyl or cyclohexadiene.

[0243] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0244] The term "hydroxy" refers to the -OH group.

[0245] The term "amino" refers to the -NH 2 group.

[0246] The term "nitro" refers to the -NO 2 group.

[0247] The term "cyano" refers to the -CN group.

[0248] The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 This alkyl group can be straight-chain or branched-chain. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups (i.e., alkyl) have the same definition as above.

[0249] The term "alkoxy" refers to -O-alkyl.

[0250] The term "alkylamino" or "monoalkylamino" refers to -NH-alkyl.

[0251] The term "dialkylamino" refers to -N(alkyl) 2 .

[0252] The term "cycloalkyl" refers to a carbocyclic ring that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, this carbocyclic ring is usually a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0253] The term "heterocyclyl" refers to a non-aromatic ring that is completely saturated or partially unsaturated (but not completely unsaturated heteroaromatic) and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, this heterocyclyl is usually a 3- to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus, and / or nitrogen. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, or etc.

[0254] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycloalkyl is generally a 3- to 12-membered ring, 3- to 7-membered ring or 5- to 8-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, and non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl or Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.

[0255] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, etc.

[0256] The term "heteroaryl" refers to a monocyclic or fused polycyclic system that contains at least one ring atom selected from N, O, S, the remaining ring atoms are C, and has at least one aromatic ring. Preferred heteroaryl has a single 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0257] The term "fused ring" refers to an all-carbon polycyclic ring having 7 to 20 members, in which two rings in the system share two adjacent carbon atoms, and at least one ring has a fully conjugated π-electron system, but the whole does not have aromaticity. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused rings, preferably bicyclic or tricyclic, more preferably 6-membered / 6-membered or 5-membered / 6-membered bicyclic. Non-limiting examples of fused rings include:

[0258] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring having 5 to 20 members with a single carbon atom (referred to as a spiro atom) shared between monocyclic rings, and one or more ring atoms in the polycyclic ring are heteroatoms selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of spiro atoms shared between rings, spiroheterocycles are classified into monospiroheterocycles, dispiroheterocycles, or polyspiroheterocycles, preferably monospiroheterocycles or dispiroheterocycles, 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 include

[0259] The term "fused heterocycloalkyl" refers to a fully saturated polycyclic ring having 5 to 20 ring atoms, and two rings share 2 ring atoms, and one or more ring atoms in the polycyclic ring are heteroatoms selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, or polycyclic bridged heterocycles, preferably bicyclic. Non-limiting examples of fused heterocycles include

[0260] The term "benzocycloalkyl" means that a benzene ring is fused to a cycloalkyl (i.e., the benzene ring and the cycloalkyl share two adjacent carbon atoms). Non-limiting examples of benzocycloalkyl include: etc.

[0261] The term "cyclenyl" refers to an unsaturated carbocyclic ring containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, and the carbocyclic ring can exist as a monocyclic, bridged, or spiro ring. Non-limiting examples of cyclenyl include: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0262] The term "benzocyclenyl" means that a benzene ring is fused to a cyclenyl (i.e., the benzene ring and the cyclenyl share two adjacent carbon atoms). Non-limiting examples of benzocyclenyl include:

[0263] The term "benzheterocyclic group" means that a benzene ring is fused to a heterocyclic group (i.e., the benzene ring and the heterocyclic group share two adjacent carbon atoms). Non-limiting examples of benzheterocyclic groups include:

[0264] The term "benzheterocycloalkyl" means that a benzene ring is fused to a heterocycloalkyl (i.e., the benzene ring and the heterocycloalkyl share two adjacent carbon atoms). Non-limiting examples of benzheterocycloalkyl include:

[0265] The term "heterocyclenyl" refers to an unsaturated cyclic group that contains at least one carbon-carbon double bond or carbon-nitrogen double bond and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle usually contains 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and / or nitrogen. Non-limiting examples of heterocyclenyl include: 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 3-pyrrolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl, dihydrothiophenyl and dihydrothiopyranyl.

[0266] The term "benzheterocyclenyl" means that a benzene ring is fused to a heterocyclenyl (i.e., the benzene ring and the heterocyclenyl share two adjacent carbon atoms). Non-limiting examples of benzheterocyclenyl include:

[0267] The term "fused heterocycle" refers to a polycycle having 7 to 20 members in which two rings share two adjacent atoms, containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and at least one ring having a fully conjugated π electron system but not being aromatic as a whole. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused rings, preferably bicyclic or tricyclic, more preferably 6-membered / 6-membered or 5-membered / 6-membered bicyclic. Non-limiting examples of fused heterocycles include:

[0268] The term "treatment" means administering the compounds or formulations described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0269] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0270] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0271] The term "prevention" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0272] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present application that (i) treats or prevents a specific disease, condition or disorder described herein, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0273] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, without undue toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0274] As pharmaceutically acceptable salts, for example, mention may be made of 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, etc.

[0275] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0276] The term "pharmaceutically acceptable excipient" refers to those excipients that have no significant irritating effect on an organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0277] The word "comprise" or "comprising" and its English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0278] Unless otherwise specifically stated, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specifically stated, the word "a" or "an" means "at least one" or "at least one kind". Unless otherwise stated, the use of "or" means "and / or".

[0279] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0280] Unless otherwise indicated, “(D)” or “(+)” represents dextrorotatory, “(L)” or “(-)” represents levorotatory, and “(DL)” or “(±)” represents racemic.

[0281] Unless otherwise indicated, a solid wedge bond and a dashed wedge bond represent the absolute configuration of a stereocenter, and a solid straight bond and a dashed straight bond represent the relative configuration of a stereocenter.

[0282] The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereoisomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereoisomeric salts are formed with a suitable optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0283] This application also includes isotopically labeled compounds of this application that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N,15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0284] Certain isotopically labeled compounds of the present application (e.g., those labeled with 3 H and 14 C) can be used in the analysis of the tissue distribution of compounds and / or substrates. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting unlabeled reagents with isotopically labeled reagents through the following procedures similar to those in the protocols and / or examples disclosed below.

[0285] In addition, substitution with heavier isotopes (such as deuterium (i.e., 2 H or D)) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in certain cases, where deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0286] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols, etc.

[0287] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0288] The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0289] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to a patient.

[0290] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0291] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0292] In all methods of administration of the compounds of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, in single or divided doses.

[0293] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the same with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0294] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0295] An important consideration in the synthesis route planning in the art is to select a suitable protecting group for reactive functional groups (such as amino groups in the present application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., and all references cited in the present application are incorporated herein by reference in their entirety.

[0296] For purposes of description and disclosure, all patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference. These publications are provided solely because their disclosures predated the filing date of the present application. All statements as to the dates of these documents or the representation as to the content of these documents are based on the information available to the applicant and do not constitute any admission as to the dates or the correctness of the content of these documents. Moreover, in any country, any reference to these publications in this application does not constitute an admission that such publication is part of the common general knowledge in the art.

[0297] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:

[0298] Route 1:

[0299]

[0300] Wherein,

[0301] Ring A, R c , R 3 , n are defined as described above. Route 2:

[0302]

[0303] Wherein,

[0304] Ring A, R 3 , n are defined as described above.

[0305] Route 3:

[0306]

[0307] Wherein,

[0308] Ring A, R 3 , n are defined as described above.

[0309] The present application uses the following abbreviations:

[0310] PBS represents fetal bovine serum; PBS represents phosphate buffered saline; PBST represents phosphate Tween buffer; BSA represents bovine serum albumin; GAPDH represents glyceraldehyde-3-phosphate dehydrogenase; DMSO represents dimethyl sulfoxide; DTT represents dithiothreitol; HTRF represents homogeneous time-resolved fluorescence. Detailed Description of the Invention

[0311] For clarity, the present invention is further illustrated by examples, but the examples do not limit the scope of the present application. It will be obvious to those skilled in the art that various changes and improvements can 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 this application are commercially available and can be used without further purification.

[0312] Example 1: Preparation of Compound 1

[0313]

[0314] Step A: Preparation of Compound 1-1

[0315] Methyl 2-amino-4-methoxybenzoate (4 g) and absolute ethanol (16 mL) were added to a 250 mL three-necked flask. Water (28 mL) and concentrated hydrochloric acid (7 mL) were added respectively under stirring at room temperature. The reaction mixture was cooled to 0 °C in an ice bath under 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 solution was transferred to room temperature and stirred overnight. Water (100 mL) was added to the reaction solution, and it was vigorously stirred for 5 min. The mixture was filtered by suction, and the filter cake was washed with water (20 mL). The solid was collected and slurried with petroleum ether (50 mL) to obtain 6.45 g of Compound 1-1.

[0316] MS (ESI, [M+H] + ): m / z = 307.81.

[0317] 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.99 (s, 1H), 6.38 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H).

[0318] Step B: Preparation of Compound 1-2

[0319] Compound 1-1 (15 g) obtained in Step A, acetonitrile (100 g), and methanesulfonic acid (37.6 g) were successively added to a 350 mL pressure-resistant flask. The reaction flask was placed in an oil bath at 120 °C and stirred for 6 h. The reaction was stopped, and the reaction solution was concentrated to dryness under reduced pressure. Water (150 mL) was added to the residual solid, and it was vigorously stirred. The pH was adjusted to alkaline with 2.5 M aqueous sodium hydroxide solution. The mixture was filtered by suction, and the filter cake was washed with a large amount of water. The solid was collected, dried, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain 5.9 g of Compound 1-2.

[0320] MS (ESI, [M+H] + ): m / z = 316.79.

[0321] 11H NMR (500 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 8.37 (s, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 2.32 (s, 3H).

[0322] Step C: Preparation of Compound 1-3

[0323] Add the compound 1-2 (1 g) obtained in Step B and chloroform (10 mL) to a 25 mL three-necked flask. While stirring at room temperature, add thionyl chloride (2.94 g) and two drops of N,N-dimethylformamide in sequence. Heat the reaction solution to 70 °C and stir for 3 h. Concentrate the reaction solution to dryness. Add water (40 mL) and dichloromethane (50 mL) to the residue. While stirring vigorously, add saturated aqueous sodium bicarbonate solution to adjust the pH value to weakly alkaline. Separate the layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter by suction, concentrate the residue, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 0.41 g of compound 1-3.

[0324] MS (ESI, [M+H] + ): m / z = 334.77.

[0325] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.42 (s, 1H), 7.18 (s, 1H), 3.98 (s, 3H), 2.50 (s, 3H).

[0326] Step D: Preparation of Compound 1-4

[0327] Add the 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) to a 25 mL single-necked flask. Under nitrogen protection, heat the mixture to 100 °C and stir for 5 h. Stop the reaction. Concentrate the reaction solution to dryness. Dissolve the residue in dichloromethane (20 mL), and wash it with saturated aqueous sodium bicarbonate solution, 1 M hydrochloric acid, and saturated brine respectively. Dry over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) on the residue to obtain 160 mg of compound 1-4.

[0328] MS (ESI, [M+H] + ): m / z = 434.00.

[0329] 1 1H NMR (500 MHz, DMSO-d 6)δ8.88(s,1H),8.29(d,J=8.0Hz,1H),7.28–7.16(m,3H),7.05-7.03(m,2H),5.58(p,J=7.0Hz,1H),3.92(s,3H),2.36(s,3H),2.29(s,3H),1.54(d,J=7.0Hz,3H).

[0330] Step E: Preparation of Compound 1

[0331] Add the compound 1-4 (0.09 g) obtained in Step D, dimethylphosphine oxide (0.017 g), triethylamine (0.032 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.13 mg), tris(dibenzylideneacetone)dipalladium (4.85 mg) and 1,4-dioxane (2 mL) into a 15 mL pressure-resistant tube. Heat the reaction mixture to 120 °C under nitrogen protection and stir for 2 h. Cool the reaction solution to room temperature, filter it by suction, concentrate the filtrate to dryness, and purify the residue by chromatography on a C18 column (120 g) (40% acetonitrile + 60% water) to obtain 58.5 mg of Compound 1.

[0332] HRMS(ESI,[M+H] + ):m / z=384.1855.

[0333] 1 H NMR(500MHz,DMSO-d 6 )δ8.80(d,J=8.0Hz,1H),8.76(d,J=13.6Hz,1H),7.32(s,1H),7.30(d,J=7.8Hz,1H),7.24(t,J=7.5Hz,1H),7.14(d,J=4.7Hz,1H),7.06(d,J=7.3Hz,1H),5.67(p,J=7.1Hz,1H),3.99(s,3H),2.43(s,3H),2.33(s,3H),1.75(s,3H),1.72(s,3H),1.60(d,J=7.1Hz,3H).

[0334] Example 2: Preparation of Compound 2

[0335]

[0336] Step A: Preparation of Compound 2-1

[0337] Refer to the method of Step D in Example 1, and react Compound 1-3 with (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine to prepare Compound 2-1.

[0338] MS(ESI,[M+H]+ ): m / z = 487.94.

[0339] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.86 (s, 1H), 8.39 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 5.62 (p, J = 7.1 Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H), 1.60 (d, J = 7.1 Hz, 3H).

[0340] Step B: Preparation of Compound 2

[0341] Referring to the method of Step E in Example 1, Compound 2 was prepared.

[0342] HRMS (ESI, [M + H] + ): m / z = 438.1599.

[0343] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.88 (d, J = 7.8 Hz, 1H), 8.76 (d, J = 13.6 Hz, 1H), 7.91 (s, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.15 (d, J = 4.8 Hz, 1H), 5.70 (p, J = 7.1 Hz, 1H), 3.99 (s, 3H), 2.42 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H).

[0344] Example 3: Preparation of Compound 3

[0345]

[0346] Step A: Preparation of Compound 3-1

[0347] Referring to the method of Step D in Example 1, Compound 1-3 was reacted with (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethan-1-ol to prepare Compound 3-1.

[0348] MS (ESI, [M + H] + ): m / z = 499.95.

[0349] 1 H NMR (500 MHz, DMSO-d6 )δ8.87(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,1H),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).

[0350] Step B: Preparation of Compound 3

[0351] Compound 3 was prepared by referring to the method of Step E in Example 1.

[0352] HRMS(ESI, [M+H] + ): m / z=450.1728.

[0353] 1 H NMR(500MHz, DMSO-d 6 )δ8.88(d,J=7.9Hz,1H),8.76(d,J=13.6Hz,1H),7.72(s,1H),7.65(d,J=7.6Hz,1H),7.48(t,J=7.7Hz,1H),7.42(d,J=7.7Hz,1H),7.15(d,J=4.7Hz,1H),5.75–5.64(m,2H),4.00(s,3H),3.88(td,J=14.1,4.3Hz,2H),2.44(s,3H),1.76(s,3H),1.73(s,3H),1.65(d,J=7.1Hz,3H).

[0354] Example 4: Preparation of Compound 4

[0355]

[0356] Step A: Preparation of Compound 4-1

[0357] Compound 4-1 was prepared by reacting Compound 1-3 with (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine by referring to the method of Step D in Example 1.

[0358] MS(ESI, [M+H] + ): m / z=484.4.

[0359] 1 H NMR(500MHz, DMSO-d 6)δ8.90(s,1H),8.46(d,J=7.3Hz,1H),7.66(d,J=7.7Hz,1H),7.38(d,J=7.5Hz,1H),7.30(dd,J=13.8,6.1Hz,1H),7.21(s,1H),7.02(s,1H),5.73(p,J=7.0Hz,1H),3.91(s,3H),2.55(s,3H),2.33(s,3H),1.52(d,J=7.0Hz,3H).

[0360] Step B: Preparation of Compound 4

[0361] Compound 4 was prepared by referring to the method of Step E in Example 1.

[0362] MS(ESI, [M+H] + ): m / z = 434.17.

[0363] 1 H NMR(500MHz, CDCl 3 )δ8.41(d,J=13.8Hz,1H),7.54(d,J=7.8Hz,1H),7.43(d,J=7.6Hz,1H),7.28 - 7.27(m,1H),7.12(d,J=5.0Hz,1H),6.83(t,J=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).

[0364] Example 5: Preparation of Compound 5

[0365]

[0366] Step A: Preparation of Compound 5-1

[0367] Compound 1-3 was reacted with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethan-1-amine by referring to the method of Step D in Example 1 to prepare Compound 5-1.

[0368] MS(ESI, [M+H] + ): m / z = 502.25.

[0369] 1 H NMR(500MHz, CDCl 3)δ8.14(s,1H),7.50–7.41(m,2H),7.14(t,J=7.7Hz,1H),7.06(s,1H),5.88–5.68(m,2H),3.96(s,3H),2.52(s,3H),2.02(td,J=1.1,18.6Hz,3H),1.70(s,3H).

[0370] Step B: Preparation of Compound 5

[0371] Referring to the method in Step E of Example 1, Compound 5 was prepared.

[0372] MS(ESI, [M+H] + ): m / z = 452.5.

[0373] 1 H NMR(500MHz, CDCl 3 )δ8.48(d,J=13.8Hz,1H),7.51–7.46(m,1H),7.43(td,J=1.7,7.5Hz,1H),7.15–7.09(m,2H),6.44(d,J=7.2Hz,1H),5.85(p,J=7.0Hz,1H),3.97(s,3H),2.52(s,3H),2.07–1.97(m,3H),1.82(s,3H),1.79(s,3H),1.66(d,J=7.0Hz,3H).

[0374] Example 6: Preparation of Compound 6

[0375]

[0376] Step A: Preparation of Compound 6-1

[0377]

[0378] Step a: Preparation of Compound 6-1-1

[0379] Add ethyl 2-(3-bromophenyl)acetate (10 g) and anhydrous tetrahydrofuran (100 mL) to a 250 mL three-necked flask. Under nitrogen protection, cool the temperature to -78 °C. Drop lithium bis(trimethylsilyl)amide (103 mL, 1 mol / L) into the reaction solution, react for 30 min, and maintain -78 °C. Then slowly drop a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (25.9 g) in anhydrous tetrahydrofuran (50 mL) into the reaction system. After the addition is complete, restore to room temperature and continue stirring the reaction for 2 h. After the reaction is completed, add water (100 mL) to the reaction solution and stir vigorously, then extract twice with ethyl acetate (100 mL), evaporate to dryness, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 97:3) to obtain 10.1 g of compound 6-1-1.

[0380] 19 F-NMR (471 MHz, Methanol-d 4 ) δ -105.17 -105.60 (m).

[0381] 1 H-NMR (500 MHz, Methanol-d 4 ) δ 7.76–7.69 (m, 2H), 7.57 (m, 1H), 7.44 (m, 1H), 4.31 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0382] Step b: Preparation of compound 6-1-2

[0383] Add the compound 6-1-1 (9 g) obtained in step a and anhydrous tetrahydrofuran (200 mL) to a 500 mL three-necked flask. Under nitrogen protection, cool the temperature to -78 °C. Slowly drop methylmagnesium bromide (22 mL, 3 mol / L) into the reaction solution. After the addition is complete, restore to 0 °C and continue stirring the reaction for 1 h. After the reaction is completed, add saturated ammonium chloride aqueous solution (100 mL) to the reaction solution and stir vigorously, then extract twice with ethyl acetate (100 mL), combine the organic phases, wash once with water (100 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and obtain 7.0 g of compound 6-1-2.

[0384] Step c: Preparation of compound 6-1-3

[0385] Add the compound 6-1-2 (6.8 g) obtained in step b, 1,4-dioxane (150 mL), tributyl(1-ethoxyvinyl)tin (18.53 g), bis(triphenylphosphine)palladium dichloride (1.811 g), and triethylamine (7.77 g) to a 250 mL three-necked flask. Under nitrogen protection, heat in an oil bath to 100 °C and react for 3 h. Cool down, evaporate to dryness, and obtain 20.0 g of compound 6-1-3.

[0386] MS (ESI, [M+H] + ): m / z = 257.1.

[0387] Step d: Preparation of Compound 6-1-4

[0388] Add Compound 6-1-3 (20 g) obtained in Step c, tetrahydrofuran (20 mL), and dilute hydrochloric acid (19 mL, 4 mol / L) to a 250 mL single-necked flask, and react at room temperature for 2.5 h. After the reaction is completed, add water (200 mL) to the reaction solution and stir vigorously, then extract once with ethyl acetate (100 mL), evaporate to dryness, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3.3 g of Compound 6-1-4.

[0389] MS (ESI, [M+H] + ): m / z = 229.1.

[0390] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.14–8.04 (m, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.79–7.69 (m, 1H), 7.63 (t, J = 7.8 Hz, 1H), 2.62 (s, 3H), 1.18 (d, J = 1.5 Hz, 6H).

[0391] Step e: Preparation of Compound 6-1-5

[0392] Add 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) to a 100 mL three-necked flask, protect with nitrogen, and heat to 80 °C in an oil bath for 4.5 h. After the reaction is completed, add water (50 mL) to the reaction solution and stir vigorously, filter, wash the filter cake three times with ethyl acetate (20 mL), separate the organic phase, evaporate to dryness, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 - 5:1) to obtain 4.2 g of Compound 6-1-5.

[0393] MS (ESI, [M+H] + ): m / z = 332.2.

[0394] 1 1H NMR (500 MHz, Methanol-d 4 ) δ 8.13 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.75–7.650 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H), 1.28–1.23 (m, 6H).

[0395] Step f: Preparation of Compound 6-1-6

[0396] Add the compound 6-1-5 (4.2 g) obtained in step e and anhydrous tetrahydrofuran (40 mL) to a 100 mL three-necked flask. Cool the temperature to -78 °C, and dropwise add lithium tri-sec-butylborohydride (28.4 mL, 1 mol / L) to the reaction system. Stir the mixture at -78 °C for 2 h. After the reaction is completed, add saturated ammonium chloride aqueous solution (20 mL) to the reaction solution and stir vigorously for 2 min. Warm up to room temperature, let it stand for liquid separation, separate the organic phase, rotary evaporate it, and perform silica gel column chromatography (methylene chloride:methanol = 98:2) to obtain 2.5 g of compound 6-1-6.

[0397] MS (ESI, [M+H] + ): m / z = 334.0.

[0398] 1 H NMR (500 MHz, Methanol-d 4 ) δ 7.53 (d, J = 1.9 Hz, 1H), 7.47–7.35 (m, 3H), 4.59–4.49 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 1.2 Hz, 6H), 1.20 (s, 9H).

[0399] Step g: Preparation of Compound 6-1

[0400] Add the compound 6-1-6 (2.3 g) obtained in step e and 1,4-dioxane hydrochloric acid solution (8 mL, 4 mol / L) to a 100 mL single-necked flask. React at room temperature for 2 h. After the reaction is completed, rotary evaporate it to obtain 2.0 g of compound 6-1.

[0401] 1 H NMR (500 MHz, Methanol-d 4 ) δ 7.63 (d, J = 1.8 Hz, 1H), 7.63–7.53 (m, 2H), 7.54 (d, J = 6.4 Hz, 1H), 4.58–4.48 (m, 1H), 1.66 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 1.6 Hz, 6H).

[0402] Step B: Preparation of Compound 6-2

[0403] Referring to the method of step D in Example 1, react compound 1-3 with compound 6-1 obtained in step A to prepare compound 6-2.

[0404] MS (ESI, [M+H] +): m / z = 527.98.

[0405] Step C: Preparation of Compound 6

[0406] Compound 6 was prepared by referring to the method in Step E of Example 1.

[0407] MS (ESI, [M+H] + ): m / z = 478.09.

[0408] 1 H NMR (500 MHz, Methanol-d 4 ) δ 8.58 (d, J = 14.0 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J = 4.2 Hz, 1H), 7.38 (d, J = 4.8 Hz, 2H), 7.09 (d, J = 5.0 Hz, 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 = 7.0 Hz, 3H), 1.21 (s, 6H).

[0409] Example 7: Preparation of Compound 7

[0410]

[0411] Step A: Preparation of Compound 7-1

[0412] Compound 7-1 was prepared by reacting Compound 1-3 with (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine by referring to the method in Step D of Example 1.

[0413] MS (ESI, [M+H] + ): m / z = 532.89.

[0414] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.82 (s, 1H), 8.61 (s, 1H), 8.48 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 11.2 Hz, 2H), 7.04 (s, 1H), 5.65 (p, J = 7.0 Hz, 1H), 3.92 (s, 3H), 2.34 (s, 3H), 1.65 (d, J = 7.1 Hz, 3H).

[0415] Step B: Preparation of Compound 7-2

[0416] Compound 7-2 was prepared by referring to the method in Step E of Example 1.

[0417] MS (ESI, [M+H] + ): m / z = 483.08.

[0418] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.92 (d, J = 7.6 Hz, 1H), 8.76 - 8.73 (m, 2H), 8.41 - 8.39 (m, 2H), 7.16 (d, J = 4.7 Hz, 1H), 5.72 (p, J = 7.1 Hz, 1H), 3.98 (d, J = 9.8 Hz, 3H), 2.41 (s, 3H), 1.79–1.70 (m, 9H).

[0419] Step C: Preparation of Compound 7

[0420] Add the compound 7-2 (100 mg) obtained in Step B, tetrahydrofuran (15 mL) and water (5.00 mL) to a 50 mL three-necked flask, stir at room temperature, add ammonium chloride (444 mg) and zinc powder (203 mg) thereto, place the reaction flask in an oil bath at 70 °C, and stir the reaction for 5 h. Stop the reaction, cool the reaction solution to room temperature, add saturated brine (15 mL) to the reaction solution, extract with ethyl acetate (15 mL × 2), dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (methanol:dichloromethane = 7:93) to obtain 32 mg of Compound 7.

[0421] HRMS (ESI, [M+H] + ): m / z = 453.1675.

[0422] 1 H NMR (500 MHz, CDCl 3 ) δ 8.55 (d, J = 13.9 Hz, 1H), 7.14 (d, J = 5.1 Hz, 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, 1.7 Hz, 6H), 1.61 (d, J = 7.0 Hz, 3H).

[0423] Example 8: Preparation of Compound 8

[0424]

[0425] Step A: Preparation of Compound 8-1

[0426] Referring to the method of Step D in Example 1, react Compound 1-3 with (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-amine to prepare Compound 8-1.

[0427] MS(ESI, [M+H] + ): m / z = 546.88.

[0428] 1 H NMR(500MHz, CD 3 OD) δ8.77(s, 1H), 8.57(d, J = 2.3Hz, 1H), 8.34(d, J = 2.3Hz, 1H), 6.94(s, 1H), 5.75(q, J = 7.0Hz, 1H), 4.87(s, 1H), 3.96(s, 3H), 2.81(s, 3H), 2.35(s, 3H), 1.65(d, J = 7.1Hz, 3H).

[0429] Step B: Preparation of Compound 8-2

[0430] Referring to the method of Step E in Example 1, prepare Compound 8-2.

[0431] MS(ESI, [M+H] + ): m / z = 497.08.

[0432] 1 H NMR(500MHz, CD 3 OD) δ8.65(d, J = 14.0Hz, 1H), 8.60(d, J = 2.3Hz, 1H), 8.35(d, J = 2.3Hz, 1H), 5.80(q, J = 7.0Hz, 1H), 4.02(s, 3H), 2.82(s, 3H), 2.39(s, 3H), 1.86(d, J = 14.0Hz, 6H), 1.69(d, J = 7.0Hz, 3H).

[0433] Step C: Preparation of Compound 8

[0434] Into a 25 mL single-necked flask, sequentially add the compound 8-2 (0.16 g) obtained in step B, methanol (10 mL), water (2 mL), and tetrahydroxy diboron (0.231 g), stir for 10 min, add thereto a solution of sodium hydroxide (0.129 g) in water (2 mL), and stir overnight at room temperature. Pour the reaction solution into water (20 mL), adjust the pH to 7-8 with saturated sodium bicarbonate solution, add ethyl acetate (10 mL) for liquid separation, take the organic phase, extract the aqueous phase with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated brine (10 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 120 mg of compound 8.

[0435] MS(ESI, [M+H] + ): m / z = 467.16.

[0436] 1 H NMR(500 MHz, CD 3 OD) δ 8.61 (s, 1H), 7.08 (d, J = 5.1 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.75 (q, J = 6.9 Hz, 1H), 4.86 (s, 3H), 4.01 (s, 3H), 2.45 (t, J = 2.9 Hz, 6H), 1.84 (dd, J = 14.0, 4.3 Hz, 6H), 1.59 (d, J = 7.0 Hz, 3H).

[0437] Example 9: Preparation of Compound 9

[0438]

[0439] Step A: Preparation of Compound 9-1

[0440] Into a 500 mL pressure-resistant flask, add 5-amino-2-chloroisonicotinic acid (15 g), ammonium acetate (67.0 g), triethyl orthoacetate (141 g), and methanol (100 mL), place the mixture in an oil bath at 125 °C and stir for reaction for 9 h. Stop the reaction, cool the reaction solution to room temperature, perform suction filtration, wash the filter cake with ethyl acetate (50 mL), and collect the solid and dry it to obtain 8.1 g of compound 9-1.

[0441] MS(ESI, [M-H] - ): m / z = 194.1.

[0442] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 7.90 (s, 1H), 2.38 (s, 3H).

[0443] Step B: Preparation of Compound 9-2

[0444] Add the compound 9-1 (10 g) obtained in Step A, 2,4,6-triisopropylbenzenesulfonyl chloride (18.58 g), triethylamine (15.52 g), 4-dimethylaminopyridine (0.625 g) and dichloromethane (100 mL) to a 250 mL single-necked flask. The mixture is stirred at room temperature overnight. Stop the reaction, pour the reaction solution into water (50 mL), separate the layers, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter by suction, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 9.7 g of compound 9-2.

[0445] Step C: Preparation of Compound 9-3

[0446] Add the 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) to a 25 mL single-necked flask. Under nitrogen protection, stir the mixture at room temperature for 2 h. Stop the reaction, pour the reaction solution into water (100 mL), extract with dichloromethane (30 mL × 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain 2.2 g of compound 9-3.

[0447] MS (ESI, [M+H] + ): m / z = 367.26.

[0448] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.87–8.80 (m, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 7.78-7.76 (t, J = 6.6 Hz, 1H), 7.62-7.56 (m, 2H), 5.62 (p, J = 7.1 Hz, 1H), 2.43 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H).

[0449] Step D: Preparation of Compound 9

[0450] Refer to the method of Step E in Example 1 to prepare compound 9.

[0451] MS (ESI, [M+H] + ): m / z = 409.4.

[0452] 1 H NMR (500 MHz, DMSO-d 6)δ9.25(d, J = 7.6Hz, 1H), 9.09(s, 1H), 8.93(d, J = 6.4Hz, 1H), 7.86(s, 1H), 7.79(d, J = 7.3Hz, 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).

[0453] Example 10: Preparation of Compound 10

[0454]

[0455] Step A: Preparation of Compound 10-1

[0456] Add the 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 (0.090 g) and 1,4-dioxane (10 mL) into a 25 mL three-necked flask. Stir and react at 100 °C for 1 h under nitrogen protection. Cool the reaction solution to room temperature, filter by suction, concentrate the filtrate to dryness, and obtain 0.94 g of compound 10-1 by silica gel column chromatography (dichloromethane:methanol = 95:5).

[0457] MS (ESI, [M + H] + ): m / z = 614.40.

[0458] 1 H NMR (500 MHz, DMSO-d 6 ) δ8.86(d, J = 7.5Hz, 1H), 8.72–8.65(m, 2H), 8.35 - 8.34(m, 2H), 7.40–7.34(m, 4H), 7.30 - 7.26(m, 1H), 7.14(d, J = 4.7Hz, 1H), 5.68(p, J = 7.1Hz, 1H), 3.99(s, 3H), 3.69(s, 2H), 3.04 - 2.96(m, 2H), 2.88 - 2.82(m, 2H), 2.48 - 2.45(m, 2H), 2.37(s, 3H), 1.83 - 1.76(m, 2H), 1.67(d, J = 7.1Hz, 3H).

[0459] Step B: Preparation of Compound 10-2

[0460] Add the compound 10-1 (0.699 g) obtained in step A and 1,2-dichloroethane (10 mL) to a 25 mL three-necked flask, stir in an ice-water bath, add 1-chloroethyl chloroformate (0.195 g) thereto, and reflux the mixture for 2 h. Concentrate the reaction solution to dryness, add methanol (5 mL) to the residue, heat under reflux and stir for 15 min. Concentrate the reaction solution to dryness, and subject the residue to silica gel column chromatography (dichloromethane:methanol = 94:6) to obtain 348 mg of compound 10-2.

[0461] MS(ESI, [M+H] + ): m / z = 524.07.

[0462] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.85 (d, J = 7.5 Hz, 1H), 8.71–8.65 (m, 2H), 8.35 (d, J = 6.7 Hz, 2H), 7.12 (d, J = 4.6 Hz, 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 = 7.1 Hz, 3H).

[0463] Step C: Preparation of compound 10-3

[0464] Add the compound 10-2 (150 mg) obtained in step B, tetrahydrofuran (1 mL), triethylamine (87 mg) and acetic anhydride (32.2 mg) to a 10 mL single-necked flask, and stir the reaction solution at room temperature for 1 h. Add water (10 mL) to the reaction solution, stir at room temperature for 5 min, extract with dichloromethane (15 mL × 2), dry over anhydrous sodium sulfate, concentrate, and subject the residue to silica gel column separation and purification (dichloromethane:methanol = 96:4) to obtain 144 mg of compound 10-3.

[0465] MS(ESI, [M+H] + ): m / z = 566.03.

[0466] 1 H NMR(500 MHz, DMSO-d 6)δ8.91(dd,J=7.2,5.3Hz,1H),8.70(dd,J=13.8,5.1Hz,1H),8.67(s,1H),8.35(d,J=6.1Hz,2H),7.12(d,J=4.8Hz,1H),5.69-5.67(m,1H),4.46(dd,J=25.9,13.2Hz,1H),4.12–4.00(m,1H),3.91(s,3H),3.74-3.72(m,1H),3.32–3.27(m,1H),2.48–2.39(m,1H),2.39–2.30(m,4H),1.98–1.79(m,2H),1.68(d,J=7.1Hz,3H).

[0467] Step D: Preparation of Compound 10

[0468] Add the compound 10-3 (114 mg) obtained in Step C, tetrahydrofuran (1.5 mL) and ethanol (4.5 mL) to a 25 mL three-necked flask. Add stannous chloride dihydrate (182 mg) under stirring at room temperature. Place the reaction flask in an oil bath at 50 °C and stir for 1 h. Stop the reaction, concentrate the reaction solution to dryness, and purify by silica gel column chromatography (dichloromethane:methanol = 94:6) to obtain 89 mg of Compound 10.

[0469] HRMS(ESI, [M+H] + ):m / z=536.2073.

[0470] 1 H NMR(500MHz,DMSO-d 6 )δ8.76(d,J=7.5Hz,1H),8.68(d,J=13.8Hz,1H),7.12(d,J=4.8Hz,1H),6.91(s,1H),6.86(s,1H),6.70(s,1H),5.61–5.50(m,3H),4.45–4.30(m,1H),4.04-3.96(m,1H),3.91(s,3H),3.77–3.67(m,1H),3.40–3.35(m,1H),2.48–2.29(m,5H),2.12(s,3H),2.03–1.81(m,2H),1.55(d,J=7.1Hz,3H).

[0471] Example 11: Preparation of Compound 11

[0472]

[0473] Step A: Preparation of Compound 11-1

[0474] Referring to the method of Step A in Example 10, using Compound 2-1 obtained in Step A of Example 2, Compound 11-1 was prepared.

[0475] HRMS(ESI, [M+H] + ): m / z = 569.2283.

[0476] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.78 (d, J = 7.7 Hz, 1H), 8.69 (d, J = 13.6 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.39 – 7.34 (m, 4H), 7.31 – 7.24 (m, 1H), 7.13 (d, J = 4.6 Hz, 1H), 5.66 (p, J = 7.1 Hz, 1H), 3.99 (s, 3H), 3.67 (s, 2H), 3.00 - 2.92 (m, 2H), 2.85 (q, J = 11.5 Hz, 2H), 2.48 - 2.45 (m, 2H), 2.38 (s, 3H), 1.82 (t, J = 16.1 Hz, 2H), 1.62 (d, J = 7.1 Hz, 3H).

[0477] Step B: Preparation of Compound 11-2

[0478] Referring to the method of Step B in Example 10, Compound 11-2 was prepared.

[0479] HRMS(ESI, [M+H] + ): m / z = 479.1814.

[0480] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.80 (d, J = 7.7 Hz, 1H), 8.68 (d, J = 13.6 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.11 (d, J = 4.6 Hz, 1H), 5.67 (p, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.17 – 3.06 (m, 4H), 2.43 – 2.34 (m, 5H), 1.79 (t, J = 16.1 Hz, 2H), 1.62 (d, J = 7.1 Hz, 3H).

[0481] Step C: Preparation of Compound 11

[0482] Referring to the method of Step C in Example 10, Compound 11 was prepared.

[0483] HRMS (ESI, [M+H] + ): m / z = 521.1961.

[0484] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.83 (dd, J = 7.6, 2.3 Hz, 1H), 8.70 (dd, J = 13.8, 3.5 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.61–7.53 (m, 2H), 7.12 (d, J = 4.8 Hz, 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 = 7.1 Hz, 3H).

[0485] Example 12: Preparation of Compound 12

[0486]

[0487] Step A: Preparation of Compound 12-1

[0488] Referring to the method of Step A in Example 10, using Compound 4-1 obtained in Step A of Example 4, Compound 12-1 was prepared.

[0489] MS (ESI, [M+H] + ): m / z = 565.55.

[0490] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.73 (d, J = 13.6 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.41–7.33 (m, 5H), 7.33–7.20 (m, 3H), 7.11 (d, J = 4.7 Hz, 1H), 5.80–5.73 (m, 1H), 3.98 (s, 3H), 3.69 (s, 2H), 2.91 (dd, J = 56.9, 16.5 Hz, 4H), 2.55 (s, 3H), 2.49–2.43 (m, 2H), 2.36 (s, 3H), 1.84 (s, 2H), 1.54 (d, J = 7.0 Hz, 3H).

[0491] Step B: Preparation of Compound 12-2

[0492] Compound 12-2 was prepared by referring to the method in Step B of Example 10.

[0493] MS(ESI, [M+H] + ): m / z = 475.18.

[0494] 1 H NMR(500MHz, DMSO-d 6 ) 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).

[0495] Step C: Preparation of Compound 12

[0496] Compound 12 was prepared by referring to the method in Step C of Example 10.

[0497] MS(ESI, [M+H] + ): m / z = 517.12.

[0498] 1 H NMR(500MHz, CDCl 3 ) 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).

[0499] Example 13: Preparation of Compound 13

[0500]

[0501] Referring to the method in Step C of Example 10, compound 12-2 was reacted with N,N-dimethylglycine to prepare compound 13.

[0502] MS(ESI, [M+H] + ): m / z = 560.11.

[0503] 1 H NMR(500 MHz, CDCl 3 ) δ 8.53 (d, J = 14.0 Hz, 1H), 7.59–7.53 (m, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.30–7.23 (m, 1H), 7.09 (d, J = 5.2 Hz, 1H), 6.83 (t, J = 55.5 Hz, 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 = 6.9 Hz, 3H).

[0504] Example 14: Preparation of Compound 14

[0505]

[0506] Referring to the method in Step C of Example 10, compound 12-2 was reacted with cyclopropanecarboxylic acid to prepare compound 14.

[0507] MS(ESI, [M+H] + ): m / z = 543.10.

[0508] 1 H NMR(500 MHz, CDCl 3)δ8.47(d, J = 14.1Hz, 1H), 7.55(d, J = 7.7Hz, 1H), 7.43(d, J = 7.6Hz, 1H), 7.30–7.23(m, 1H), 7.09(d, J = 5.2Hz, 1H), 6.83(t, J = 55.5Hz, 1H), 6.47-6.42(m, 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).

[0509] Example 15: Preparation of Compound 15

[0510]

[0511] Step A: Preparation of Compound 15-1

[0512] Referring to the method in Step A of Example 10, Compound 15-1 was prepared.

[0513] MS(ESI, [M+H] + ): m / z = 583.1.

[0514] 1 H NMR(500MHz, CDCl 3 )δ8.57(dd, J = 3.6, 13.9Hz, 1H), 7.48(d, J = 6.4Hz, 1H), 7.42(t, J = 7.4Hz, 1H), 7.39–7.34(m, 4H), 7.31–7.27(m, 1H), 7.14–7.07(m, 2H), 6.66(d, J = 7.6Hz, 1H), 5.84(p, J = 7.1Hz, 1H), 4.02(d, J = 1.3Hz, 3H), 3.73–3.69(m, 2H), 3.16(dd, J = 12.3, 29.5Hz, 2H), 2.99(dt, J = 9.6, 19.6Hz, 2H), 2.62(td, J = 6.0, 12.7, 13.2Hz, 2H), 2.52(s, 3H), 2.02(t, J = 18.6Hz, 3H), 1.78(ddt, J = 2.9, 14.8, 20.3Hz, 2H), 1.65(d, J = 7.0Hz, 3H).

[0515] Step B: Preparation of Compound 15-2

[0516] Referring to the method in Step B of Example 10, Compound 15-2 was prepared.

[0517] MS(ESI, [M+H] + ): m / z = 493.08.

[0518] 1 H NMR(500MHz, CDCl 3 ) δ8.56(d, J = 13.9Hz, 1H), 7.52–7.47(m, 1H), 7.42(t, J = 7.4Hz, 1H), 7.12(t, J = 7.0Hz, 2H), 6.60(s, 1H), 5.84(p, J = 7.0Hz, 1H), 4.00(s, 3H), 3.40(ddd, J = 3.2, 9.3, 21.8Hz, 4H), 2.52(s, 5H), 2.02(t, J = 18.6Hz, 3H), 1.85(ddt, J = 2.8, 14.6, 20.0Hz, 2H), 1.66(d, J = 7.0Hz, 3H), 1.34–1.20(m, 1H).

[0519] Step C: Preparation of Compound 15

[0520] Referring to the method in Step C of Example 10, Compound 15 was prepared.

[0521] MS(ESI, [M+H] + ): m / z = 535.13.

[0522] 1 H NMR(500MHz, CDCl 3 ) δ8.55(dd, J = 3.3, 14.2Hz, 1H), 7.49(q, J = 6.8Hz, 1H), 7.46–7.40(m, 1H), 7.12(dd, J = 6.3, 11.4Hz, 2H), 6.65(dd, J = 4.3, 7.3Hz, 1H), 5.84(pd, J = 2.7, 6.7Hz, 1H), 4.92(dd, J = 13.7, 28.7Hz, 1H), 4.20–4.08(m, 1H), 3.93(s, 3H), 3.89(dd, J = 6.6, 13.9Hz, 1H), 3.36(td, J = 6.6, 13.0Hz, 1H), 2.52(d, J = 1.9Hz, 3H), 2.45(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).

[0523] Example 16: Preparation of Compound 16

[0524]

[0525] Referring to the method of Step C in Example 10, Compound 16 was prepared by reacting Compound 15-2 with N,N-dimethylglycine.

[0526] MS(ESI, [M+H] + ): m / z = 578.14.

[0527] 1 H NMR(500MHz, CDCl 3 ) δ8.55(dd, J = 4.3, 14.2Hz, 1H), 7.49(q, J = 7.5Hz, 1H), 7.43(t, J = 7.4Hz, 1H), 7.12(d, J = 5.4Hz, 2H), 6.56(d, J = 6.6Hz, 1H), 5.85(td, J = 3.3, 7.1Hz, 1H), 4.96(dd, J = 13.6, 29.1Hz, 1H), 4.48(dd, J = 14.0, 27.4Hz, 1H), 3.91(s, 3H), 3.81(td, J = 6.1, 13.3Hz, 1H), 3.40–3.32(m, 2H), 3.09(d, J = 13.2Hz, 1H), 2.58–2.49(m, 5H), 2.35(s, 6H), 2.02(t, J = 18.6Hz, 3H), 1.88(q, J = 12.4, 13.7Hz, 2H), 1.67(d, J = 7.0Hz, 3H).

[0528] Example 17: Preparation of Compound 17

[0529]

[0530] Referring to the method of Step C in Example 10, Compound 17 was prepared by reacting Compound 15-2 with cyclopropanecarboxylic acid.

[0531] MS(ESI, [M+H] + ): m / z = 561.11.

[0532] 1 H NMR(500MHz, CDCl 3)δ8.56(d,J=14.2Hz,1H),7.58–7.38(m,2H),7.18–7.06(m,2H),6.63(d,J=7.0Hz,1H),5.85(p,J=7.0Hz,1H),4.88(dd,J=13.2,28.4Hz,1H),4.54(dd,J=15.2,26.9Hz,1H),3.96(s,1H),3.92(s,3H),2.61–2.54(m,2H),2.52(s,3H),2.03(s,2H),1.86(tt,J=4.5,7.9Hz,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).

[0533] Example 18: Preparation of Compound 18

[0534]

[0535] Step A: Preparation of Compound 18-1

[0536] Referring to the method of Step A in Example 10, using Compound 8-1 obtained in Step A of Example 8, Compound 18-1 was prepared.

[0537] MS(ESI, [M+H] + ): m / z=628.18.

[0538] 1 H NMR(500MHz, CD 3 OD): δ8.65(d,J=14.0Hz,1H),8.57(d,J=2.3Hz,1H),8.35(d,J=2.2Hz,1H),7.39(d,J=7.2Hz,2H),7.34(dd,J=12.5,4.8Hz,3H),7.28(d,J=7.2Hz,1H),7.10(d,J=4.8Hz,1H),5.79(q,J=7.0Hz,1H),4.05(s,3H),3.72(s,2H),3.12(dd,J=26.6,12.6Hz,2H),3.02–2.90(m,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).

[0539] Step B: Preparation of Compound 18-2

[0540] Referring to the method in Step B of Example 10, Compound 18-2 was prepared.

[0541] MS(ESI, [M+H] + ): m / z = 538.09.

[0542] Step C: Preparation of Compound 18-3

[0543] Referring to the method in Step C of Example 10, Compound 18-3 was prepared.

[0544] MS(ESI, [M+H] + ): m / z = 580.07.

[0545] Step D: Preparation of Compound 18

[0546] Referring to the method in Step C of Example 8, Compound 18 was prepared.

[0547] MS(ESI, [M+H] + ): m / z = 550.09.

[0548] 1 H NMR(500MHz, CD 3 OD): δ8.62(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, 3H), 3.87(dd, J = 23.5, 11.3Hz, 1H), 3.50(dd, J = 23.2, 12.5Hz, 1H), 2.65–2.52(m, 2H), 2.44(d, J = 5.8Hz, 6H), 2.23(s, 3H), 2.16–1.99(m, 2H), 1.59(d, J = 7.0Hz, 3H).

[0549] Example 19: Preparation of Compound 19

[0550]

[0551] Step A: Preparation of Compound 19-1

[0552] To a 25 mL single-necked flask, successively add compound 9-1 (0.13 g), N,N-dimethylformamide (1.3 mL), benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (0.45 g), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 g). While stirring at room temperature, add dropwise to the above mixture a mixed solution of (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (0.178 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 g) in N,N-dimethylformamide (1.3 mL). After addition, stir at 50 °C overnight. After the reaction is completed, pour the reaction solution into water (15 mL), extract with ethyl acetate (30 mL), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain 0.14 g of compound 19-1.

[0553] MS (ESI, [M+H] + ) m / z = 385.06.

[0554] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.91 (d, J = 6.8 Hz, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 7.82 (t, J = 6.9 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.72 (m, 1H), 2.38 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H).

[0555] Step B: Preparation of compound 19-2

[0556] To a 10 mL microwave tube, add the 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). After purging with nitrogen, heat to 165 °C at 150 W in a microwave reactor and react for 50 minutes. Filter by suction, pour the filtrate into water (30 mL), extract with ethyl acetate (30 mL × 2), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 97:3) to obtain 0.15 g of compound 19-2.

[0557] MS (ESI, [M+H] +) m / z = 558.16.

[0558] 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.31 (d, J = 6.9 Hz, 1H), 9.13 (s, 1H), 8.99 (d, J = 6.4 Hz, 1H), 7.84 (t, J = 7.0 Hz, 1H), 7.66 (t, J = 7.1 Hz, 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 = 12.0 Hz, 2H), 2.45–2.32 (m, 5H), 1.92 (t, J = 14.6 Hz, 2H), 1.64 (d, J = 7.1 Hz, 3H).

[0559] Step C: Preparation of Compound 19-3

[0560] Add the compound 19-2 (0.15 g) obtained in Step B and 1,2-dichloroethane (14 mL) to a 50 mL single-necked flask. Dropwise add 1-chloroethyl chloroformate (0.077 g) thereto under an ice bath, and heat the mixture to reflux for 2.5 h. Concentrate the reaction solution to dryness, add methanol (5 mL) to the residue, and continue to reflux for 30 minutes. Concentrate the reaction solution to dryness to obtain 0.16 g of Compound 19-3.

[0561] MS (ESI, [M+H] + ) m / z = 468.13.

[0562] 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 9.75–9.44 (m, 2H), 9.38 (s, 1H), 8.04 (t, J = 7.1 Hz, 1H), 7.72 (t, J = 7.0 Hz, 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 = 7.1 Hz, 3H).

[0563] Step D: Preparation of Compound 19

[0564] Under an ice-water bath, methanesulfonyl chloride (0.043 g) was added dropwise to a solution of compound 19-3 (0.16 g) and triethylamine (0.104 g) in tetrahydrofuran (3.2 mL) obtained in step C. After the addition was complete, the reaction was carried out at the same temperature for 2 h. The reaction solution was concentrated to dryness, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by C18 column chromatography (acetonitrile:water = 40:60) to obtain 86 mg of compound 19.

[0565] HRMS(ESI,[M+H] + )m / z=546.13611.

[0566] 1 H NMR(500MHz,CD 3 OD)δ9.11(d,J=0.8Hz,1H),8.85(dd,J=0.9,6.8Hz,1H),7.78–7.73(m,1H),7.59–7.54(m,1H),7.28(t,J=7.8Hz,1H),5.85(q,J=7.1Hz,1H),3.93(m,2H),3.82–3.73(m,2H),2.98(s,3H),2.65(m,2H),2.50(s,3H),2.27–2.18(m,2H),1.73(d,J=7.1Hz,3H).

[0567] 31 P NMR(202MHz,CD 3 OD)δ31.1.

[0568] Example 20: Preparation of Compound 20

[0569]

[0570] Step A: Preparation of Compound 20-1

[0571] Referring to the method of step B in Example 19, compound 20-1 was prepared.

[0572] MS(ESI,[M+H] + )m / z=369.09.

[0573] 1 H NMR(500MHz,DMSO-d 6)δ 12.80 (s, 1H), 9.14 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.37–7.29 (m, 5H), 3.63 (s, 2H), 2.95–2.76 (m, 4H), 2.44 (s, 3H), 2.41–2.31 (m, 2H), 1.94 (t, J = 15.5 Hz, 2H).

[0574] Step B: Preparation of Compound 20-2

[0575] Referring to the method of Step A in Example 19, Compound 20-1 was reacted with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to prepare Compound 20-2.

[0576] MS (ESI, [M+H] + ) m / z = 540.16.

[0577] 1 1H NMR (500 MHz, CDCl 3 ) δ 9.18 (s, 1H), 8.78 (d, J = 6.6 Hz, 1H), 7.48–7.42 (m, 2H), 7.38–7.31 (m, 5H), 7.13 (t, J = 7.7 Hz, 1H), 6.89 (t, J = 55.0 Hz, 1H), 5.78 (p, J = 7.1 Hz, 1H), 3.67 (s, 2H), 3.05–3.00 (m, 4H), 2.57 (s, 4H), 2.05 (s, 3H), 1.68 (d, J = 7.0 Hz, 3H).

[0578] Step C: Preparation of Compound 20-3

[0579] Referring to the method of Step C in Example 19, Compound 20-3 was prepared.

[0580] MS (ESI, [M+H] + ) m / z = 450.16.

[0581] Step D: Preparation of Compound 20

[0582] Referring to the method of Step D in Example 19, Compound 20 was prepared.

[0583] HRMS (ESI, [M+H] + ) m / z = 528.1443.

[0584] 1 1H NMR (500 MHz, DMSO-d 6)δ 9.40 (d, J = 7.2 Hz, 1H), 9.11 (d, J = 4.0 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.36–7.30 (m, 1H), 7.30–7.13 (m, 1H), 5.82 (p, J = 7.0 Hz, 1H), 3.76–3.64 (m, 4H), 3.34 (s, 2H), 3.02 (s, 3H), 2.44 (s, 3H), 2.10 (d, J = 13.7 Hz, 2H), 1.65 (d, J = 7.1 Hz, 3H).

[0585] Example 21: Preparation of Compound 21

[0586]

[0587] Under an ice-water bath, cyclopropanesulfonyl chloride (0.13 g) was added dropwise to a solution of Compound 20-3 (0.1 g) and triethylamine (0.055 g) in dichloromethane (2 mL). After the addition was complete, the reaction was allowed to proceed at this temperature for 20 minutes. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by C18 column chromatography (acetonitrile:water = 40:60) to obtain 49 mg of Compound 21.

[0588] HRMS (ESI, [M+H] + ) m / z = 554.1635.

[0589] 1 H NMR (500 MHz, CD 3 OD) δ 9.11 (s, 1H), 8.85 (dd, J = 6.8, 0.9 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.1 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.00 (m, 1H), 5.87 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H), 1.11 (m, 2H), 1.08 (dt, J = 8.2, 2.2 Hz, 2H).

[0590] Example 22: Preparation of Compound 22

[0591]

[0592] Step A: Preparation of Compound 22-1

[0593] Referring to the method of Step A in Example 19, 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.

[0594] MS(ESI, [M+H] + ) m / z = 377.10.

[0595] 1 H NMR(500MHz, Acetone-d 6 ) δ8.81(s, 1H), 8.26(s, 1H), 7.66(d, J = 7.6Hz, 1H), 7.48(dd, J = 7.6, 1.2Hz, 1H), 7.08(t, J = 7.6Hz, 1H), 5.80(p, J = 7.1Hz, 1H), 4.81(t, J = 16.3Hz, 2H), 2.46(s, 3H), 1.69(d, J = 7.0Hz, 3H).

[0596] Step B: Preparation of compound 22-2

[0597] Referring to the method of Step B in Example 19, compound 22-2 was prepared.

[0598] MS(ESI, [M+H] + ) m / z = 550.13.

[0599] 1 H NMR(500MHz, DMSO-d 6 ) δ9.17(d, J = 7.4Hz, 1H), 9.12(d, J = 0.8Hz, 1H), 8.99(d, J = 6.4Hz, 1H), 7.60(d, J = 7.5Hz, 1H), 7.51(dd, J = 7.6, 1.4Hz, 1H), 7.35(d, J = 6.0Hz, 3H), 7.27(s, 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, 4H), 2.44(s, 3H), 2.43–2.34(m, 2H), 1.93(t, J = 10.5Hz, 2H), 1.60(d, J = 7.0Hz, 3H).

[0600] Step C: Preparation of compound 22-3

[0601] Referring to the method of Step C in Example 19, compound 22-3 was prepared.

[0602] MS(ESI, [M+H]+ ) m / z = 460.17.

[0603] Step D: Preparation of Compound 22

[0604] Refer to the method in Step D of Example 19 to prepare Compound 22.

[0605] HRMS(ESI, [M+H] + ) m / z = 538.1596.

[0606] 1 H NMR(500MHz, CD 3 OD) 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).

[0607] 31 P NMR(202MHz, CD 3 OD) δ 31.22.

[0608] Example 23: Preparation of Compound 23

[0609]

[0610] Refer to the preparation method of Example 19, and replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to synthesize Compound 23.

[0611] HRMS(ESI, [M+H] + ) m / z = 542.1608.

[0612] 1 H NMR(500MHz, DMSO-d 6)δ9.18(s,1H),8.64(d,J=6.8Hz,1H),7.45(t,J=7.6Hz,2H),7.13(t,J=7.8Hz,1H),6.91-6.90(m,1H),5.82(p,J=7.1Hz,1H),4.07-4.01(m,2H),3.83-3.77(m,2H),2.93(s,3H),2.65-2.58(m,5H),2.20-2.14(m,2H),2.00(t,J=18.6Hz,3H),1.70(d,J=7.0Hz,3H).

[0613] Example 24: Preparation of Compound 24

[0614]

[0615] Step A: Preparation of Compound 24-1

[0616] To a 50 mL single-necked flask, 5-amino-2-chloropyridine-4-carboxylic acid (3 g) and methanol (11.14 g) were added successively. The mixture was stirred in an ice-salt bath, and thionyl chloride (4.14 g) and two drops of N,N-dimethylformamide were added dropwise thereto. After the addition was complete, the mixture was heated to 65 °C and reacted for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate. The layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.8 g of Compound 24-1.

[0617] MS(ESI, [M+H] + ): m / z = 186.97.

[0618] Step B: Preparation of Compound 24-2

[0619] To a 15 mL pressure-resistant flask, Compound 24-1 (1.7 g) obtained in Step A, fluoroacetonitrile (2.69 g), and methanesulfonic acid (7.0 g) were added successively. The reaction was heated to 105 °C and stirred for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature. Water (5 mL) was added to the reaction solution, and the pH was adjusted to alkaline with 4 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (20 mL × 5). The organic phase was dried over anhydrous sodium sulfate, filtered by suction, and concentrated to dryness. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol = 97:3) to obtain 0.43 g of Compound 24-2.

[0620] MS(ESI, [M+H] + ): m / z = 214.02.

[0621] 11H NMR (500 MHz, DMSO-d 6 ) δ 12.90 (br, 1H), 8.93 (s, 1H), 7.99 (s, 1H), 5.40 (s, 1H), 5.31 (s, 1H).

[0622] Step C: Preparation of Compound 24-3

[0623] Referring to the method of Step A in Example 19, Compound 24-3 was prepared.

[0624] MS (ESI, [M+H] + ): m / z = 403.06.

[0625] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 9.13 (d, J = 6.8 Hz, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.1 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 5.74 (m, 1H), 5.26 (m, 2H), 1.64 (d, J = 7.1 Hz, 3H).

[0626] Step D: Preparation of Compound 24-4

[0627] Referring to the method of Step B in Example 19, Compound 24-4 was prepared.

[0628] MS (ESI, [M+H] + ): m / z = 576.11.

[0629] 1 1H NMR (500 MHz, CD 3 OD) δ 9.23 (s, 1H), 8.86 (d, J = 6.5 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (m, 2H), 5.83 (q, J = 7.1 Hz, 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 = 15.5 Hz, 2H), 1.73 (d, J = 7.1 Hz, 3H).

[0630] Step E: Preparation of Compound 24-5

[0631] Referring to the method in Step C of Example 19, Compound 24-5 was prepared.

[0632] MS(ESI, [M+H] + ): m / z = 486.11.

[0633] Step F: Preparation of Compound 24

[0634] Referring to the method in Step D of Example 19, Compound 24 was prepared by reacting Compound 24-5 with methanesulfonyl chloride.

[0635] HRMS(ESI, [M+H] + ): m / z = 564.1277.

[0636] 1 H NMR(500MHz, CD 3 OD) 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), 5.30(m, 2H), 4.01–3.88(m, 2H), 3.82 - 3.74(m, 2H), 2.98(s, 3H), 2.69 - 2.62(m, 2H), 2.27 - 2.20(m, 2H), 1.74(d, J = 7.1Hz, 3H).

[0637] Example 25: Preparation of Compound 25

[0638]

[0639] Step A: Preparation of Compound 25-2

[0640]

[0641] Step a: Preparation of Compound 25-2-1

[0642] Add 2-fluoro-3-(trifluoromethyl)benzoic acid (15 g), N,N-dimethylformamide (100 mL), dimethylhydroxylamine hydrochloride (7.17 g), N,N-diisopropylethylamine (37.3 g) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.9 g) to a 500 mL single-necked flask respectively. Stir the mixture at room temperature for 2.5 h. Stop the reaction, pour the reaction solution into water (500 mL), extract with ethyl acetate (200 mL), wash the organic phase successively with water (200 mL) and saturated brine (100 mL), dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 17.4 g of compound 25-2-1.

[0643] MS(ESI, [M+H] + ) m / z = 252.04.

[0644] 1 H NMR(500 MHz, DMSO-d 6 ) δ 7.93–7.83 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 3.31 (s, 3H), 2.70 (s, 3H).

[0645] Step b: Preparation of compound 25-2-2

[0646] Under 0 °C and nitrogen protection, slowly drop a 1 M solution of methylmagnesium bromide in tetrahydrofuran (29.9 mL) into a stirred solution of compound 25-2-1 (5 g) obtained in step a in super-dry tetrahydrofuran (50 mL). After the addition is complete, heat the mixture to 35 °C and stir for 2 h. Stop the reaction, slowly add saturated ammonium chloride aqueous solution (150 mL) to the reaction solution, stir at room temperature for 10 minutes, let it stand for liquid separation, take the organic phase and dry over anhydrous sodium sulfate, and concentrate to obtain 4 g of compound 25-2-2.

[0647] 1H NMR(500 MHz, DMSO-d 6 ) δ 8.17 - 8.10 (m, 1H), 8.09 - 7.99 (m, 1H), 7.54 (t, J = 7.8 Hz, 1H), 2.64 (d, J = 4.1 Hz, 3H).

[0648] Step c: Preparation of compound 25-2-3

[0649] To a 100 mL single-necked flask, add 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) respectively. Heat the mixture to 80 °C and react for 3 h. Stop the reaction. While stirring the reaction solution at room temperature, add ice water (150 mL) and ethyl acetate (150 mL), stir for 5 minutes, filter by suction, separate the liquid of the filtrate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 5.8 g of compound 25-2-3.

[0650] MS(ESI, [M+H] + ) m / z = 309.97.

[0651] Step d: Preparation of compound 25-2-4

[0652] To a 250 mL three-necked flask, add 25-2-3 (3 g) obtained in step c and tetrahydrofuran (30 mL) in sequence. Under nitrogen protection, cool down to -50 °C, and add sodium borodeuteride (0.731 g) thereto in batches. After addition, keep the temperature and continue to stir and react for 3 h. Drop the reaction solution into heavy water (20 mL) to quench the reaction. The obtained solution is extracted with ethyl acetate (30 mL × 2), the organic phases are combined, dried with anhydrous sodium sulfate, concentrated, and the residue is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain 0.62 g of compound 25-2-4.

[0653] MS(ESI, [M+H] + ) m / z = 313.00.

[0654] 1 H NMR(500 MHz, DMSO-d 6 ) δ 7.89 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 5.89 (s, 1H), 1.43 (s, 3H), 1.10 (s, 9H).

[0655] Step e: Preparation of compound 25-2

[0656] To a 100 mL single-necked flask, add 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) in sequence. Stir the reaction solution at room temperature for 2 h, concentrate the reaction solution under reduced pressure to dryness, and triturate the residue with methyl tert-butyl ether (5 mL) to obtain 0.38 g of compound 25-2.

[0657] MS(ESI, [M-HCl+H] +) m / z = 209.04.

[0658] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.87 (s, 3H), 8.12 (t, J = 7.2 Hz, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 1.57 (s, 3H).

[0659] Step B: Preparation of Compound 25-3

[0660] Referring to the method of Step A in Example 19, Compound 25-3 was prepared from Compound 25-2 prepared in the above Step A and Compound 20-1.

[0661] MS (ESI, [M+H] + ) m / z = 559.14.

[0662] 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 9.13 (s, 1H), 8.99 (d, J = 6.4 Hz, 1H), 7.84 (t, J = 7.1 Hz, 1H), 7.65 (t, J = 7.1 Hz, 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 = 12.1 Hz, 2H), 2.45–2.35 (m, 5H), 1.92 (t, J = 14.7 Hz, 2H), 1.64 (s, 3H).

[0663] Step C: Preparation of Compound 25-4

[0664] Referring to the method of Step C in Example 19, Compound 25-4 was prepared.

[0665] MS (ESI, [M+H] + ): m / z = 469.28.

[0666] Step D: Preparation of Compound 25

[0667] Referring to the method of Step D in Example 19, Compound 25 was prepared by reacting Compound 25-4 with methanesulfonyl chloride.

[0668] HRMS (ESI, [M+H] + ): m / z = 547.1432.

[0669] 11H NMR (500 MHz, CD 3 OD) δ 9.11 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 7.75 (t, J = 7.1 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 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).

[0670] Example 26: Preparation of Compound 26

[0671]

[0672] Step A: Preparation of Compound 26-1

[0673]

[0674] Step a: Preparation of Compound 26-1-1

[0675] Compound 26-1-1 was prepared by replacing 2-fluoro-3-trifluoromethylbenzoic acid with 2-methyl-3-trifluoromethylbenzoic acid according to the method of Step a in Reference Example 25.

[0676] MS (ESI, [M+H] + ) m / z = 248.07.

[0677] 1 1H NMR (500 MHz, CD 3 OD) δ 7.73 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 3.44 (s, 3H), 2.83 (s, 3H), 2.39 (s, 3H).

[0678] Step b: Preparation of Compound 26-1-2

[0679] Compound 26-1-2 was prepared by referring to the method of Step b in Reference Example 25.

[0680] GCMS: [M] + = 202.

[0681] 1 1H NMR (500 MHz, CD 3OD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.77 (dd, J = 8.0, 1.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 2.58 (s, 3H), 2.48 (q, J = 1.8 Hz, 3H).

[0682] Step c: Preparation of Compound 26-1-3

[0683] To a 100 mL three-necked flask, add successively a tetrahydrofuran solution of 1 M lithium bis(trimethylsilyl)amide (17.68 mL) and dry tetrahydrofuran (50 mL). Under nitrogen protection at -74 °C, slowly add a tetrahydrofuran (5 mL) solution of the compound 26-1-2 (2.75 g) obtained in step b to the above reaction solution. The mixture is stirred at -74 °C for 10 minutes. Slowly add trimethylchlorosilane (1.921 g) to the above reaction solution. After 2 minutes, the addition is complete. Stir the reaction at -74 °C for 1 h, then warm up to room temperature and continue the reaction for 20 minutes. After the reaction is completed, add saturated ammonium chloride solution (10 mL) to the reaction solution and stir vigorously for 5 minutes. Extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter by suction, concentrate, dissolve the residue in acetonitrile (50 mL), stir at 0 °C, add a selective fluorine reagent (5.30 g) thereto, warm up to room temperature and continue stirring the reaction for 5 h. After the reaction is completed, concentrate the reaction solution to dryness. Add water (20 mL) to the residue, extract with ethyl acetate (40 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter by suction, concentrate, and purify the obtained residue by silica gel column chromatography (petroleum ether:ethyl acetate = 91:10) to obtain 1.34 g of compound 26-1-3.

[0684] 1 H NMR (500 MHz, CD 3 OD) δ 7.84 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 5.43 (d, J = 46.9 Hz, 2H), 2.50 (q, J = 1.8 Hz, 3H).

[0685] Step d: Preparation of Compound 26-1-4

[0686] Referring to the method of step c in Reference Example 25, react the compound 26-1-3 obtained in the above step c with S-tert-butylsulfinamide to prepare compound 26-1-4.

[0687] MS (ESI, [M + H] + ) m / z = 324.10.

[0688] Step e: Preparation of Compound 26-1

[0689] Under nitrogen protection at -78 °C, 940 mg of the compound 26-1-4 obtained in step d and 10 mL of dry tetrahydrofuran were successively added to a 100 mL three-necked flask. A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (51.0 mL) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at -78 °C for 0.5 h. The reaction was terminated. Saturated ammonium chloride solution (30 mL) was added dropwise to the reaction solution. After vigorous stirring for 10 minutes, the temperature was raised to room temperature. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (methylene chloride:methanol = 98:2) to obtain 360 mg of a yellow oily liquid. To a 100 mL single-necked flask were successively added the above-obtained yellow oily liquid, 1,4-dioxane (20 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.857 mL). After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to dryness, and the residue was triturated with methyl tert-butyl ether (10 mL) to obtain 250 mg of compound 26-1.

[0690] MS (ESI, [M+H] + ) m / z = 221.99.

[0691] 1 H NMR (500 MHz, D 2 O) δ 7.83 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 5.22 (m, 1H), 4.90 (dd, J = 10.8, 3.9 Hz, 1H), 4.86–4.81 (m, 1H), 2.53 (d, J = 1.5 Hz, 3H).

[0692] Step B: Preparation of compound 26-2

[0693] Referring to the method of step A of Example 19, compound 9-1 was replaced with 6-bromo-2-methylquinazolin-4(3H)-one to prepare compound 26-2.

[0694] MS (ESI, [M+H+2] + ) m / z = 444.04.

[0695] Step C: Preparation of compound 26-3

[0696] Referring to the method of step B of Example 19, compound 26-3 was prepared.

[0697] MS (ESI, [M+H] + ) m / z = 571.78.

[0698] Step D: Preparation of Compound 26-4

[0699] Compound 26-4 was prepared by referring to the method in Step C of Example 19.

[0700] MS(ESI, [M+H] + ) m / z = 481.31.

[0701] Step E: Preparation of Compound 26

[0702] Compound 26 was prepared by referring to the method in Step D of Example 19.

[0703] HRMS(ESI, [M+H]+) m / z = 559.1558.

[0704] 1 H NMR(500 MHz, CD 3 OD) δ 8.72 (dd, J = 13.3, 1.7 Hz, 1H), 8.04 (ddd, J = 10.2, 8.5, 1.7 Hz, 1H), 7.70 (dd, J = 8.7, 2.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 6.06 (m, 1H), 4.83 (dd, J = 9.9, 7.9 Hz, 0.5H), 4.73–4.69 (m, 1H), 4.62 (dd, J = 9.9, 4.8 Hz, 0.5H), 3.97 (m, 2H), 3.51 (q, J = 11.8, 10.9 Hz, 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).

[0705] 31 P NMR(202 MHz, CD 3 OD) δ 32.62.

[0706] Example 27: Preparation of Compound 27

[0707]

[0708] Step A: Preparation of Compound 27-1

[0709] Compound 9-1 was replaced with 6-bromo-2-methylquinazolin-4(3H)-one and Compound 27-1 was prepared by referring to the method in Step A of Example 19.

[0710] MS(ESI, [M+H] +)m / z = 410.05.

[0711] Step B: Preparation of Compound 27-2

[0712] Referring to the method of Step B in Example 19, Compound 27-2 was prepared.

[0713] MS(ESI, [M+H] + )m / z = 539.15.

[0714] Step C: Preparation of Compound 27-3

[0715] Referring to the method of Step C in Example 19, Compound 27-3 was prepared.

[0716] MS(ESI, [M+H] + )m / z = 449.15.

[0717] Step D: Preparation of Compound 27

[0718] Referring to the method of Step D in Example 19, Compound 27 was prepared by reacting Compound 27-3 with methanesulfonyl chloride.

[0719] HRMS(ESI, [M+H] + )m / z = 527.1489.

[0720] 1 H NMR(500MHz,CD 3 OD)δ8.80(dd,J = 13.2,1.1Hz,1H),8.20–8.04(m,1H),7.78(dd,J = 8.6,2.4Hz,1H),7.63(t,J = 7.4Hz,1H),7.48(t,J = 6.9Hz,1H),7.23(t,J = 7.7Hz,1H),7.01(t,J = 54.9Hz,1H),5.87(q,J = 7.1Hz,1H),4.05(m,2H),3.62(q,J = 11.1Hz,2H),3.00–2.96(m,3H),2.63–2.53(m,2H),2.49–2.44(m,3H),2.25(t,J = 16.0Hz,2H),1.72(d,J = 7.1Hz,3H).

[0721] Example 28: Preparation of Compound 28

[0722]

[0723] Step A: Preparation of Compound 28-1

[0724] To a 25 mL single-necked flask, 2-amino-4-methoxybenzoic acid (1 g), ethylene glycol monomethyl ether (10 mL), and N-iodosuccinimide (1.48 g) were successively added, and the mixture was stirred at room temperature for 3 h. The reaction was stopped, saturated sodium chloride solution (100 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, concentrated, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2) to obtain 1.34 g of compound 28-1.

[0725] MS (ESI, [M-H] - ) m / z = 291.79.

[0726] 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.98 (s, 1H), 6.35 (s, 1H), 3.78 (s, 3H), 2.57 (s, 2H).

[0727] Step B: Preparation of compound 28-2

[0728] To a 50 mL single-necked flask, the compound 28-1 (1.3 g) obtained in the above step A, 2-methoxyethanol (13 mL), and formamidine acetate (0.924 g) were successively added, and the mixture was stirred at 120 °C for 2 h. The reaction was stopped, cooled to room temperature, filtered by suction, the filter cake was washed with methanol (10 mL), the collected filter cake was slurried with methanol (30 mL), filtered by suction, and the collected filter cake was dried to obtain 0.95 g of compound 28-2. MS (ESI, [M+H] + ) m / z = 302.81

[0729] Step C: Preparation of compound 28-3

[0730] To a 50 mL single-necked flask, the compound 28-2 (0.5 g) obtained in the above step B, N,N-dimethylformamide (10 mL), 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (1.723 g) were successively added, and 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 under stirring at room temperature. After addition, the mixture was stirred at room temperature overnight. The reaction was stopped, purified water (100 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, concentrated, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 0.422 g of compound 28-3.

[0731] MS (ESI, [M+H] +) m / z = 473.97.

[0732] 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.01 (s, 1H), 8.51 (d, J = 7.3 Hz, 1H), 8.36 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.1 Hz, 1H), 7.37–7.12 (m, 2H), 7.10 (s, 1H), 5.81–5.71 (m, 1H), 3.96 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H).

[0733] Step D: Preparation of Compound 28-4

[0734] Referring to the method of Step A in Example 10, using Compound 28-3, Compound 28-4 was prepared.

[0735] MS (ESI, [M+H] + ) m / z = 555.14.

[0736] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.94 (d, J = 7.4 Hz, 1H), 8.81 (d, J = 13.6 Hz, 1H), 8.39 (s, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.1 Hz, 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 = 22.5 Hz, 4H), 1.60 (d, J = 7.1 Hz, 3H).

[0737] Step E: Preparation of Compound 28-5

[0738] Into a 100 mL single-necked flask, acetonitrile (50 mL), ammonium cerium(IV) nitrate (2.471 g), and water (10 mL) were added in sequence. After stirring for 2 minutes until completely dissolved, the Compound 28-4 (0.5 g) obtained in the above Step D was added, and the reaction was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was quenched with saturated aqueous sodium bicarbonate solution. The reaction solution was extracted with dichloromethane (100 mL × 2), and the organic phases were combined and washed successively with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered by suction, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 0.208 g of Compound 28-5.

[0739] MS (ESI, [M+H] + ) m / z = 465.2

[0740] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.93 (d, J = 7.4 Hz, 1H), 8.79 (d, J = 13.5 Hz, 1H), 8.38 (s, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.1 Hz, 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 = 7.2 Hz, 3H), 1.40 (s, 1H).

[0741] Step F: Preparation of Compound 28

[0742] Referring to the method of Step C in Example 10, Compound 28 was prepared by reacting Compound 28-5 with acetic anhydride.

[0743] HRMS (ESI, [M+H] + ) m / z = 507.1772.

[0744] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.97 (d, J = 7.3 Hz, 1H), 8.87–8.77 (m, 1H), 8.39 (d, J = 1.7 Hz, 1H), 7.73–7.63 (m, 1H), 7.50 (t, J = 7.1 Hz, 1H), 7.36–7.12 (m, 3H), 5.86–5.76 (m, 1H), 4.47–4.37 (m, 1H), 4.09–3.99 (m, 1H), 3.94 (s, 3H), 3.81–3.69 (m, 1H), 3.41–3.31 (m, 1H), 2.49–2.30 (m, 2H), 2.13 (s, 3H), 2.03–1.84 (m, 2H), 1.61 (d, J = 7.1 Hz, 3H).

[0745] Example 29: Preparation of Compound 29

[0746]

[0747] Step A: Preparation of Compound 29

[0748] Referring to the method in Step D of Example 19, compound 29 was prepared by reacting compound 28-5 with methanesulfonyl chloride.

[0749] HRMS(ESI, [M+H] + ) m / z = 543.1441.

[0750] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.98 (d, J = 7.4 Hz, 1H), 8.86 (d, J = 14.0 Hz, 1H), 8.40 (s, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.1 Hz, 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 = 13.7 Hz, 2H), 2.09–1.96 (m, 2H), 1.61 (d, J = 7.1 Hz, 3H).

[0751] Example 30: Preparation of Compound 30

[0752]

[0753] Step A: Preparation of Compound 30-1

[0754] To a 15 mL pressure-resistant flask, compound 1-1 (1 g), fluoroacetonitrile (1.923 g), and methanesulfonic acid (2.504 g) were successively added. The reaction flask was placed in an oil bath at 120 °C and stirred for 4 h. The reaction was stopped, and the reaction solution was allowed to cool to room temperature naturally. The reaction solution was concentrated, and the pH was adjusted to alkaline directly with 4 M aqueous sodium hydroxide solution. Filtration was carried out, and the filter cake was washed with a large amount of water. The solid was collected and dried to obtain 0.68 g of compound 30-1.

[0755] MS(ESI, [M+H] + ) m / z = 334.74.

[0756] Step B: Preparation of Compound 30-2

[0757] Referring to the method in Step A of Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to prepare compound 30-2.

[0758] MS(ESI, [M+H] + ) m / z = 505.99.

[0759] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.99 (s, 1H), 8.63 (d, J = 7.3 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 54.4 Hz, 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 = 7.1 Hz, 3H).

[0760] Step C: Preparation of Compound 30-3

[0761] Referring to the method of Step A in Example 10, Compound 30-3 was prepared.

[0762] MS (ESI, [M+H] + ) m / z = 587.20.

[0763] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 9.06 (d, J = 7.4 Hz, 1H), 8.80 (d, J = 13.6 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.40–7.34 (m, 4H), 7.32–7.25 (m, 3H), 7.23 (t, J = 54.5 Hz, 1H), 5.82 (p, J = 7.0 Hz, 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 = 11.7 Hz, 2H), 2.50 - 2.47 (m, 2H), 1.85 (t, J = 16.4 Hz, 2H), 1.62 (d, J = 7.1 Hz, 3H).

[0764] Step D: Preparation of Compound 30-4

[0765] Referring to the method of Step B in Example 10, Compound 30-4 was prepared.

[0766] MS (ESI, [M+H] + ) m / z = 497.16.

[0767] Step E: Preparation of Compound 30

[0768] Referring to the method of Step C in Example 10, Compound 30 was prepared by reacting Compound 30-4 with acetic anhydride.

[0769] HRMS(ESI, [M+H] + ) m / z = 539.1835.

[0770] 1 H NMR(500 MHz, CD 3 OD) δ 8.69 (d, J = 14.3 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.26 - 7.24 (m, 2H), 7.00 (m, 1H), 5.83 (q, J = 7.0 Hz, 1H), 5.24 (dt, J = 48.0, 13.5 Hz, 2H), 4.67 - 4.59 (m, 1H), 4.24 - 4.16 (m, 1H), 4.02 (s, 3H), 3.90 - 3.87 (m, 1H), 3.54 - 3.47 (m, 1H), 2.67–2.54 (m, 2H), 2.24 (s, 3H), 2.20–2.02 (m, 2H), 1.70 (d, J = 7.1 Hz, 3H).

[0771] Example 31: Preparation of Compound 31

[0772]

[0773] Step A: Preparation of Compound 31-1

[0774] Referring to the method of Step B in Reference Example 24, replace Compound 24-1 with methyl 2-amino-5-bromobenzoate to prepare Compound 31-1.

[0775] MS(ESI, [M+H] + ) m / z = 256.94.

[0776] 1 H NMR(500 MHz, DMSO-d 6 ) δ 12.74 (br, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 8.7, 2.3 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 5.36 (s, 1H), 5.26 (s, 1H).

[0777] Step B: Preparation of Compound 31-2

[0778] Referring to the method of Step A in Reference Example 19, prepare Compound 31-2.

[0779] MS(ESI, [M+H] + ) m / z = 428.03.

[0780] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.79 (t, J = 4.9 Hz, 2H), 7.93 (dd, J = 8.9, 1.9 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 54.4 Hz, 1H), 5.83–5.75 (m, 1H), 5.33–5.13 (m, 2H), 1.62 (d, J = 7.0 Hz, 3H).

[0781] Step C: Preparation of Compound 31-3

[0782] Compound 31-3 was prepared by referring to the method of Step B in Example 19.

[0783] MS (ESI, [M+H] + ) m / z = 557.13.

[0784] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 9.08 (d, J = 7.2 Hz, 1H), 8.90 (d, J = 12.2 Hz, 1H), 8.14 (t, J = 9.0 Hz, 1H), 7.81 (dd, J = 8.5, 1.8 Hz, 1H), 7.71 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 6.9 Hz, 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 = 15.6 Hz, 2H), 1.65 (d, J = 7.1 Hz, 3H).

[0785] Step D: Preparation of Compound 31-4

[0786] Compound 31-4 was prepared by referring to the method of Step B in Example 10.

[0787] MS (ESI, [M+H] + ) m / z = 467.20.

[0788] Step E: Preparation of Compound 31

[0789] Referring to the method in Step E of Example 30, compound 31 was prepared by reacting compound 31-4 with acetic anhydride.

[0790] HRMS(ESI, [M+H] + ) m / z = 509.1730.

[0791] 1 H NMR(500MHz, CD 3 OD) δ8.81(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, 1H), 7.48(t, J = 7.0Hz, 1H), 7.24(t, J = 7.7Hz, 1H), 7.00(t, J = 54.9Hz, 1H), 5.85(q, J = 7.0Hz, 1H), 5.27(td, J = 47.5, 13.5Hz, 2H), 4.61–4.47(m, 1H), 4.18 - 4.09(m, 1H), 3.96 - 3.89(m, 1H), 3.62(dd, J = 22.6, 10.9Hz, 1H), 2.57–2.41(m, 2H), 2.29–2.11(m, 5H), 1.72(d, J = 7.1Hz, 3H).

[0792] 31 P NMR(202MHz, CD 3 OD) δ34.37.

[0793] Example 32: Preparation of Compound 32

[0794]

[0795] Step A: Preparation of Compound 32-1

[0796] Referring to the method in Step A of Example 24, 5-amino-2-chloropyridine-4-carboxylic acid was replaced with 2-amino-5-bromo-4-fluorobenzoic acid to prepare compound 32-1.

[0797] MS(ESI, [M+H] + ) m / z = 249.05.

[0798] 1 H NMR(500MHz, DMSO-d 6 ) δ7.90(d, J = 8.1Hz, 1H), 7.01(s, 2H), 6.72(d, J = 11.5Hz, 1H), 3.79(s, 3H).

[0799] Step B: Preparation of Compound 32-2

[0800] Compound 32-2 was prepared by referring to the method in Step B of Reference Example 24.

[0801] 1 H NMR(500MHz,DMSO-d 6 )δ12.78(s,1H),8.35(d,J=7.6Hz,1H),7.69(d,J=9.7Hz,1H),5.36(s,1H),5.27(s,1H).

[0802] Step C: Preparation of Compound 32-3

[0803] Compound 32-3 was prepared by referring to the method in Step A of Reference Example 19.

[0804] MS(ESI,[M+H+2] + )m / z=448.02.

[0805] 1 H NMR(500MHz,DMSO-d 6 )δ8.98(d,J=7.5Hz,1H),8.85(d,J=7.2Hz,1H),7.70(dd,J=7.5Hz,1H),7.65(d,J=9.9Hz,1H),7.52(dd,J=7.1Hz,1H),7.35–7.10(m,2H),5.78(p,J=7.1Hz,1H),5.33–5.11(m,2H),1.62(d,J=7.1Hz,3H).

[0806] Step D: Preparation of Compound 32-4

[0807] Compound 32-4 was prepared by referring to the method in Step B of Reference Example 19.

[0808] MS(ESI,[M+H] + )m / z=575.11.

[0809] 1 H NMR(500MHz,CD 3OD) δ 8.70–8.64 (m, 1H), 7.52 (dd, J = 7.9 Hz, 1H), 7.37 (m, 2H), 7.28–7.24 (m, 2H), 7.21 (dd, J = 7.5 Hz, 2H), 7.17–7.10 (m, 2H), 6.88 (t, J = 54.9 Hz, 1H), 5.72 (q, J = 7.0 Hz, 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 = 7.1 Hz, 3H).

[0810] Step E: Preparation of Compound 32-5

[0811] Compound 32-5 was prepared by referring to the method of Step C in Example 19.

[0812] MS (ESI, [M+H] + ) m / z = 485.15.

[0813] Step F: Compound 32 was prepared by referring to the method of Step C in Example 10.

[0814] HRMS (ESI, [M+H] + ) m / z = 527.1646.

[0815] 1 H NMR (500 MHz, CD 3 OD) δ 8.80 (dd, J = 13.5, 6.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.49 (m, 2H), 7.24 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 54.9 Hz, 1H), 5.84 (q, J = 7.1 Hz, 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 = 7.2 Hz. 3H).

[0816] 31 P NMR (202 MHz, CD 3 OD) δ 31.37.

[0817] Example 33: Preparation of Compound 33

[0818]

[0819] Step A: Preparation of Compound 33-1

[0820] Add 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) to a 25 mL single-necked flask. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 0.7 g of compound 33-1.

[0821] MS (ESI, [M+H+2] + ) m / z = 432.00.

[0822] 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.10 (d, J = 7.3 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.8, 2.1 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.54 (t, J = 7.1 Hz, 1H), 7.37–7.32 (m, 1H), 7.32–7.07 (m, 1H), 5.70 (m, 1H), 1.62 (d, J = 7.0 Hz, 3H).

[0823] Step B: Preparation of compound 33-2

[0824] Add the compound 33-1 (0.5 g) obtained in step A, 1-benzyl-1,4-azaphospholidine 4-oxide (0.267 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.134 g), tris(dibenzylideneacetone)dipalladium (0.106 g), N,N-diisopropylethylamine (0.225 g) and 1,4-dioxane (10 mL) to a 25 mL single-necked flask. Heat the reaction mixture to 70 °C under nitrogen protection and stir for 2 h. Cool the reaction mixture to room temperature, filter by suction, concentrate the filtrate to dryness, and separate and purify the residue by silica gel column chromatography (methylene chloride:methanol = 95:5) to obtain 0.5 g of compound 33-2.

[0825] MS (ESI, [M+H] + ) m / z = 559.09.

[0826] 1 H NMR (500 MHz, DMSO-d 6)δ9.41(d, J = 7.3Hz, 1H), 8.92(d, J = 12.1Hz, 1H), 8.27(br, 1H), 8.17(t, J = 9.1Hz, 1H), 7.77–7.68(m, 2H), 7.55(t, J = 7.2Hz, 1H), 7.39–7.34(m, 4H), 7.33(d, J = 7.9Hz, 1H), 7.29(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).

[0827] Step C: Preparation of Compound 33-3

[0828] Add the compound 33-2 (0.18 g) obtained in Step B, ammonium cerium nitrate (0.883 g), acetonitrile (20 mL) and water (4 mL) to a 100 mL single-necked flask, and stir the reaction at room temperature for 1 h. Quench the reaction by adding saturated aqueous sodium bicarbonate solution, extract with dichloromethane (30 mL × 3), wash the organic phase successively with water and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate to dryness to obtain 0.3 g of crude compound 33-3, and directly carry out the next reaction.

[0829] MS(ESI, [M+H] + )m / z = 469.12.

[0830] Step D: Preparation of Compound 33

[0831] Refer to the method of Step C in Example 10 to react Compound 33-3 with acetic anhydride to prepare Compound 33.

[0832] HRMS(ESI, [M+H] + )m / z = 511.1277.

[0833] 1 H NMR(500MHz, CDCl 3)δ8.79(d, J = 13.0 Hz, 1H), 7.81(q, J = 6.2, 5.6 Hz, 2H), 7.65–7.41(m, 3H), 7.17(q, J = 7.5 Hz, 1H), 6.88(td, J = 55.0, 3.0 Hz, 1H), 5.79(t, J = 7.1 Hz, 1H), 4.76–4.54(m, 1H), 4.14–3.84(m, 2H), 3.58(q, J = 12.0 Hz, 1H), 2.33–2.24(m, 1H), 2.20(d, J = 8.8 Hz, 3H), 2.09(s, 3H), 1.71(t, J = 6.0 Hz, 3H).

[0834] 31 P NMR(202 MHz, CDCl 3 )δ29.70.

[0835] Example 34: Preparation of Compound 34

[0836]

[0837] Step A: Preparation of Compound 34-1

[0838] Referring to the method in Step A of Example 19, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was used instead of (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to react with Compound 1-2 to obtain Compound 34-1.

[0839] MS(ESI, [M+H] + )m / z = 488.02.

[0840] Step B: Preparation of Compound 34

[0841] Add the compound 34-1 (0.075 g) obtained in Step A, diethylphosphine oxide (0.016 g), N,N-diisopropylethylamine (0.04 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.9 mg), tris(dibenzylideneacetone)dipalladium (7.05 mg), and N,N-dimethylformamide (3 mL) to a 5 mL microwave tube. After adding, replace the air with nitrogen, then heat to 170 °C in a microwave reactor at 150 W for 35 minutes. After the reaction, take out the sample. Filter the reaction solution through diatomaceous earth, pour the filtrate into water (30 mL), extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 97:3) to obtain 29 mg of Compound 34.

[0842] HRMS(ESI, [M+H] +)m / z = 466.1886.

[0843] 1 H NMR(500 MHz, CD 3 OD) δ 8.59 (d, J = 13.0 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.1 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.13–6.88 (m, 2H), 5.87 (q, J = 7.1 Hz, 1H), 4.00 (s, 3H), 2.44 (s, 3H), 2.13 (m, 4H), 1.69 (d, J = 7.1 Hz, 3H), 1.07 (m, 6H).

[0844] 31 P NMR(202 MHz, CD 3 OD) δ 49.9.

[0845] Example 35: Preparation of Compound 35

[0846]

[0847] Step A: Preparation of Compound 35-1

[0848] Referring to the method of Step A in Example 19, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was used to replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride and reacted with Compound 9-1 to prepare Compound 35-1.

[0849] MS(ESI, [M+H] + )m / z = 367.05.

[0850] 1 H NMR(500 MHz, CD 3 OD) δ 8.76 (s, 1H), 8.33 (s, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 6.9 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 54.9 Hz, 1H), 5.80 (q, J = 7.1 Hz, 1H), 2.46 (s, 3H), 1.69 (d, J = 7.1 Hz, 3H).

[0851] Step B: Preparation of Compound 35-2

[0852]

[0853] Step a: Preparation of Compound 35-2-1

[0854] Add ammonium hypophosphite (28 g, 337 mmol) to a 500 mL three-necked flask, and dropwise add hexamethyldisilazane (109 g). After the addition is complete, heat the reaction solution to 120 °C under nitrogen protection and stir for 4 h. Then, dropwise add bis(2-bromoethyl) ether (78 g) into the reaction flask, and continue the reaction at the same temperature for 4 h. Cool the reaction solution with stirring in an ice-water bath, and dropwise add anhydrous ethanol (150 mL). After the addition is complete, heat the reaction solution to reflux for 1 h. Stop the reaction, cool the reaction solution to room temperature, filter by suction, wash the filter cake with dichloromethane, and concentrate the filtrate to obtain 42.4 g of crude compound 35-2-1.

[0855] GCMS: [M] + = 136.

[0856] Step b: Preparation of compound 35-2-2

[0857] Add the compound 35-2-1 (1 g) obtained in step a and dichloromethane (20 mL) to a 25 mL three-necked flask. Cool the mixture to below 0 °C under nitrogen protection, and dropwise add oxalyl chloride (1.578 g). After the addition is complete, transfer the mixture to room temperature and stir overnight. Concentrate the reaction solution to dryness, dissolve the residue in toluene (10 mL), and then concentrate to dryness to obtain 1.8 g of crude compound 35-2-2, which is directly used in the next step without purification.

[0858] Step c: Preparation of compound 35-2

[0859] Under nitrogen protection at -70 °C, slowly add a toluene solution of 1 M diisobutylaluminum hydride (6.48 mL) to a stirred solution of the compound 35-2-2 (1.8 g) obtained in step b in dichloromethane (15 mL). Stir the mixture at -70 °C for 2 h. After the reaction is completed, add methanol (3 mL) to the reaction solution at -70 °C and stir for 5 minutes. Transfer the reaction solution to an ice-water bath and continue stirring until the reaction solution warms up to 0 °C. Then add 10 vol% acetic acid aqueous solution (10 mL), stir at room temperature for 10 minutes, separate the resulting solution, extract the aqueous phase with dichloromethane (20 mL × 5), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain 1.7 g of crude compound 35-2, which is directly used in the next step without purification.

[0860] Step C: Preparation of compound 35

[0861] Referring to the method of step B in Example 19, react compound 35-1 with compound 35-2 to prepare compound 35.

[0862] HRMS (ESI, [M + H] + ) m / z = 451.1510.

[0863] 1 H NMR(500MHz,CD 3 OD)δ9.12(s,1H),8.83(d,J=6.8Hz,1H),7.63(t,J=7.3Hz,1H),7.49(t,J=7.0Hz,1H),7.24(t,J=7.7Hz,1H),7.00(t,J=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).

[0864] 31 P NMR(202MHz,CD 3 OD)δ30.08.

[0865] Example 36: Preparation of Compound 36

[0866]

[0867] Step A: Preparation of Compound 36-1

[0868] Referring to the method of Step A in Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was replaced with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride to prepare Compound 36-1.

[0869] MS(ESI, [M+H] + )m / z=411.96.

[0870] 1 H NMR(500MHz,DMSO-d 6 )δ9.50(s,1H),8.75(d,J=2.2Hz,1H),7.96(s,1H),7.87(dd,J=8.9,2.1Hz,1H),7.72–7.68(m,1H),7.56–7.53(m,1H),7.36–7.11(m,2H),5.79(m,1H),2.37(s,3H),1.61(d,J=7.0Hz,3H).

[0871] Step B: Preparation of Compound 36

[0872] Referring to the method of Step B in Example 19, Compound 36 was prepared.

[0873] HRMS(ESI, [M+H]+ ) m / z = 450.1552.

[0874] 1 H NMR (500 MHz, CD 3 OD) δ 8.69 (dd, J = 13.1, 1.7 Hz, 1H), 8.02 (m, 1H), 7.68 (dd, J = 8.6, 2.5 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 54.9 Hz, 1H), 5.78 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H).

[0875] 31 P NMR (202 MHz, CD 3 OD) δ 31.65.

[0876] Example 37: Preparation of Compound 37

[0877]

[0878] Step A: Preparation of Compound 37-1

[0879] Referring to the method of Step A in Example 19, (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was reacted with 6-bromo-2-methylquinazolin-4(3H)-one to prepare Compound 37-1.

[0880] MS (ESI, [M+H] + ) m / z = 428.08.

[0881] Step B: Preparation of Compound 37

[0882] Referring to the method of Step B in Example 19, Compound 37-1 was reacted with Compound 35-2 to prepare Compound 37.

[0883] HRMS (ESI, [M+H] + ) m / z = 468.1479.

[0884] 1 H NMR (500 MHz, CD 3OD) δ 8.80 (dd, J=13.1, 1.4 Hz, 1H), 8.13 (m, 1H), 7.79 (dd, J=8.6, 2.5 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.56 (t, J=6.9 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 5.86 (q, J=7.1 Hz, 1H), 4.26–4.01 (m, 4H), 2.61 (m, 2H), 2.45 (s, 3H), 2.14 (t, J=16.1 Hz, 2H), 1.73 (d, J=7.1 Hz, 3H).

[0885] 31 P NMR(202 MHz, CD 3 OD) δ 31.62.

[0886] Example 38: Preparation of Compound 38

[0887]

[0888] Step A: Preparation of Compound 38-1

[0889] Referring to the method of Step A in Example 19, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride was reacted with 6-bromo-7-fluoro-2-methylquinazolin-4(3H)-one to prepare Compound 38-1.

[0890] MS(ESI, [M+H] + ) m / z=428.05.

[0891] 1 H NMR(500 MHz, DMSO-d 6 ) δ 8.91 (d, J=7.5 Hz, 1H), 8.63 (d, J=7.1 Hz, 1H), 7.68 (t, J=7.3 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.37–7.18 (m, 2H), 5.78 (m, 1H), 2.34 (s, 3H), 1.60 (d, J=7.1 Hz, 3H).

[0892] Step B: Preparation of Compound 38

[0893] Referring to the method of Step B in Example 19, Compound 38 was prepared.

[0894] HRMS(ESI, [M+H] + ) m / z=468.1463.

[0895] 1 H NMR(500 MHz, CD3 OD) δ 8.66 (dd, J = 13.5, 6.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.26 (dd, J = 11.4, 4.4 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.90 (t, J = 54.9 Hz, 1H), 5.77 (q, J = 7.1 Hz, 1H), 4.04 (m, 4H), 2.52 (m, 2H), 2.35 (s, 3H), 2.22–2.02 (m, 2H), 1.61 (d, J = 7.1 Hz, 3H).

[0896] 31 P NMR (202 MHz, CD 3 OD) δ 28.87.

[0897] Example 39: Preparation of Compound 39

[0898]

[0899] Step A: Preparation of Compound 39-1

[0900] To a 500 mL single-necked flask were successively added 2-amino-3-fluorobenzoic acid (10 g) and dichloromethane (170 mL). The mixture was stirred at room temperature, and N-iodosuccinimide (14.50 g) was added thereto. After the addition was completed, the mixture was stirred at room temperature overnight. After the reaction was completed, suction filtration was performed. The filter cake was slurried with dichloromethane (50 mL), suction filtered, and dried to obtain 12.9 g of Compound 39-1.

[0901] 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.81–7.80 (m, 1H), 7.57 (dd, J = 10.8, 2.0 Hz, 1H).

[0902] Step B: Preparation of Compound 39-2

[0903] Compound 39-2 was prepared by referring to the method of Step A in Example 24.

[0904] 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.84–7.79 (m, 1H), 7.61 - 7.59 (m, 1H), 6.69 (s, 2H), 3.82 (s, 3H).

[0905] Step C: Preparation of Compound 39-3

[0906] Referring to the method of Step B in Example 1, compound 39-3 was prepared.

[0907] MS(ESI, [M+H] + ) m / z = 304.75.

[0908] Step D: Preparation of compound 39-4

[0909] Referring to the method of Step E in Example 1, compound 39-4 was prepared.

[0910] MS(ESI, [M+H] + ) m / z = 297.04.

[0911] 1 H NMR(500MHz, DMSO-d 6 ) δ12.64(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).

[0912] Step E: Preparation of compound 39

[0913] Referring to the method of Step A in Example 19, compound 39 was prepared.

[0914] HRMS(ESI, [M+H] + ) m / z = 468.1466.

[0915] 1 H NMR(500MHz, CD 3 OD) δ8.50(d, J = 12.9Hz, 1H), 7.81(t, J = 10.6Hz, 1H), 7.53(t, J = 7.3Hz, 1H), 7.39(t, J = 7.0Hz, 1H), 7.14(t, J = 7.7Hz, 1H), 6.91(t, J = 54.9Hz, 1H), 5.77(q, J = 7.1Hz, 1H), 4.14–3.91(m, 4H), 2.50(m, 2H), 2.39(s, 3H), 2.04(t, J = 16.5Hz, 2H), 1.62(d, J = 7.1Hz, 3H).

[0916] 31 P NMR(202MHz, CD 3 OD) δ31.53.

[0917] Example 40: Preparation of compound 40

[0918]

[0919] Step A: Preparation of Compound 40-1

[0920] Into a 350 mL pressure-resistant reaction flask, 4,6-dichloro-2-methylpyrimidine (16.3 g) and ammonia water (80 mL) were successively added. After sealing, the mixture was heated to 90 °C and reacted overnight. The reaction was stopped, the reaction solution was cooled to room temperature, filtered, the filter cake was collected, and dried under reduced pressure to obtain 14 g of Compound 40-1.

[0921] MS(ESI, [M+H] + ) m / z = 143.93.

[0922] Step B: Preparation of Compound 40-2

[0923] Into a 100 mL three-necked flask, Compound 40-1 (2 g) obtained in Step A and methanol (20 mL) were successively added. When the temperature was lowered to 0 °C in an ice-salt bath, a methanol (20 mL) solution of iodine monochloride (15.58 g) was added dropwise thereto. After the addition, it was transferred to room temperature and stirred overnight. After the reaction was completed, the reaction solution was poured into water (100 mL), then saturated sodium sulfite solution (200 mL) was added, the pH was adjusted to 6-7 with 2M sodium hydroxide solution, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.3 g of Compound 40-2.

[0924] MS(ESI, [M+H] + ) m / z = 269.86.

[0925] 1 H NMR(500MHz,DMSO-d 6 ) δ 7.28(d,2H),2.29(s,3H).

[0926] Step C: Preparation of Compound 40-3

[0927] Into a 250 mL single-necked flask, sequentially add the compound 40-2 (2.8 g) obtained in step B, N,N-dimethylformamide (28 mL), tert-butyl acrylate (1.598 g), triethylamine (2.103 g), palladium acetate (0.058 g), and tri-o-tolylphosphine (0.158 g). Replace the air with nitrogen three times. Under nitrogen protection, heat the mixture to 100 °C and react for 8 h. After the reaction is completed, cool the reaction solution to room temperature, pour the reaction solution into water (100 mL), extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated brine (60 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain 1.7 g of compound 40-3.

[0928] MS(ESI, [M+H] + ) m / z = 270.38.

[0929] 1 H NMR(500 MHz, DMSO-d 6 ) δ 7.45 - 7.40 (m, 3H), 6.34 (d, J = 16.4 Hz, 1H), 2.31 (s, 3H), 1.48 (s, 9H).

[0930] Step D: Preparation of compound 40-4

[0931] Into a 25 mL reaction flask, sequentially add the compound 40-3 (0.4 g) obtained in step C and acetonitrile (8 mL). Place the reaction flask under a 365 nm wavelength lamp and stir at room temperature for 4 h. Stop the reaction, filter, and collect the filter cake to obtain 0.22 g of compound 40-4.

[0932] MS(ESI, [M+H] + ) m / z = 270.08.

[0933] 1 H NMR(500 MHz, DMSO-d 6 ) δ 6.88 (s, 2H), 6.70 (d, J = 11.6 Hz, 1H), 6.05 (d, J = 11.6 Hz, 1H), 2.30 (s, 3H), 1.29 (s, 9H).

[0934] Step E: Preparation of compound 40-5

[0935] Into a 250 mL reaction flask, sequentially add the compound 40-4 (2.8 g) obtained in step D, trifluoroethanol (1.038 g), and potassium tert-butoxide (2.56 g). Heat the mixture to 80 °C and react for 2 h. After the reaction is completed, cool the reaction solution to room temperature. Pour the reaction solution into saturated ammonium chloride solution (30 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and add the obtained residue to methyl tert-butyl ether (20 mL) for pulping to obtain 2.2 g of compound 40-5.

[0936] MS(ESI, [M+H] + ) m / z = 260.05.

[0937] 1 H NMR(500 MHz, DMSO-d 6 ) δ 12.46 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 6.51 (d, J = 9.6 Hz, 1H), 5.19 (q, J = 8.9 Hz, 2H), 2.55 (s, 3H).

[0938] Step F: Preparation of compound 40-6

[0939] Into a 250 mL single-necked flask, sequentially add the compound 40-5 (2 g) obtained in step E and N,N-dimethylformamide (20 mL). Cool the mixture to below 5 °C in an ice-water bath, add sodium hydride (0.370 g) thereto. After addition, stir at room temperature for 5 minutes, and then dropwise add iodomethane (1.314 g) to the reaction flask under ice bath. After addition, naturally warm to room temperature and stir for 2 h. After the reaction is completed, pour the reaction solution into ice water (20 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain 1.7 g of compound 40-6.

[0940] MS(ESI, [M+H] + ) m / z = 274.03.

[0941] 1 H NMR(500 MHz, DMSO-d 6 ) δ 7.90 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 9.6 Hz, 1H), 5.21 (q, J = 8.9 Hz, 2H), 3.60 (s, 3H), 2.62 (s, 3H).

[0942] Step G: Preparation of compound 40-7

[0943] To a 100 mL single-necked flask, sequentially add the compound 40-6 (0.65 g) obtained in step F and an aqueous solution of 48% hydrobromic acid (8 mL). Stir the reaction at room temperature, and add sodium bromate (1.077 g) thereto in batches. After addition, transfer the reaction flask to an oil bath at 60 °C and stir for 2 h. After the reaction is completed, pour the reaction solution into ice water (10 mL), then add a saturated sodium sulfite solution (30 mL), stir vigorously for 5 minutes, adjust the pH to 6-7 with a saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 0.7 g of compound 40-7.

[0944] MS(ESI,[M+H] + )m / z = 351.92.

[0945] 1 H NMR(500MHz,DMSO-d 6 )δ8.31(s,1H),5.23(q,J = 8.9Hz,2H),3.68(s,3H),2.62(s,3H).

[0946] Step H: Preparation of compound 40-8

[0947] To a 100 mL single-necked flask, sequentially add the compound 40-7 (0.7 g) obtained in step G and an aqueous solution of 48% hydrobromic acid (7 mL). After addition, heat the mixture to 100 °C and react for 2.5 h. After the reaction is completed, cool the reaction solution to room temperature, pour the reaction solution into ice water (100 mL), adjust the pH to 6-7 with a saturated sodium bicarbonate solution, filter, and collect the filter cake and dry to obtain 0.537 g of compound 40-8.

[0948] MS(ESI,[M+H+2] + )m / z = 271.96.

[0949] 1 H NMR(500MHz,DMSO-d 6 )δ12.90(s,1H),8.24(s,1H),3.63(s,3H),2.41(s,3H).

[0950] Step I: Preparation of compound 40-9

[0951] Refer to the method of step A in Example 19 to prepare compound 40-9.

[0952] 1 H NMR(500MHz,DMSO-d 6)δ8.93(s,1H),8.44(d,J=6.9Hz,1H),7.73(d,J=7.8Hz,1H),7.54(d,J=7.6Hz,1H),7.36(t,J=7.8Hz,1H),5.64(p,J=6.9Hz,1H),3.57(s,3H),2.59(s,3H),2.31(s,3H),1.52(d,J=7.0Hz,3H).

[0953] Step J: Preparation of Compound 40

[0954] Referring to the method of Step B in Example 19, Compound 40 was prepared by reacting Compound 40-9 with Compound 35-2 obtained in Step c of Example 35.

[0955] HRMS(ESI,[M+H] + )m / z=495.1768.

[0956] 1 H NMR(500MHz,CD 3 OD)δ8.78(d,J=14.5Hz,1H),7.68(d,J=7.8Hz,1H),7.52(d,J=7.8Hz,1H),7.29(t,J=7.8Hz,1H),5.79(q,J=7.0Hz,1H),4.19(m,2H),4.07(q,J=11.3Hz,2H),3.64(s,3H),2.81(m,2H),2.62(s,3H),2.41(s,3H),1.87(t,J=16.8Hz,2H),1.60(d,J=7.0Hz,3H).

[0957] Example 41: Preparation of Compound 41

[0958]

[0959] Step A: Preparation of Compound 41-1

[0960] To a 100 mL single-necked flask were successively added methyl 5-amino-2-chloroisonicotinate (2 g), N,N-dimethylformamide (20 mL), and N-bromosuccinimide (1.9 g). The reaction solution was heated to 80 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (200 mL), and extracted with methyl tert-butyl ether (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 2.6 g of Compound 41-1.

[0961] MS(ESI,[M+H+2] +) m / z = 266.87.

[0962] 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.63 (s, 1H), 6.78 (s, 2H), 3.88 (s, 3H).

[0963] Step B: Preparation of Compound 41-2

[0964] To a 35 mL microwave tube, add successively the compound 41-1 (1.1 g) obtained in Step A, acetonitrile (3.40 g), and methanesulfonic acid (3.98 g). After stirring at room temperature for 10 minutes, place it in a microwave reactor and heat to 120 °C at 50 W for 2 h. After the reaction is completed, concentrate the obtained sample solution under reduced pressure to dryness, dilute with water (20 mL), adjust the pH to alkaline with 15% aqueous sodium hydroxide solution, and filter by suction to obtain 0.8 g of compound 41-2.

[0965] MS (ESI, [M-H] - ) m / z = 273.89.

[0966] 1 H NMR (500 MHz, CD 3 OD) δ 7.94 (s, 1H), 2.48 (s, 3H).

[0967] Step C: Preparation of Compound 41-3

[0968] To a 5 mL microwave tube, add successively the compound 41-2 (0.2 g) obtained in Step B, N,N-dimethylformamide (2 mL), zinc cyanide (39.4 mg), and tetrakis(triphenylphosphine)palladium (78 mg). After purging with nitrogen 3 times, place it in a microwave reactor and heat to 110 °C at 50 W for 1 h. After the reaction is completed, pour the reaction solution into water (20 mL), extract with ethyl acetate (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol = 80:20) to obtain 136 mg of compound 41-3.

[0969] MS (ESI, [M-H] - ) m / z = 218.95.

[0970] 1 H NMR (500 MHz, CD 3 OD) δ 7.97 (s, J = 7.2 Hz, 1H), 2.51 (s, 3H).

[0971] Step D: Preparation of Compound 41-4

[0972] Refer to the method of step A in Example 19, and compound 41-4 was prepared.

[0973] MS(ESI, [M+H] + ) m / z = 410.12.

[0974] Step E: Preparation of compound 41

[0975] Refer to the method of step B in Example 19, and react the compound 41-1 prepared in the above step D with compound 35-2 to prepare compound 41.

[0976] HRMS(ESI, [M+H] + ) m / z = 494.1365.

[0977] 1 H NMR(500MHz, CD 3 OD) 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).

[0978] 31 P NMR(202MHz, CD 3 OD) δ 29.64.

[0979] Example 42: Preparation of compound 42

[0980]

[0981] Step A: Preparation of compound 42

[0982] Refer to the method of step B in Example 19, and react compound 19-1 with phospholane 1-oxide to prepare compound 42.

[0983] HRMS(ESI, [M+H] + ): m / z = 467.1620.

[0984] 1 H NMR(500MHz, CD 3OD) δ 9.10 (s, 1H), 8.81–8.78 (m, 1H), 7.75 (t, J = 6.9 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.85 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H), 1.66 - 1.59 (m, 1H).

[0985] Example 43: Preparation of Compound 43

[0986]

[0987] Step A: Preparation of Compound 43

[0988] Referring to the method of Step B in Example 19, Compound 43 was prepared by reacting Compound 19-1 with 1-oxaphospholane.

[0989] HRMS (ESI, [M+H] + ): m / z = 453.1594.

[0990] 1 H NMR (500 MHz, CD 3 OD) δ 9.09 (s, 1H), 8.81 (dd, J = 6.5, 0.7 Hz, 1H), 7.75 (t, J = 6.9 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.85 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H).

[0991] For the following Examples 44 - 47 (Table 1), referring to the method of Example 1, methyl 2-amino-4-methoxybenzoate was replaced with the following Fragment 1-1 respectively, and (R)-1-(m-tolyl)ethan-1-amine was replaced with the following Fragment 1-2 for reaction, and finally referring to the method of Step C in Example 7, Compounds 44 - 47 were prepared.

[0992] Table 1:

[0993]

[0994]

[0995] The following intermediates (Table 2-1) can be prepared by referring to the method of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the following fragment a respectively, and reacting with the corresponding fragment b to obtain intermediate compounds 2a-1 to 2a-6.

[0996] Table 2-1:

[0997]

[0998]

[0999] Examples 48 to 60 (Table 2) can be prepared by referring to the method of Example 10, replacing compound 7-1 with the above-prepared intermediates 2a-1 to 2a-6, and replacing acetic anhydride with the following fragment 2 respectively for substitution, reductive amination or condensation reaction to obtain compounds 48 to 60.

[1000] Table 2:

[1001]

[1002]

[1003]

[1004] The following intermediates (Table 3-1) can be prepared by referring to the method of Step A of Example 9, replacing 5-amino-2-chloroisonicotinic acid with the following fragment 2a respectively to obtain the following intermediate compounds 3a-1 to 3a-2.

[1005] Table 3-1:

[1006]

[1007] The following Examples 61 to 64 (Table 3) can be prepared by referring to the method of Example 19, replacing (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the following fragment 3-1 respectively, and replacing compound 9-1 with the above-prepared intermediate compounds to obtain compounds 61 to 64.

[1008] Table 3:

[1009]

[1010]

[1011] Example 65 (Table 4) can refer to the method of Example 35, replace compound 9-1 with intermediate 3a-2, replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the corresponding fragment 4-1, and react compound 35-2 with the corresponding fragment 4-2. Finally, refer to the method of Step C in Example 7 to prepare compound 65. Examples 66-71 (Table 4) can refer to the method of Example 35, replace compound 9-1 with intermediate 3a-2, replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride with the following fragments 4-1 respectively, and replace compound 35-2 with the following fragments 4-2 respectively to prepare compounds 66-71.

[1012] Table 4:

[1013]

[1014]

[1015]

[1016] Test Example 1 In vitro cell-level phosphorylation activity inhibition test 1.1 Test reagents and instruments

[1017] 1.1.1 Test reagents

[1018]

[1019] 1.1.2 Instruments

[1020]

[1021]

[1022] 1.2 In vitro cell-level phosphorylation activity inhibition test method

[1023] Take a plate of H358 human non-small cell lung cancer cells (Nanjing Kebai Biotechnology Co., Ltd.) in good condition in the exponential growth phase, collect the cells into a centrifuge tube, use a low-speed tabletop centrifuge, centrifuge at 1000 rpm for 5 min, discard the supernatant, and use a pipette to add 5 mL of seeding medium containing 5% FBS to resuspend the cells. Use a cell counter to count, dilute with the seeding medium, and adjust the cell density to 1.5×10 5 cells / mL. Use a multi-channel pipette to inoculate on a black-bottom transparent 384-well plate, 40 μL / well, and place it at 37 °C in an atmosphere containing 5% CO 2After culturing overnight in a cell incubator with saturated humidity, a Tecan D300e ultra-micro sampler was used for compound addition. After 1 hour, the culture medium was discarded, 40 μL of 4% paraformaldehyde was added to each well, incubated at room temperature for 20 min, and washed with PBS. 40 μL of methanol was added to each well, incubated at room temperature for 10 min, and washed with PBST. 20 μL of 5% BSA blocking buffer was added to each well, blocked at room temperature for 1 h, then the blocking solution was discarded, and 20 μL of primary antibody mixture was added to each well, where Rabbit anti-pERK was diluted at 1:1000 (final concentration) and mouse anti-GAPDH was diluted at 1:5000 (final concentration), incubated overnight at 4 °C, and washed with PBST. 20 μL of secondary antibody mixture was added to each well, where goat anti-rabbit 800 and goat anti-mouse 647 were both diluted at 1:1000 (final concentration), incubated in the dark at room temperature for 45 min, and washed with PBST. Scanned and read by Azure Biosystems, with the logarithm of compound concentration as the abscissa and phosphorylation inhibition rate as the ordinate, the EC 50 value was calculated and analyzed using a four-parameter logistic model, and the results are shown in Table 5.

[1024] Table 5

[1025] Example <![CDATA[EC 50 (nM)]]> 12 103 14 108 15 148 17 82 18 71 。

[1026] Experimental Example 2 Guanine Nucleotide Exchange Assay

[1027] This assay quantitatively examines the ability of SOS1 to mediate KRAS activation. His-tagged KRAS G12C was added to the system, and the anti-His antibody labeled with the lanthanide element Eu bound to it. Then, the accessory protein SOS1cat and the fluorescent group-labeled GTP analog EDA-GTP-DY-647P1 were added. The fluorescent group-labeled GTP analog was loaded onto KRAS G12C with the assistance of the accessory protein, and thus energy resonance transfer occurred between Anti-6HIS-Cryptate (FRET donor) and EDA-GTP-DY-647P1 (FRET acceptor). After pre-treatment with the SOS1 inhibitor compound, the ability of SOS1 to bind and mediate KRAS activation was weakened, and the FRET ability between the donor and the acceptor was also weakened.

[1028] 2.1 Experimental Reagents and Instruments

[1029] 2.1.1 Experimental Reagents

[1030]

[1031]

[1032] 2.1.2 Instruments

[1033] Name Manufacturer Model Pipette Thermo 100 - 1000 μl Pipette Thermo 20 - 200 μl Pipette Thermo 10 - 100 μl Pipette RNIN 2 - 20 μl Pipette RNIN 0.5 - 10 μl Ultra - micro pipette Tecan D300E

[1034] 2.2 Nucleotide Exchange Test Procedure

[1035] Preparation of His-KRAS G12C: The K-Ras4B-G12C (UniProt P01116-2, amino acid 1-169) sequence was codon-optimized and gene-synthesized, and finally subcloned into the pET-30a(+) vector, transformed into BL21(DE3) competent cells. Appropriate clones were selected, cultured in TB medium and induced for expression at low temperature with IPTG, and the bacterial cells were collected. The cells were lysed using an ultrasonic cell disruptor, and the supernatant was collected by centrifugation and filtration. Ni Sepharose HP and Superdex 200pg (16 / 60) were used for purification to obtain a protein with a purity > 90%, and the activity was measured for later use.

[1036] Preparation of SOS1cat: The human SOS1 (UniProt Q07889, amino acid 564-1049) sequence was codon-optimized and gene-synthesized, and finally subcloned into the pET-30a(+) vector, transformed into BL21(DE3) competent cells. Appropriate clones were selected, cultured in TB medium and induced for expression at low temperature with IPTG, and the bacterial cells were collected. The cells were lysed using an ultrasonic cell disruptor, and the supernatant was collected by centrifugation and filtration. Ni Sepharose HP, Superdex 200pg (16 / 60) and Superdex 200pg (16 / 60) were used for purification to obtain a protein with a purity > 90%, and the activity was measured for later use.

[1037] Prepare the test buffer, whose components are: HEPES pH 7.4: 20 mM; NaCl: 150 mM; MgCl 2 : 0.5 mM; DTT: 2 mM; BSA: 0.05%; Igepal: 0.0025%.

[1038] Prepare the KRAS G12C working solution, SOS1cat working solution and blank control solution respectively with the test buffer. Among them, the KRAS G12C working solution contains 100 nM His-KRAS G12C and 2 nM anti-His-terbium; the SOS1cat working solution contains 20 nM SOS1cat and 200 nM EDA–GTP–DY-647P1; the blank control solution contains 100 nM EDA–GTP–DY-647P1.

[1039] The entire test process was completed at 20 °C. 5 μL of SOS1cat working solution was added to each well in the test group. Meanwhile, 5 μL of blank control working solution was added to each well in the control group, and they were incubated at 20 °C for 10 min. Subsequently, a compound was added using a Tecan D300e ultra-micro pipettor. The highest final concentration of the compound was 10 μM, and it was serially diluted by 2-fold, with a total of 8 concentration gradients set, and incubated at 20 °C for 30 min. Finally, 5 μL of KRAS G12C working solution was added to each well, incubated at 20 °C for 15 min, and the fluorescence ratio at 665 nm / 620 nm was detected using an Envision microplate reader to reflect the degree of nucleotide conversion. The inhibition rate was calculated. Inhibition rate (%) = (average value of negative control group - average value of test group) / (average value of negative control group - average value of blank group) × 100%, where the negative control group did not contain the compound, and the other conditions were the same as those in the test group. With the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, a four-parameter logistic model was used to calculate and analyze the IC 50 value, and the results are shown in Table 6.

[1040] Test Example 3 KRAS / SOS1 Protein Binding Assay

[1041] This assay can be used on the one hand to detect the potency of a compound in inhibiting the protein-protein interaction between SOS1 and KRAS G12C, and on the other hand to verify the molecular mode of action of the compound. A low IC 50 value indicates that the SOS1 inhibitor compound can efficiently inhibit protein-protein interaction.

[1042] 3.1 Test Reagents and Buffers

[1043] 3.1.1 Reagents:

[1044] GST-SOS1(564-1049), internally produced: The sequence of human SOS1 (UniProt Q07889, amino acid 564-1049) was codon-optimized and gene-synthesized, and finally subcloned into the pGEX-4T-1 vector, transformed into BL21(DE3) competent cells, appropriate clones were selected, cultured using TB medium, and induced for expression at low temperature with IPTG, and the bacterial cells were collected. The cells were lysed using an ultrasonic cell disruptor, and the supernatant was collected by centrifugation and filtration. Ni Sepharose HP and Superdex200pg (16 / 60) were used for purification to obtain a protein with a purity > 90%, and the activity was measured for later use;

[1045] Kras-G12C-6xHis(1-169), In-house production: The sequence of K-Ras4B-G12C (UniProt P01116-2, amino acid 1-169) was codon-optimized and gene-synthesized, and finally subcloned into the pET-30a(+) vector, transformed into BL21(DE3) competent cells. Appropriate clones were selected, cultured in TB medium, and induced for expression at low temperature with IPTG. The bacterial cells were collected. The cells were lysed using an ultrasonic cell disruptor, and the supernatant was collected by centrifugation and filtration. Purification was performed using Ni Sepharose HP and Superdex 200pg (16 / 60) to obtain a protein with a purity > 90%, and the enzyme activity was measured for later use;

[1046] GDP (Sigma, catalog number G7127);

[1047] MAb Anti-GST-XL665 (Cisbio, catalog number 61GSTXLA);

[1048] MAb Anti-6HIS-Tb cryptate Gold (Cisbio, catalog number 61HI2TLA).

[1049] 3.1.2 Buffers:

[1050] Diluent Buffer (Cisbio, catalog number 62DLBDDF);

[1051] Detection buffer (Cisbio, catalog number 62DB2FDG);

[1052] GST-SOS1 working solution: Prepared with Diluent Buffer, with a concentration of 92 nM;

[1053] GDP-Kras-G12C-His working solution: Prepared with Diluent Buffer, with a final concentration of GDP of 40 μM and a final concentration of Kras-G12C-His of 100 nM;

[1054] Antibody working solution: Prepared with Detection buffer, with the concentrations of MAb Anti-GST-XL665 and MAb Anti-6HIS-Tb cryptate Gold both being 4X and mixed in a 1:1 ratio.

[1055] 3.2 Test procedure:

[1056] Add 5 μL of GST-SOS1 working solution to each well of the experimental group and the negative group. At the same time, add 5 μL of Diluent Buffer to each well of the control group. Then, use a Tecan D300e ultra-micro pipettor to add compounds to the experimental group at a maximum concentration of 5000 nM, diluted serially by 3-fold, with a total of 7 concentration gradients, and incubate at room temperature for 30 min. Next, add 5 μL of the pre-prepared GDP-Kras-G12C-His working solution (GDP and Kras-G12C-His were incubated at room temperature for 10 min) to each well and incubate at room temperature for 15 min. Finally, add 10 μL of the antibody working solution to each well and incubate at room temperature for 50 min. Detect the fluorescence ratio at 665 nm / 620 nm using an Envision microplate reader. Calculate the inhibition rate, where inhibition rate (%) = (mean value of negative control group - mean value of experimental group) / (mean value of negative control group - mean value of blank group) × 100%, and the negative control group does not contain compounds, with other conditions the same as the experimental group. Using the logarithm of the compound concentration as the abscissa and the inhibition rate as the ordinate, use the four-parameter logistic model to calculate the IC 50 value, and the results are shown in Table 6.

[1057] Test Example 4 Determination of Proliferation Inhibitory Activity of K562 Cells

[1058] The K562 cell line can be purchased from the American Type Culture Collection (ATCC).

[1059] Collect K562 cells in good growth state into a centrifuge tube, adjust the cell density to 3×10 4 cells / mL, inoculate onto a 96-well plate (100 μL / well), culture overnight in a cell incubator, use a nanoliter pipettor to add compounds, so that the final concentration of the compound is 10000 nM - 4.6 nM, with 2 replicates, and set up a control at the same time. After continuing to culture in the cell incubator for 72 hours, add the detection reagent CCK-8 (Cell Counting Kit-8, Dojindo Laboratories, 10 μL / well), incubate in the cell incubator for 1 hour, and detect the absorbance at 450 nm using an Envision microplate reader. Perform four-parameter analysis, fit the dose-effect curve, and calculate the IC 50 , and the results are shown in Table 6.

[1060] Table 6

[1061]

[1062] .

[1064] Test Example 5 Pharmacodynamic Evaluation of SOS1 Inhibitor in a MIA PaCa-2 Human Pancreatic Cancer Xenograft Model in Nude Mice

[1065] SPF-grade female BALB / C nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) were subcutaneously inoculated with 1×10 7 MIA PaCa-2 cells (Kras G12C mutant tumor cells, Nanjing Kebai Biotechnology Co., Ltd.) in the right axillary subcutaneous area. When the average tumor volume reached about 200 mm 3 , the animals were divided into a drug administration group and a control group, with 8 animals in each group. The day of grouping was day d0, and gavage administration started on day d1, twice a day. The administration volume of the drug administration group was 10 mL / kg. The control group was given a vehicle control. Continuous administration was carried out, and the tumor volume was measured 2-3 times a week, while the body weight of the mice was weighed and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumors were dissected, weighed, and photographed.

[1066] Tumor volume calculation formula:

[1067] Tumor volume (mm 3 ) = 1 / 2×(a×b 2 )(where a represents the long diameter and b represents the short diameter);

[1068] Relative tumor proliferation rate, T / C%, that is, at a certain time point, the percentage value of the relative tumor volume of the treatment group and the control group;

[1069] Relative tumor inhibition rate, TGI (%), the calculation formula is as follows: TGI% = (1 - tumor weight of the treatment group / tumor weight of the control group) × 100%;

[1070] Body weight change rate (weight change rate, WCR) (%), the calculation formula is: WCR = (Wt t - Wt 0 ) / Wt 0 ×100%, Wt 0 is the body weight of the animal at the time of grouping (i.e., day d0), and Wt t is the body weight of the animal at each measurement.

[1071] The compound of the present application has good in vivo pharmacodynamic activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, X and Y are each independently selected from CR a , C(O), N or NR b ; Depending on X and Y, it represents a single bond or a double bond respectively; R a Selected from hydrogen, hydroxyl, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more deuteriums or halogens; R b selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy; R 1 and R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl-or N(R c )(C 1-6 alkyl)-C 1-6 alkyl-, or R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- to 10-membered heterocyclic group, wherein the C 1-6 alkyl or 5- to 10-membered heterocyclic group is optionally substituted by one or more R c ; Each R c is independently selected from hydrogen, O═, HN═, C 1-6 alkyl-N═, C 1-6 alkyl-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O) 2 -, 3- to 6-membered cycloalkyl-S(O) 2 -, C 1-6 alkylOC(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 heteroalkyl-, 3- to 6-membered heteroalkyl-C(O)-, 3- to 6-membered heteroalkyl-C 1-6 alkyl-, C 6-10 aryl-C 1-6 alkyl- or C 1-6 alkyl- substituted with one or more hydroxyl or cyano groups, where the R c is optionally substituted with one or more halogens when it is not hydrogen and O═; Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring or 8- to 12-membered fused heterocycle; n is 0, 1, 2 or 3; Each R 3 is independently selected from amino, nitro, halogen, C 1-8 alkyl-, 3- to 6-membered cycloalkyl-, or phenyl, wherein said C 1-8 alkyl-, 3- to 6-membered cycloalkyl-, or phenyl is optionally substituted with one or more R d substituents; R d selected from hydroxy, halogen or C 1-6 alkyl-NH-C 1-6 alkyl-; R 4 、R 5 are each independently selected from hydrogen, deuterium or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens; R 6 selected from hydrogen, a halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogens.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, is a double bond, and X and Y are each independently selected from CR a and N; or is a single bond, and X is NR b , Y is C(O); Optionally, both X and Y are selected from CR a ; alternatively, X is selected from CH and Y is selected from CR a ; alternatively, X is selected from CH and Y is selected from C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF or C(OCD 3 ); alternatively, X is selected from CH and Y is selected from N; alternatively, X is selected from N(CH 3 ), and Y is selected from C(O); alternatively, X is selected from CF or C(CN), and Y is selected from CH or N.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 1 and R 2 are each independently selected from C 1-6 alkyl, or R 1 and R 2 together with the phosphorus atom to which they are attached form a 5- to 6-membered heterocyclic group, wherein the C 1-6 alkyl or 5- to 6-membered heterocyclic group is optionally substituted by one or more R c substituents; Optionally, R 1 , R 2 are each independently selected from C 1-3 alkyl; Alternatively, R 1 , R 2 are each independently selected from methyl or ethyl; Optionally, R 1 , R 2 and the phosphorus atom to which they are attached together form a 5- to 6-membered heteroalkyl group, wherein at least one N atom is included among the ring atoms of the 5- to 6-membered heteroalkyl group, and N is connected to R c ; Alternatively, R 1 , R 2 and the phosphorus atom to which it is attached together form a 6-membered heteroalkyl ring, wherein only one N atom is contained in the ring atoms of the 6-membered heteroalkyl ring, and N is connected to R c ; Optionally, the structural unit is the structural unit Optionally, each R c is independently selected from hydrogen, 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 alkylOC(O)-, C 1-6 alkyl-O-C 1-6 alkyl-, C 1-6 alkyl-O-C 1-6 alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-, di(C 1-6 alkyl)amino-C 1-6 alkyl-C(O)-, di(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, 3- to 6-membered cycloalkyl-, 3- to 6-membered cycloalkyl-C(O)-, 3- to 6-membered cycloalkyl-C 1-6 alkyl-, 3- to 6-membered heterocycloalkyl-, phenyl-C 1-3 alkyl- or C 1-6 alkyl- substituted with one or more hydroxyl or cyano groups, wherein when the said R c is not hydrogen, it is optionally substituted with one or more halogens; Alternatively, each R c is independently selected from C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3- to 5-membered cycloalkyl-S(O) 2 -, C 1-3 alkylOC(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 1-3 alkyl substituted with one hydroxyl or cyano group, wherein when the said R c is not hydrogen, it is optionally substituted with 1, 2 or 3 halogen atoms; Alternatively, each R c is independently selected from hydrogen, methyl, ethyl, isopropyl, acetyl, 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ring A is selected from phenyl, thienyl, 2,3-dihydrobenzofuranyl or benzofuranyl; Alternatively, ring A is selected from phenyl, thienyl or 2,3-dihydro-1H-indenyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R 3 is independently selected from amino, nitro, halogen, C 1-6 alkyl- or phenyl, wherein said C 1-6 alkyl or phenyl is optionally substituted by one or more R d substituents; Alternatively, each R 3 is independently selected from amino, nitro, halogen, C 1-4 alkyl or phenyl, wherein the C 1-4 alkyl or phenyl is optionally substituted with one or more R d , and R d is selected from hydroxy, halogen or C 1-3 alkyl-NH-C 1-3 alkyl-; Alternatively, each R 3 is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 2 OH or Optionally, n is 1, 2 or 3; or, n is 2.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Structural unit Selected from Further selected from 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 4 selected from methyl, wherein said methyl is optionally substituted with one or more fluorines; R 5 selected from hydrogen or deuterium; Optionally, R 4 is selected from methyl or -CH 2 F, and R 5 is selected from hydrogen or deuterium.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 6 selected from hydrogen, a halogen or a C 1-3 alkyl group, wherein said C 1-3 alkyl group is optionally substituted with one or more halogens; Alternatively, R 6 is selected from hydrogen, fluorine, chlorine or methyl, wherein the methyl is optionally substituted with 1, 2 or 3 fluorine atoms; Alternatively, R 6 is selected from hydrogen, chlorine, methyl or -CH 2 F.

9. A pharmaceutical composition of the following compound or a pharmaceutically acceptable salt thereof: The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

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