Benzylamino-substituted heteropolycyclic compounds and their compositions, preparations and uses

Abstract

This invention belongs to the field of pharmaceutical chemistry and relates to benzylamino-substituted heteropolycyclic compounds, their compositions, formulations, and uses. Specifically, the general structure of the heteropolycyclic compound is shown in Formula I. The compounds of this invention exhibit excellent in vitro inhibitory activity against SOS1, making them useful as SOS1 inhibitors, inhibiting cell proliferation and angiogenesis. They also possess excellent anti-tumor activity and are effective in treating neoplastic diseases in mammals (including humans). #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry and relates to a series of novel benzylamino-substituted heteropolycyclic compounds, pharmaceutical compositions and pharmaceutical preparations containing the same, and medical uses thereof. Background Art

[0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, bile duct cancer, and thyroid cancer. RAS is a GTP-binding protein. RAS exists in two main forms in the body: an inactive state bound to GDP and an activated state bound to GTP. Its activity is regulated by two proteins: guanylate exchange factors (GEFs), such as SOS1, which release GDP from RAS proteins, allowing GTP binding and activation of RAS; and GTPase-activating proteins, which activate the GTPase activity of RAS proteins, hydrolyzing GTP bound to RAS proteins into GDP, inactivating RAS. When in the GTP-bound state, RAS family proteins are active and engage effector proteins (including RAF and PI3K) to promote pathways such as RAF / MEK / ERK and PI3K / AKT / mTOR. These pathways influence various cellular processes, such as proliferation, survival, and metabolism.

[0003] SOS1 has two binding sites for RAS family proteins: one is a catalytic site that binds to GDP-bound RAS family proteins to promote guanine nucleotide exchange, and the other is an allele site that binds to GTP-bound RAS family proteins, thereby further increasing SOS1's catalytic GEF function (Biochem. Pharmacol., 2011, 82(9):1049-1056). SOS1 plays an important role in the activation of mutant KRAS and oncogenic signaling in cancer (Nat. Commun., 2012, 3:1168). In tumor cells carrying KRAS mutations, reducing SOS1 content can reduce the proliferation rate of tumor cells, while no effect is observed in KRAS wild-type cell lines.

[0004] RAS, the first oncogene to be identified, is the most frequently mutated oncogene, accounting for 25% of human cancers. In recent decades, the interaction between RAS family proteins and SOS1 has gained increasing recognition. Currently, only Boehringer Ingelheim's SOS1 inhibitor, BI1701963, has entered Phase I clinical trials, and no SOS1 inhibitors have been developed or marketed. Therefore, the development of new SOS1 inhibitors holds immense clinical value and broad market potential. Summary of the Invention

[0005] Problems to be solved by the invention

[0006] In order to develop new SOS1 inhibitors, the present invention aims to provide a novel benzylamino-substituted heteropolycyclic compound and its composition, preparation and use. The derivative has excellent SOS1 inhibitory activity, good pharmacodynamic properties and high metabolic stability.

[0007] Solutions for solving problems

[0008] In a first aspect, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof:

[0009]

[0010] in:

[0011] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl;

[0012] U and V are independently N or CR 2 ;

[0013] W is N or CR 6 ;

[0014] Every R 1 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, amino, halogen, cyano, and nitro;

[0015] Every R 2 are independently selected from hydrogen, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, halogen, cyano, -OR 2a and -NR 2a R 2b ;

[0016] R 2a and R 2b are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0017] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6Cycloalkyl and halogen;

[0018] R 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 2-4 Alkenyl, C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a 、-OR 4a 、-C(=O)OR 4a 、-NR 4a R 4b and -C(=O)NR 4a R 4b wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, amino, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0019] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic group, -C(=O)NH-3 to 14-membered heterocyclic group, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10 membered heteroaryl and -S(=O) m -C 1-6 wherein said alkyl, alkenyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of amino, halogen, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0020] R 5 Selected from hydrogen, amino, halogen, nitro and -OC 1-6 alkyl;

[0021] Or, R 4 and R 5Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, =O, =CH2, =NH, -C(=O)R 5a 、-OR 5a 、-C(=O)OR 5a 、-NR 5a R 5b and -C(=O)NR 5a R 5b , or, any two of the substituents together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group;

[0022] R 5a and R 5b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0023] R 6 Selected from hydrogen, amino, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group and -OC 1-6 alkyl;

[0024] m is 0, 1, or 2;

[0025] n is 0, 1, 2, or 3;

[0026] The heterocyclyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

[0027] In a second aspect, the present invention provides the following non-limiting examples of the compounds having the structure of Formula I:

[0028] (1) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0029] (2) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-nitropyrido[2,3-d]pyrimidin-4-amine;

[0030] (3) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-fluoro-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0031] (4) (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0032] (5) (R)-6-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0033] (6) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-iodo-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0034] (7) (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0035] (8) (R)-6-bromo-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine;

[0036] (9) (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine;

[0037] (10) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(thien-3-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0038] (11) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0039] (12) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyridin-2-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0040] (13) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0041] (14) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0042] (15) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0043] (16) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0044] (17) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(piperidin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0045] (18) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0046] (19) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0047] (20) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(thiazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0048] (21) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one;

[0049] (22) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0050] (23) (R)-6-cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0051] (24) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-phenylpyrido[2,3-d]pyrimidin-4-amine;

[0052] (25) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2-methoxyphenyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0053] (26) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-methoxyphenyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0054] (27) (R)-6-(2-chlorophenyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0055] (28) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-fluorophenyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0056] (29) (R)-6-(2-chloropyridin-3-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0057] (30) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2-methoxypyridin-3-yl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0058] (31) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0059] (32) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0060] (33) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2,5-dihydro-1H-pyrrol-3-yl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0061] (34) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0062] (35) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0063] (36) (R)-6-(3-aminophenyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0064] (37)(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0065] (38) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)methanesulfonamide;

[0066] (39) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-2-fluoroacrylamide;

[0067] (40) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)acetamide;

[0068] (41) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)benzamide;

[0069] (42) (R)-1-cyclopropyl-3-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)urea;

[0070] (43) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)morpholine-4-carboxamide;

[0071] (44)(R)-N 6 -cyclopentyl-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0072] (45)(R)-N 6 -cyclohexyl-N 4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0073] (46)(R)-N 6 -(cyclohexylmethyl)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0074] (47)(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-N 6 -(2-morpholinoethyl)pyrido[2,3-d]pyrimidine-4,6-diamine;

[0075] (48) (R)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-ol;

[0076] (49) (R)-1-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)ethan-1-one;

[0077] (50) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-amine;

[0078] (51) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-((S)-tetrahydrofuran-3-yloxy)pyrido[2,3-d]pyrimidin-4-amine;

[0079] (52) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0080] (53) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrrolin-1-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0081] (54) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(4-methyl-1,4-diazolyl)- -1-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0082] (55) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0083] (56) 6-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0084] (57)(R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -((Hexahydro-1H-pyrin-7a-yl)methyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0085] (58)N 4 -((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-N 6 -((S)-tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidine-4,6-diamine;

[0086] (59) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0087] (60) (R)-6-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-[1,3]dioxolo[4,5-g]quinazolin-8-amine;

[0088] (61) (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methyl-[1,3]dioxolo[4,5-g]quinazolin-8-amine;

[0089] (62) (R)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0090] (63) (R)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0091] (64) (R)-2-methyl-N-(1-phenylethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0092] (65) (S)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0093] (66) (R)-2-methyl-N-(1-(m-tolyl)ethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0094] (67) (R)-N-(1-(3-chlorophenyl)ethyl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine;

[0095] (68) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-9-methyl-2,3-dihydro-[1,4]dioxino[2,3-g]phthalazin-6-amine;

[0096] (69) (R)-N-(1-(3-amino-5-(difluoromethyl)phenyl)ethyl)-9-methyl-2,3-dihydro-[1,4]dioxino[2,3-g]phthalazin-6-amine;

[0097] (70) 9-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-1,3,4,6-tetramethyl-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0098] (71) (R)-8-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-1,3,3,5-tetramethyl-1H-pyrrolo[3,2-g]phthalazin-2(3H)-one;

[0099] (72) (R)-9-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-1,3,6-trimethylpyridazino[4,5-g]quinoxalin-2(1H)-one;

[0100] (73) (R)-6-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-4,9-dimethyl-2H-[1,4]oxazino[2,3-g]phthalazin-3(4H)-one;

[0101] (74) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-15-methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxacyclododecatetraeno[2,3-g]phthalazin-12-amine;

[0102] (75) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-18-methyl-2,3,5,6,8,9,11,12-octahydro-[1,4,7,10,13]pentaoxadiazolepentadecapenta[2,3-g]phthalazin-15-amine;

[0103] (76) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-17-methyl-2,3,5,6,7,8,10,11-octahydro-[1,4,7,10]tetraoxacyclotetradecapenta[5,6-g]phthalazin-14-amine;

[0104] (77) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-12-methyl-2,3,5,6-tetrahydro-[1,4,7]trioxino[2,3-g]phthalazin-9-amine;

[0105] (78) (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide;

[0106] (79) 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-imino-1,2,3,6-tetrahydro-1λ 6 -Thiopyran 1-oxide;

[0107] (80) (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-iminohexahydro-1λ 6 -Thiopyran 1-oxide;

[0108] (81) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0109] (82) (R)-cyclopropyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)methanone;

[0110] (83) (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-methylpiperazin-2-one;

[0111] (84) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(piperidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0112] (85) (R)-cyclopentyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)methanone;

[0113] (86) (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)(furan-3-yl)methanone;

[0114] (87) (R)-1-(4-(4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one;

[0115] (88) (R)-N-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-N-(methylsulfonyl)methanesulfonamide;

[0116] (89) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine;

[0117] (90)(R)-N 6 -cycloheptyl-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4,6-diamine;

[0118] (91) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one;

[0119] (92) (R)-6-(1-(cyclopropylsulfonyl)piperidin-4-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0120] (93) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one;

[0121] (94) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylpropan-1-one;

[0122] (95) (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)(tetrahydro-2H-pyran-4-yl)methanone;

[0123] (96) (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-N,N-dimethylpiperidine-1-carboxamide;

[0124] (97) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one;

[0125] (98) (R)-cyclobutyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)methanone;

[0126] (99) 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylic acid;

[0127] (100) (R)-6-(3-aminoazetidin-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine;

[0128] (101) (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethan-1-one;

[0129] (102) (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol;

[0130] (103) N-(4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-oxido-3,6-dihydro-2H-1λ 6 -thiopyran-1-ylidene)acetamide;

[0131] (104) 4-(4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-imino-1,2,3,6-tetrahydro-1λ 6 -Thiopyran 1-oxide;

[0132] (105) 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-imino-1,2,3,6-tetrahydro-1λ 6 -Thiopyran 1-oxide;

[0133] (106) (R)-N-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-1-oxido-1λ 6 -thiomorpholin-1-ylidene)-2,2,2-trifluoroacetamide;

[0134] (107) (R)-8-(1-(3-amino-5-(trifluoromethyl)phenyl)ethylamino)-1,3,3,5-tetramethyl-1,3-dihydro-2H-pyrrolo[2,3-g]phthalazin-2-one;

[0135] (108) (R)-1-cyclopropyl-8-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)-3,3,5-trimethyl-1,3-dihydro-2H-pyrrolo[2,3-g]phthalazin-2-one;

[0136] (109) (R)-2-methyl-3-(1-((1,3,3,5-tetramethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0137] (110) (R)-8-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethylamino)-1,3,3,5-tetramethyl-1,3-dihydro-2H-pyrrolo[2,3-g]phthalazin-2-one; and

[0138] (111) (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-15-methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxacyclododecatetraeno[2,3-g]phthalazin-12-amine.

[0139] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0140] Preferably, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier includes (but is not limited to) a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH regulator, a solvent, a cosolvent, a surfactant, a light-shielding agent (opacifying agent), etc.

[0141] In a fourth aspect, the present invention provides a pharmaceutical preparation, which is made from the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or is made from the above-mentioned pharmaceutical composition.

[0142] In a fifth aspect, the present invention provides the use of the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by the SOS1 protein.

[0143] Preferably, in the above use, the disease mediated at least in part by the SOS1 protein is cancer, in particular a cancer selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0144] In a sixth aspect, the present invention provides a drug combination comprising the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional cancer therapeutic agent.

[0145] Effects of the Invention

[0146] The compounds of the present invention have excellent in vitro inhibitory activity against SOS1 and also exhibit excellent inhibitory activity against MIA-PaCa2 cell proliferation, making them useful as SOS1 inhibitors, having the effects of inhibiting cell proliferation and angiogenesis, having good anti-tumor activity, and having a good effect in treating tumor diseases in mammals (including humans). DETAILED DESCRIPTION

[0147] Before the present invention is further described, it is to be understood that the present invention is not limited to the particular embodiments described herein; it is to be understood that the terminology used herein is for the purpose of describing only and not limiting of the particular embodiments.

[0148] [Definition of terms]

[0149] Unless otherwise specified, the following terms have the following meanings.

[0150] The term "pharmaceutically acceptable salt" refers to a salt of a compound having the structure of Formula I that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic or organic acids, which are also known as acid addition salts. Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), phosphoric acid (which can form phosphates or acid phosphates), etc. Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid (which can form citric acid monosalt, disalt or trisalt), maleic acid (which can form maleic acid monosalt or disalt), fumaric acid (which can form fumaric acid monosalt or disalt), succinic acid (which can form succinic acid monosalt or disalt), tartaric acid (which can form tartaric acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), malonic acid (which can form malonic acid monosalt or disalt), malic acid (which can form malic acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0151] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, trihydrates, and the like.

[0152] The term "solvate" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, formed by binding at least one solvent molecule through non-covalent intermolecular forces. The term "solvate" includes "hydrates." Common solvates include (but are not limited to) hydrates, ethanolates, and acetonides. It should be understood that the present invention encompasses all solvate forms that possess SOS1 inhibitory activity.

[0153] The term "isomers" refers to compounds that have the same number and types of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0154] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light. Because the compounds of the present invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Because the compounds of the present invention and their salts contain asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described below, a single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are nonsuperimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the invention.

[0155] The term "tautomer" (or "tautomeric form") refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0156] The term "cis-trans isomers" refers to stereoisomers formed by the different positions of the atoms (or groups) on either side of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, and in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis- and trans-isomeric forms of the compounds of the present invention are within the scope of the present invention.

[0157] The term "isotopically labeled" refers to a compound in which a specific atom in the structure is replaced by an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0158] The term "prodrug" refers to a derivative compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, can increase the bioavailability of the compound of the invention (e.g., facilitate absorption into the bloodstream) or compounds that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0159] The term "aryl" refers to a monocyclic or condensed polycyclic monovalent group having aromaticity, wherein the ring atoms are all C atoms, for example, 6 to 20, 6 to 14 or 6 to 12 carbon atoms. Non-limiting examples of aryl include (but are not limited to) phenyl, naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthalene. The term "C 6-10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms, C 6-10 Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and tetralin, and the like.

[0160] The term "heteroaryl" refers to a monocyclic or condensed polycyclic monovalent group having aromatic properties, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C, for example, a 5- to 10-membered ring, especially a 5- to 8-membered ring. Non-limiting examples of heteroaryl groups include (but are not limited to) The term "5- to 10-membered heteroaryl" refers to a heteroaryl group having 5 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O and S. Non-limiting examples of 5- to 10-membered heteroaryl groups include (but are not limited to) furyl, pyrrolyl, thienyl, pyridyl, indolyl and quinolinyl.

[0161] The term "heterocyclyl" refers to a fully saturated or partially unsaturated (but not fully unsaturated, e.g., having 1 or 2 double bonds) monocyclic, bridged, or spirocyclic monovalent group, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C, and may be, for example, a 3- to 14-membered ring, or even a 3- to 6-membered ring. The term "3- to 14-membered heterocyclyl" refers to a heterocyclyl having 3 to 14 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, and S; the term "3- to 6-membered heterocyclyl" refers to a heterocyclyl having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O, and S; and the term "5- to 15-membered heterocyclyl" refers to a heterocyclyl having 5 to 15 ring atoms, which may contain 1 to 5 heteroatoms selected from N, O, and S.

[0162] Non-limiting examples of saturated 3-membered heterocyclic groups include, but are not limited to, oxirane, thioethane, cyclonitroethane, and the like; non-limiting examples of saturated 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxetidinyl, thiatidinyl, and the like; non-limiting examples of saturated 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, and the like; non-limiting examples of saturated 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl (or derivative structures thereof, such as ), cyclopentylsulfoxide, cyclopentylsulfone, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl (or its derivative structure, for example ), 1,3-dithianyl, 1,4-dithianyl, etc.; non-limiting examples of saturated 7-membered heterocyclic groups include (but are not limited to) azepanyl, oxepanyl, thiepanyl, etc.

[0163] Non-limiting examples of partially unsaturated heterocyclic groups include, but are not limited to,

[0164] wait.

[0165] The term "alkyl" refers to a linear or branched monovalent hydrocarbon group containing no unsaturation.1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), and the like.

[0166] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms; the term "C 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, 2-methyl-2-buten-1-yl, pentenyl, hexenyl, and the like.

[0167] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms; the term "C 2-4 "Alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.

[0168] The term "haloalkyl" refers to a linear or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a halogen atom, and does not contain unsaturation. 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms; the term "C 1-4 "Haloalkyl" refers to a haloalkyl group having 1 to 4 carbon atoms. 1-6 Non-limiting examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, and the like.

[0169] The term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic (eg, spirocyclic, fused, or bridged) monovalent cyclic hydrocarbon group, for example, having 3 to 20, 3 to 12, 3 to 6, or 5 to 6 carbon atoms. 3-14 "Cycloalkyl" refers to a cycloalkyl group having 3 to 14 carbon atoms; the term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. 3-14 Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like; polycyclic C 3-14 Cycloalkyl groups include, but are not limited to, decahydronaphthyl, adamantyl, and the like.

[0170] The term "cycloalkenyl" refers to a monovalent cyclic hydrocarbon group having one or more carbon-carbon double bonds, which is monocyclic or polycyclic (e.g., spirocyclic, fused or bridged, but not aromatic) and which may have, for example, 3 to 20, 3 to 12, 3 to 6 or 5 to 6 carbon atoms. 3-14 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 14 carbon atoms, C 3-14 Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

[0171] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in Group VII of the Periodic Table of the Elements.

[0172] The term "hydroxy" refers to an -OH group.

[0173] The term "amino" refers to a -NH2 group. In some cases, amino can also mean that at least one of the H atoms in the structure is further replaced by an alkyl group (e.g., C 1-6 The monovalent group formed by substitution with an alkyl) group.

[0174] The term "nitro" refers to a -NO2 group.

[0175] The term "cyano" refers to a -CN group.

[0176] The term "single bond" refers to a chemical bond between atoms used to connect or interact with each other, such as an ionic bond, a covalent bond, a coordination bond, etc.; in the molecular structure of organic compounds, a single bond is usually a covalent bond.

[0177] The term "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, a heterocyclyl group is "optionally" substituted with a halogen, which means that the heterocyclyl group may be unsubstituted, monosubstituted, polysubstituted, or fully substituted with halogen atoms. It will be understood by those skilled in the art that any group containing one or more substituents does not introduce any substitution or substitution pattern that is sterically impossible and / or cannot be synthesized.

[0178] [Benzylamino-substituted heteropolycyclic compounds]

[0179] The present invention provides a series of novel benzylamino-substituted heteropolycyclic compounds or pharmaceutically acceptable forms thereof, such as salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs of such compounds.

[0180] In the first embodiment of the present invention, the structure of the compound is shown in Formula I:

[0181]

[0182] in:

[0183] Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl;

[0184] U and V are independently N or CR 2 ;

[0185] W is N or CR 6 ;

[0186] Every R 1 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, amino, halogen, cyano, and nitro;

[0187] Every R 2 are independently selected from hydrogen, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, halogen, cyano, -OR 2a and -NR 2a R 2b ;

[0188] R 2a and R 2bare independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0189] R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl and halogen;

[0190] R 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 2-4 Alkenyl, C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a 、-OR 4a 、-C(=O)OR 4a 、-NR 4a R 4b and -C(=O)NR 4a R 4b wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, amino, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0191] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic group, -C(=O)NH-3 to 14-membered heterocyclic group, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10 membered heteroaryl and -S(=O) m -C 1-6 wherein said alkyl, alkenyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of amino, halogen, C 3-14Cycloalkyl and 3- to 14-membered heterocyclyl;

[0192] R 5 Selected from hydrogen, amino, halogen, nitro and -OC 1-6 alkyl;

[0193] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, =O, =CH2, =NH, -C(=O)R 5a 、-OR 5a 、-C(=O)OR 5a 、-NR 5a R 5b and -C(=O)NR 5a R 5b , or, any two of the substituents together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group;

[0194] R 5a and R 5b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0195] R 6 Selected from hydrogen, amino, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group and -OC 1-6 alkyl;

[0196] m is 0, 1, or 2;

[0197] n is 0, 1, 2, or 3;

[0198] The heterocyclyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

[0199] In one embodiment of the present invention, ring A in formula I is selected from C 6-10 aryl and 5- to 10-membered heteroaryl.

[0200] In a preferred embodiment of the present invention, Ring A in Formula I is C 6-10 Aryl.

[0201] In a more preferred embodiment of the present invention, ring A in formula I is selected from phenyl and naphthyl, preferably phenyl.

[0202] In one embodiment of the present invention, n in formula I is 0, 1 or 2, preferably n is 1 or 2, more preferably n is 2.

[0203] In a preferred embodiment of the present invention, n in formula I is 0, i.e., ring A is not replaced by R 1 Substituent substitution.

[0204] In another preferred embodiment of the present invention, n in Formula I is 1, that is, Ring A is surrounded by 1 R 1 Substituent substituted, and the R 1 The substituent is substituted at any substitutable position of Ring A.

[0205] In another preferred embodiment of the present invention, n in Formula I is 2, that is, Ring A is surrounded by two R 1 Substituents, and the two R 1 The substituents are independently substituted at any substitutable position of Ring A.

[0206] In one embodiment of the present invention, each R 1 Independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, amino, halogen, cyano and nitro.

[0207] In a preferred embodiment of the present invention, each R 1 Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, amino, halogen and cyano.

[0208] In a more preferred embodiment of the present invention, each R 1 Independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, amino, fluoro, chloro, bromo, iodo and cyano.

[0209] In an even more preferred embodiment of the present invention, each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluoro and cyano.

[0210] In one embodiment of the present invention, each R 2 are independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl, preferably hydrogen and C 1-4 alkyl.

[0211] In a preferred embodiment of the present invention, each R 2 Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

[0212] In a more preferred embodiment of the present invention, each R 2 are independently selected from hydrogen and methyl.

[0213] In one embodiment of the present invention, R 3 Selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0214] In a preferred embodiment of the present invention, R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2 and -CH2CH2CF3.

[0215] In a more preferred embodiment of the present invention, R 3 For hydrogen.

[0216] In one embodiment of the present invention, R 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a 、-OR 4a 、-C(=O)OR 4a 、-NR 4a R 4b and -C(=O)NR 4a R 4bwherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, amino, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0217] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C(=O)-C 3-14 Cycloalkyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic group, -C(=O)NH-3 to 14-membered heterocyclic group, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10 membered heteroaryl and -S(=O) m -C 1-6 wherein said alkyl, alkenyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of amino, halogen, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0218] In a preferred embodiment of the present invention, R 4 Selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a 、-OR 4a and -NR 4a R 4b wherein each of the heterocyclyl, aryl and heteroaryl groups is optionally substituted with a substituent; if present, the substituent is selected from the group consisting of: =O, =NH, amino, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl and -C(=O)-C 1-6 alkyl;

[0219] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, -C(=O)-C 1-6Alkyl, -C(=O)-C 2-6 Alkenyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic group, -C(=O)-C 6-10 Aryl and -S(=O) m -C 1-6 Alkyl, wherein the alkyl and alkenyl are each optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of halogen, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0220] In a more preferred embodiment of the present invention, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl), imidazolyl, pyrazolyl (e.g., 1H-pyrazol-3-yl or 1H-pyrazol-4-yl), furanyl, oxazolyl, isoxazolyl, thiophenyl (e.g., thiophenyl-2-yl or thiophenyl-3-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl), isothiazolyl, dihydropyrrolyl (e.g., For example, 2,5-dihydro-1H-pyrrol-3-yl), dihydrofuranyl, dihydrothiophenyl, pyrrolinyl (e.g., pyrrolin-1-yl, pyrrolin-2-yl or pyrrolin-3-yl), tetrahydrofuranyl, tetrahydrothiophenyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl), pyranyl, thiopyranyl, dihydropyridinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-4-yl), piperidine yl (e.g., piperidin-1-yl, piperidin-4-yl), dihydropyranyl (e.g., 3,6-dihydro-2H-pyran-4-yl), tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), dihydrothiopyranyl (e.g., 3,6-dihydro-2H-thiopyran-4-yl), oxidized dihydrothiopyranyl (e.g., 1-oxidized-3,6-dihydro-2H-thiopyran-4-yl), dioxidized dihydrothiopyranyl (e.g., 1,1-dioxidized-3,6-dihydro-2H-thiopyran-4-yl), iminooxidized dihydrothiopyranyl (e.g., 1-imino-1-oxido-3,6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), oxidized tetrahydrothiopyranyl (e.g., 1-oxidized-tetrahydro-2H-thiopyran-4-yl), dioxidized tetrahydrothiopyranyl (e.g., 1,1-dioxidized-tetrahydro-2H-thiopyran-4-yl), iminooxidized tetrahydrothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl), piperazinyl (e.g., piperazin-1-yl), 1,4-diazo yl (e.g., 1,4-diazo -1-yl), 3,8-diazabicyclo[3.2.1]octyl (e.g., 3,8-diazabicyclo[3.2.1]oct-3-yl), 2-oxa-6-azaspiro[3.3]heptyl (e.g., 2-oxa-6-azaspiro[3.3]hept-6-yl), morpholinyl (e.g., morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl), indolyl, indazolyl (e.g., 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, or 1H-indazol-7-yl), 2,3-dihydro-1,4-benzodioxin-5-yl (e.g., 2,3-dihydro-1,4-benzodioxin-6-yl), formyl, acetyl, and propionyl;

[0221] wherein the phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrimidinyl, pyridinyl, pyranyl, thiopyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl, 1,4-dihydro- ... Each of the alkyl, morpholinyl, indolyl and indazolyl groups is optionally substituted with a substituent; if present, the substituent is selected from the group consisting of: =O, =NH, amino, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, acetyl and propionyl.

[0222] In another preferred embodiment of the present invention, R 4 is a 3- to 14-membered heterocyclyl group, which is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, and C 1-6 alkyl.

[0223] In another more preferred embodiment of the present invention, R 4 selected from tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-4-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), dihydrothiopyranyl (e.g., 3,6-dihydro-2H-thiopyran-4-yl), iminooxidodihydrothiopyranyl (e.g., 1-imino-1-oxido-3,6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), iminooxidotetrahydrothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl), piperazinyl (e.g., piperazin-1-yl), 1,4-diazo yl (e.g., 1,4-diazo -1-yl) and 2-oxa-6-azaspiro[3.3]heptyl (e.g., 2-oxa-6-azaspiro[3.3]hept-6-yl);

[0224] wherein the tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl and 1,4-dihydropyridinyl The alkyl groups are each optionally substituted with one substituent; if present, the substituent is selected from the group consisting of: =0, =NH, methyl, ethyl, n-propyl and isopropyl, preferably =0, =NH and methyl.

[0225] In another more preferred embodiment of the present invention, R 4 For-OR 4a , R 4a is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, pyrrolinyl, tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), tetrahydrothiophenyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl, and morpholinyl.

[0226] In another more preferred embodiment of the present invention, R 4 -NR 4a R 4b , R 4a and R 4b independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, a 3- to 14-membered heterocyclyl, acetyl, propionyl, acryloyl, crotonyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, piperidine-1-carboxyl, piperazine-1-carboxyl, morpholine-4-carboxyl, benzoyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and isopropylsulfonyl, wherein each of the methyl, ethyl, n-propyl, isopropyl, acryloyl, and crotonyl groups is optionally substituted with one substituent; if present, the substituent is selected from the group consisting of fluoro, chloro, bromo, iodo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl.

[0227] In one embodiment of the present invention, R 5 is selected from hydrogen, amino, halogen and nitro.

[0228] In a preferred embodiment of the present invention, R 5 is selected from hydrogen and halogen.

[0229] In a more preferred embodiment of the present invention, R5 For hydrogen.

[0230] In one embodiment of the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, =O, =CH2, =NH, -C(=O)R 5a 、-OR 5a 、-C(=O)OR 5a 、-NR 5a R 5b and -C(=O)NR 5a R 5b ; R 5a and R 5b independently selected from hydrogen and C 1-6 alkyl.

[0231] In a preferred embodiment of the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of: C 1-6 Alkyl, C 3-14 Cycloalkyl and =O, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and =O.

[0232] In a more preferred embodiment of the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5-, 6-, 9-, 12-, 14- or 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and =O, preferably methyl, cyclopropyl and =O.

[0233] In one embodiment of the present invention, R 6 Selected from hydrogen, C 1-4 Alkyl and -OC 1-5 alkyl.

[0234] In a preferred embodiment of the present invention, R 6is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy.

[0235] In a more preferred embodiment of the present invention, R 6 It is a methyl group.

[0236] In one embodiment of the present invention, U in formula I is CR 2 , V is N, W is N, and the structure of the compound of formula I is as shown in formula I-1:

[0237]

[0238] Among them: Ring A, n, R 1 、R 2 、R 3 、R 4 and R 5 As defined above.

[0239] In a more preferred embodiment of the present invention, in Formula I-1,

[0240] Ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1 Selected from the following groups:

[0241] R 2 is selected from hydrogen and methyl, preferably methyl;

[0242] R 3 is hydrogen;

[0243] R 4 is a 3- to 14-membered heterocyclyl group, which is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, and C 1-6 Alkyl; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, iminooxydihydrothiopyranyl, tetrahydrothiopyranyl, iminooxytetrahydrothiopyranyl, piperazinyl, 1,4-dihydro and 2-oxa-6-azaspiro[3.3]heptyl, wherein the tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl and 1,4-diazo Each of the groups is optionally substituted with a substituent; if present, the substituent is selected from the group consisting of: =O, =NH, methyl, ethyl, n-propyl and isopropyl, preferably =O, =NH and methyl;

[0244] R 5is hydrogen;

[0245] The heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.

[0246] In a preferred embodiment of the present invention, the structure of the compound of formula I-1 is shown in formula I-1A:

[0247]

[0248] Where: n, R 1 、R 2 、R 3 、R 4 and R 5 As defined above.

[0249] In a more preferred embodiment of the present invention, in Formula I-1A,

[0250] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1A Selected from the following groups:

[0251] R 2 is selected from hydrogen and methyl, preferably methyl;

[0252] R 3 is hydrogen;

[0253] R 4 is a 3- to 14-membered heterocyclyl group, which is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, and C 1-6 Alkyl; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, iminooxydihydrothiopyranyl, tetrahydrothiopyranyl, iminooxytetrahydrothiopyranyl, piperazinyl, 1,4-dihydro and 2-oxa-6-azaspiro[3.3]heptyl, wherein the tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl and 1,4-diazo Each of the groups is optionally substituted with a substituent; if present, the substituent is selected from the group consisting of: =O, =NH, methyl, ethyl, n-propyl and isopropyl, preferably =O, =NH and methyl;

[0254] R 5 is hydrogen;

[0255] The heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.

[0256] In a more preferred embodiment of the present invention, the structure of the compound of formula I-1A is as shown in formula I-1B (especially formula I-1B-1 or formula I-1B-2):

[0257]

[0258] Where: n, R 1 、R 2 and R 4 As defined above.

[0259] In a more preferred embodiment of the present invention, in Formula I-1B (especially Formula I-1B-1 or Formula I-1B-2),

[0260] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1B (especially formula I-1B-1 or formula I-1B-2) Selected from the following groups:

[0261] R 2 is selected from hydrogen and methyl, preferably methyl;

[0262] R 4 is a 3- to 14-membered heterocyclyl group, which is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, and C 1-6 Alkyl; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, iminooxydihydrothiopyranyl, tetrahydrothiopyranyl, iminooxytetrahydrothiopyranyl, piperazinyl, 1,4-dihydro and 2-oxa-6-azaspiro[3.3]heptyl, wherein the tetrahydropyridinyl, piperidinyl, dihydrothiopyranyl, tetrahydrothiopyranyl, piperazinyl and 1,4-diazo Each of the groups is optionally substituted with a substituent; if present, the substituent is selected from the group consisting of: =O, =NH, methyl, ethyl, n-propyl and isopropyl, preferably =O, =NH and methyl;

[0263] The heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.

[0264] In one embodiment of the present invention, U in formula I is CR 2 , V is CR 2 , W is N, and the structure of the compound of formula I is shown in formula I-2:

[0265]

[0266] Among them: Ring A, n, R 1 、R 2 、R 3 、R 4 and R 5 As defined above.

[0267] In a more preferred embodiment of the present invention, in formula I-2,

[0268] Ring A is phenyl;

[0269] n is 1 or 2, preferably 1;

[0270] Every R 1 Independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably -CHF2, -CF3, amino, fluorine, chlorine and nitro;

[0271] Every R 2 independently selected from hydrogen and methyl;

[0272] R 3 is hydrogen;

[0273] R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 8-membered heterocyclyl containing one or more heteroatoms selected from N, O and S as ring atoms;

[0274] but not including

[0275] In a preferred embodiment of the present invention, the structure of the compound of formula I-2 is shown in formula I-2A:

[0276]

[0277] in:

[0278] Ring B is a 5- to 15-membered, preferably a 5- to 8-membered heterocyclyl group containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O and S as ring atoms;

[0279] Every R 7 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, or any two R 7 Forming =O or =CH2;

[0280] p is 0, 1, 2, 3, 4, 5, or 6;

[0281] n、R 1 and R2 As defined above.

[0282] In a more preferred embodiment of the present invention, in Formula I-2A,

[0283] n is 1 or 2, preferably 1;

[0284] Every R 1 Independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably -CHF2, -CF3, amino, fluorine, chlorine and nitro;

[0285] Every R 2 independently selected from hydrogen and methyl;

[0286] Ring B is a 5- to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms;

[0287] but not including

[0288] Preferably, in the above-mentioned compound of formula I-2A, ring B is a 5- or 6-membered heterocyclic group, which contains 1 to 3 heteroatoms selected from N, O and S as ring atoms, preferably contains 1 or 2 heteroatoms selected from N, O and S as ring atoms, and more preferably contains 2 O atoms as ring atoms.

[0289] In one embodiment of the present invention, U in formula I is N, V ​​is CR 2 , W is CR 6 , at this time the structure of the compound of formula I is as shown in formula I-3:

[0290]

[0291] Among them: Ring A, n, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined above.

[0292] In a more preferred embodiment of the present invention, in formula I-3,

[0293] Ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3 Selected from the following groups:

[0294] R 2 is selected from hydrogen and methyl, preferably hydrogen;

[0295] R3 is hydrogen;

[0296] R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of: C 1-6 Alkyl, C 3-14 Cycloalkyl and =O, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and =O, more preferably methyl, cyclopropyl and =O;

[0297] R 6 is methyl;

[0298] The heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.

[0299] In a preferred embodiment of the present invention, the structure of the compound of formula I-3 is shown in formula I-3A:

[0300]

[0301] in:

[0302] Ring B is a 5- to 15-membered heterocyclic group containing 1 to 5 heteroatoms selected from N, O and S;

[0303] Every R 7 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, or any two R 7 Forming =O or =CH2;

[0304] p is 0, 1, 2, 3, 4, 5, or 6;

[0305] n、R 1 、R 2 and R 6 As defined above.

[0306] Preferably, in the above-mentioned compound of formula I-3A, ring B is a 5-, 6-, 9-, 12-, 14- or 15-membered heterocyclic group, which contains 1 to 3 heteroatoms selected from N, O and S as ring atoms, preferably contains 1 or 2 heteroatoms selected from N, O and S as ring atoms, and more preferably contains 1 or 2 heteroatoms selected from N and O as ring atoms.

[0307] Preferably, in the above-mentioned compound of formula I-3A, each R 7independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic group, or any two R 7 =O or =CH2 is formed.

[0308] More preferably, in the above-mentioned compound of formula I-3A, each R 7 Independently selected from C 1-6 Alkyl and C 3-14 Cycloalkyl, or any two R connected to the same ring atom 7 Formation =O.

[0309] Even more preferably, in the above compound of formula I-3A, each R 7 are independently selected from methyl and cyclopropyl, or any two R 7 Formation =O.

[0310] Preferably, in the above compound of formula I-3A, p is 0, 1, 2, 3 or 4.

[0311] More preferably, in the above compound of formula I-3A, p is 1, 2, 3 or 4.

[0312] Even more preferably, in the above compounds of formula I-3A, p is 2, 3 or 4.

[0313] In a more preferred embodiment of the present invention, in Formula I-3A,

[0314] n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3A Selected from the following groups:

[0315] R 2 is selected from hydrogen and methyl, preferably hydrogen;

[0316] R 6 is methyl;

[0317] Every R 7 are independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or any two R connected to the same ring atom 7 Formation = O;

[0318] Ring B and p are as defined above.

[0319] In a more preferred embodiment of the present invention, the structure of the compound of formula I-3A is shown in formula I-3B (especially formula I-3B-1 or formula I-3B-2):

[0320]

[0321] in:

[0322] Each X is independently C(R 7 )2、NR 7 , O or S;

[0323] Every R 7 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or any two R 7 Forming =O or =CH2;

[0324] q is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;

[0325] n、R 1 、R 2 and R 6 As defined above.

[0326] Preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2、NR 7 or O.

[0327] More preferably, in the compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2 or NR 7 .

[0328] Or, more preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2 or O.

[0329] Preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each R 7 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic group, or any two R 7 =O or =CH2 is formed.

[0330] Preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each R 7 are independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or any two R connected to the same ring atom 7 Formation =O.

[0331] Preferably, in the compounds of the above formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 3, 4, 7, 8, 9, 10, 11, 12 or 13.

[0332] More preferably, in the compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 3, 4, 7, 10, 12 or 13.

[0333] Even more preferably, in the compounds of the above formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 3.

[0334] Alternatively, even more preferably, in the compounds of formula I-3B above (especially formula I-3B-1 or formula I-3B-2), q is 4.

[0335] Alternatively, even more preferably, in the compounds of formula I-3B above (especially formula I-3B-1 or formula I-3B-2), q is 7.

[0336] Alternatively, even more preferably, in the compounds of the above formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 10.

[0337] Alternatively, even more preferably, in the compounds of the above formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 12.

[0338] Alternatively, even more preferably, in the compounds of the above formula I-3B (especially formula I-3B-1 or formula I-3B-2), q is 13.

[0339] In a more preferred embodiment of the present invention, in Formula I-3B (especially Formula I-3B-1 or Formula I-3B-2),

[0340] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3B (especially formula I-3B-1 or formula I-3B-2) Selected from the following groups:

[0341] Each X is independently C(R 7 )2、NR7 or O;

[0342] R 2 is selected from hydrogen and methyl, preferably hydrogen;

[0343] R 6 is methyl;

[0344] Every R 7 are independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or any two R connected to the same ring atom 7 Formation = O;

[0345] q is as defined above.

[0346] Further preferably, in the compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), The fragments were selected from the following structures:

[0347]

[0348] Preferably, The fragments were selected from the following structures:

[0349]

[0350] Every R 7 are independently selected from hydrogen, C 1-6 Alkyl (preferably methyl) and C 3-14 Cycloalkyl (preferably cyclopropyl), or any two R 7 Formation =O.

[0351] Alternatively, in a second class of embodiments of the present invention, in the compound of formula I,

[0352] Ring A is C 6-10 Aryl, preferably phenyl;

[0353] U and V are independently N or CR 2 ;

[0354] W is N or CR 6 ;

[0355] Every R 1 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, amino, halogen, cyano and nitro, preferably methyl, difluoromethyl, trifluoromethyl, amino, fluorine, chlorine, cyano and nitro;

[0356] Every R 2 independently selected from hydrogen and C 1-6 Alkyl, preferably hydrogen and methyl;

[0357] R 3 is hydrogen;

[0358] R 4 Selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3 to 14 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(=O)R 4a 、-OR 4a and -NR 4a R 4b wherein each of the cycloalkenyl, heterocyclyl, aryl and heteroaryl groups is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of: =O, =NH, amino, halogen, hydroxy, carboxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-14 cycloalkyl, -C(=O)-3 to 14-membered heterocyclyl, -C(=O)-5 to 10-membered heteroaryl, -C(=O)-NR 4a R 4b 、-S(=O) m -C 1-6 Alkyl and -S(=O) m -C 3-14 Cycloalkyl;

[0359] R 4a and R 4b are independently selected from hydrogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3- to 14-membered heterocyclic group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C(=O)NH-C 3-14 Cycloalkyl, -C(=O)-3 to 14-membered heterocyclic group, -C(=O)-C 6-10 Aryl and -S(=O) m -C 1-6 Alkyl, wherein the alkyl and alkenyl are each optionally substituted with one or more substituents; if present, each of the substituents is independently selected from the group consisting of halogen, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0360] R 5 Selected from hydrogen and -OC1-6 alkyl;

[0361] Or, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of: C 1-6 Alkyl, C 3-14 Cycloalkyl and =O;

[0362] R 6 C 1-6 Alkyl, preferably methyl;

[0363] Each m is independently 0, 1 or 2, preferably 2;

[0364] n is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 1 or 2, further preferably 2;

[0365] The heterocyclyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

[0366] In a preferred embodiment of the present invention, R 4 is a 3- to 14-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: =O, =NH, amino, hydroxy, C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-14 cycloalkyl, -C(=O)-3 to 14-membered heterocyclyl, -C(=O)-5 to 10-membered heteroaryl, -C(=O)-NR 4a R 4b 、-S(=O)2-C 1-6 Alkyl and -S(=O)2-C 3-14 Cycloalkyl;

[0367] R 4a and R 4b Independently C 1-6 Alkyl, preferably methyl.

[0368] In a more preferred embodiment of the present invention, R 4is selected from azetidinyl (e.g., azetidin-1-yl), piperazinyl (e.g., piperazin-1-yl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-4-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), dihydrothiopyranyl (e.g., 3,6-dihydro-2H-thiopyran-4-yl), iminooxydihydrothiopyranyl (e.g., , 1-imino-1-oxido-3,6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), iminooxidotetrahydrothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), and iminooxidothiomorpholinyl (e.g., 1-imino-1-oxido-thiomorpholin-4-yl);

[0369] wherein the azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, dihydrothiopyranyl, iminooxydihydrothiopyranyl, tetrahydrothiopyranyl, iminooxytetrahydrothiopyranyl, thiomorpholinyl, and iminooxythiomorpholinyl are each optionally substituted with one or more substituents; each of the substituents, if present, being independently selected from the group consisting of: =O, =NH, amino, hydroxy, methyl, -C(=O), -methyl, -C(=O)-ethyl, -C(=O)-isopropyl, -C(=O)-trifluoromethyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-(tetrahydropyran-4-yl), -C(=O)-(furan-3-yl), -C(=O)-N(CH3)2, -S(=O)2-methyl and -S(=O)2-cyclopropyl.

[0370] In a preferred embodiment of the present invention, R 5 is selected from hydrogen and methoxy.

[0371] In a more preferred embodiment of the present invention, R 5 For hydrogen.

[0372] In another preferred embodiment of the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, =O, =CH2, =NH, -C(=O)R 5a 、-OR 5a 、-C(=O)OR 5a 、-NR 5a R5b and -C(=O)NR 5a R 5b ; R 5a and R 5b independently selected from hydrogen and C 1-6 alkyl.

[0373] In a preferred embodiment of the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each said substituent is independently selected from the group consisting of methyl, cyclopropyl, and =0.

[0374] Alternatively, in another embodiment of the present invention, in the compound of formula I-1, ring A, n, R 1 、R 2 、R 3 、R 4 and R 5 As defined above.

[0375] In a preferred embodiment of the present invention, in formula I-1,

[0376] Ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1 Selected from the following groups:

[0377] R 2 is selected from hydrogen and methyl, preferably methyl;

[0378] R 3 is hydrogen;

[0379] R 4 is a 3- to 14-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: =O, =NH, amino, hydroxy, C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-14 cycloalkyl, -C(=O)-3 to 14-membered heterocyclyl, -C(=O)-5 to 10-membered heteroaryl, -C(=O)-NR 4a R 4b 、-S(=O)2-C 1-6 Alkyl and -S(=O)2-C 3-14 Cycloalkyl;

[0380] R 4a and R 4b Independently selected from C 1-6 Alkyl, preferably methyl;

[0381] R 5 is hydrogen;

[0382] The heterocyclic group and the heteroaryl group each independently contain one or more heteroatoms selected from N, O and S as ring atoms.

[0383] Alternatively, in another embodiment of the present invention, in the compound of formula I-1A, n, R 1 、R 2 、R 3 、R 4 and R 5 As defined above.

[0384] In a preferred embodiment of the present invention, in Formula I-1A,

[0385] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1A Selected from the following groups:

[0386] R 2 is selected from hydrogen and methyl, preferably methyl;

[0387] R 3 is hydrogen;

[0388] R 4 is selected from azetidinyl (e.g., azetidin-1-yl), piperazinyl (e.g., piperazin-1-yl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-4-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), dihydrothiopyranyl (e.g., 3,6-dihydro-2H-thiopyran-4-yl), iminooxydihydrothiopyranyl (e.g., , 1-imino-1-oxido-3,6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), iminooxidotetrahydrothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), and iminooxidothiomorpholinyl (e.g., 1-imino-1-oxido-thiomorpholin-4-yl);

[0389] wherein the azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, dihydrothiopyranyl, iminooxydihydrothiopyranyl, tetrahydrothiopyranyl, iminooxytetrahydrothiopyranyl, thiomorpholinyl, and iminooxythiomorpholinyl are each optionally substituted with one or more substituents; each of the substituents, if present, being independently selected from the group consisting of: =O, =NH, amino, hydroxy, methyl, -C(=O), -methyl, -C(=O)-ethyl, -C(=O)-isopropyl, -C(=O)-trifluoromethyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-(tetrahydropyran-4-yl), -C(=O)-(furan-3-yl), -C(=O)-N(CH3)2, -S(=O)2-methyl and -S(=O)2-cyclopropyl;

[0390] R 5 For hydrogen.

[0391] Alternatively, in another embodiment of the present invention, in Formula I-1B (especially Formula I-1B-1 or Formula I-1B-2), n, R 1 、R 2 and R 4 As defined above.

[0392] In a preferred embodiment of the present invention, in formula I-1B (especially formula I-1B-1 or formula I-1B-2),

[0393] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-1B (especially formula I-1B-1 or formula I-1B-2) Selected from the following groups:

[0394] R 2 is selected from hydrogen and methyl, preferably methyl;

[0395] R 4 selected from dihydrothiopyranyl (e.g., 3,6-dihydro-2H-thiopyran-4-yl), iminooxidodihydrothiopyranyl (e.g., 1-imino-1-oxido-3,6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), and iminooxidotetrahydrothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl);

[0396] wherein the dihydrothiopyranyl and tetrahydrothiopyranyl are each optionally substituted by one or more substituents; if present, each of the substituents is independently selected from the following groups: =O, =NH, hydroxy, -C(=O)-methyl, -C(=O)-trifluoromethyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-(tetrahydropyran-4-yl), -C(=O)-(furan-3-yl), -C(=O)-N(CH3)2, -S(=O)2-methyl and -S(=O)2-cyclopropyl.

[0397] Alternatively, in another embodiment of the present invention, in the compound of formula I-3, ring A, n, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined above.

[0398] In a preferred embodiment of the present invention, in formula I-3,

[0399] Ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3 Selected from the following groups:

[0400] R 2 is selected from hydrogen and methyl, preferably hydrogen;

[0401] R 3 is hydrogen;

[0402] R 4 and R 5 Together with the atoms to which they are attached, they form a 5- to 15-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from the group consisting of: C 1-6 Alkyl, C 3-14 Cycloalkyl and =O, preferably methyl, cyclopropyl and =O;

[0403] R 6 is methyl;

[0404] The heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.

[0405] Alternatively, in another embodiment of the present invention, in the compound of formula I-3A,

[0406] Ring B is a 5- to 15-membered heterocyclic group containing 1 to 5 heteroatoms selected from N, O and S, preferably N and O;

[0407] Every R 7 Independently selected from C 1-6 Alkyl and C 3-14 Cycloalkyl, or any two R connected to the same ring atom 7 Formation = O;

[0408] p is 0, 1, 2, 3, 4, 5, or 6;

[0409] n、R 1 、R 2 and R 6 As defined above.

[0410] Preferably, in the above compounds of formula I-3A, ring B is a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, preferably N and O, as ring atoms.

[0411] Preferably, in the above-mentioned compound of formula I-3A, each R 7 are independently selected from methyl and cyclopropyl, or any two R 7 Formation =O.

[0412] Preferably, in the above compound of formula I-3A, p is 0, 1, 2, 3, 4 or 5.

[0413] More preferably, in the above compound of formula I-3A, p is 1, 2, 3, 4 or 5.

[0414] Even more preferably, in the above compounds of formula I-3A, p is 2, 3, 4 or 5.

[0415] In a preferred embodiment of the present invention, in Formula I-3A,

[0416] n is 2; each R 1 Independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3A Selected from the following groups:

[0417] R 2 is selected from hydrogen and methyl, preferably hydrogen;

[0418] R 6 is methyl;

[0419] Every R 7 are independently selected from methyl and cyclopropyl, or any two R 7 Formation = O;

[0420] Ring B and p are as defined above.

[0421] Alternatively, in another embodiment of the present invention, in Formula I-3B (especially Formula I-3B-1 or Formula I-3B-2),

[0422] Each X is independently CH2, NR 7 , O or S, preferably CH2, NR 7 or O;

[0423] Every R 7 are independently selected from methyl and cyclopropyl, or any two R 7 Formation = O;

[0424] q is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;

[0425] n、R 1 、R 2 and R 6 As defined above.

[0426] Preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2、NR 7 or O.

[0427] More preferably, in the compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2 or NR 7 .

[0428] Or, more preferably, in the above-mentioned compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), each X is independently C(R 7 )2 or O.

[0429] In a preferred embodiment of the present invention, in Formula I-3B (especially Formula I-3B-1 or Formula I-3B-2),

[0430] n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluorine and cyano; preferably, in formula I-3B (especially formula I-3B-1 or formula I-3B-2) Selected from the following groups:

[0431] Each X is independently CH2, NR 7 or O;

[0432] R2 is selected from hydrogen and methyl, preferably hydrogen;

[0433] R 6 is methyl;

[0434] Every R 7 are independently selected from methyl and cyclopropyl, or any two R 7 Formation = O;

[0435] q is as defined above.

[0436] Further preferably, in the compound of formula I-3B (especially formula I-3B-1 or formula I-3B-2), The fragments were selected from the following structures:

[0437]

[0438] Every R 7 are independently selected from hydrogen, methyl and cyclopropyl, or any two R 7 Formation =O.

[0439] Specifically, the benzylamino-substituted heteropolycyclic compounds of the present invention include (but are not limited to) the following compounds:

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] [Pharmaceutical composition]

[0447] The term "pharmaceutical composition" refers to a composition that can be used as a medicament, which comprises a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.

[0448] The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the active ingredient of the drug and is harmless to the subject, including (but not limited to) one or more of a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH adjuster, a solvent, a cosolvent, a surfactant, an opacifying agent (opacifying agent), etc.

[0449] The present invention provides a pharmaceutical composition comprising a compound of the above-mentioned Formula I, Formula I-1, Formula I-IA, Formula I-IB, I-1B-1, I-1B-2, Formula I-2, Formula I-2A, Formula I-2B, I-2B-1, I-2B-2, Formula I-3, Formula I-3A, Formula I-3B, I-3B-1 or I-3B-2 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof.

[0450] In one embodiment of the present invention, the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0451] [Drug preparations]

[0452] The term "pharmaceutical preparation" refers to a finished drug prepared in a certain form for use by patients.

[0453] The present invention provides a pharmaceutical preparation, which is prepared from the above pharmaceutical composition.

[0454] In one embodiment of the present invention, the pharmaceutical preparation is a solid preparation for oral administration, including (but not limited to) pharmaceutically acceptable capsules, tablets, pills, powders, granules, etc. The solid preparation can be coated or microencapsulated with a coating or shell material (such as an enteric coating or other materials known in the art). The solid preparation can contain an opacifying agent, and the active ingredient therein can be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. In addition, the active ingredient can also be formed into a microcapsule form with one or more of the above-mentioned carriers.

[0455] In another embodiment of the present invention, the pharmaceutical preparation is a liquid dosage form for oral administration, including (but not limited to) pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.

[0456] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation is a dosage form for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.

[0457] In another embodiment of the present invention, the pharmaceutical preparation is in the form of a topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants and the like.

[0458] [Medical use]

[0459] Whether it is the above-mentioned formula I, formula I-1, formula I-IA, formula I-IB, I-1B-1, I-1B-2, formula I-2, formula I-2A, formula I-2B, I-2B-1, I-2B-2, formula I-3, formula I-3A, formula I-3B, I-3B-1 or I-3B-2 compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, it can be used for S OS1 exhibits inhibitory activity, and therefore the present invention provides the use of the above-mentioned compounds of Formula I, Formula I-1, Formula I-IA, Formula I-IB, Formula I-2, Formula I-2A, Formula I-2B, Formula I-3, Formula I-3A or Formula I-3B, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopically labeled or prodrugs thereof, or the above-mentioned pharmaceutical compositions or the above-mentioned pharmaceutical preparations in the preparation of medicaments for preventing and / or treating diseases mediated at least in part by SOS1 protein.

[0460] The present invention provides the use of the above-mentioned compounds of Formula I, Formula I-1, Formula I-IA, Formula I-IB, I-1B-1, I-1B-2, Formula I-2, Formula I-2A, Formula I-2B, I-2B-1, I-2B-2, Formula I-3, Formula I-3A, Formula I-3B, I-3B-1 or I-3B-2 or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopically labeled substances or prodrugs, or the above-mentioned pharmaceutical compositions or the above-mentioned pharmaceutical preparations in the preparation of drugs for preventing and / or treating cancer.

[0461] The term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growths at ectopic locations. Non-limiting examples of cancer include, but are not limited to, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0462] The present invention also provides the above-mentioned compounds of Formula I, Formula I-1, Formula I-IA, Formula I-IB, I-1B-1, I-1B-2, Formula I-2, Formula I-2A, Formula I-2B, I-2B-1, I-2B-2, Formula I-3, Formula I-3A, Formula I-3B, I-3B-1 or I-3B-2, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopically labeled or prodrugs thereof, or the above-mentioned pharmaceutical compositions or the above-mentioned pharmaceutical preparations, for use in preventing and / or treating diseases (especially cancer) mediated at least in part by SOS1 protein.

[0463] The present invention also provides a method for preventing and / or treating a disease (particularly cancer) mediated at least in part by the SOS1 protein, comprising administering a preventive and / or therapeutically effective amount of the above-mentioned compound of Formula I, Formula I-1, Formula I-IA, Formula I-IB, I-1B-1, I-1B-2, Formula I-2, Formula I-2A, Formula I-2B, I-2B-1, I-2B-2, Formula I-3, Formula I-3A, Formula I-3B, I-3B-1 or I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof, or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation to an individual in need thereof.

[0464] [Combination medication]

[0465] The present invention provides a pharmaceutical combination comprising a compound of Formula I, I-1, I-IA, I-IB, I-1B-1, I-1B-2, I-2, I-2A, I-2B, I-2B-1, I-2B-2, I-3, I-3A, I-3B, I-3B-1 or I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof, or a pharmaceutical composition or a pharmaceutical formulation, and at least one additional cancer therapeutic agent.

[0466] The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical preparation that can effectively control and / or combat cancer. Common cancer therapeutic agents include (but are not limited to) anti-purine drugs (such as pentostatin, etc.), anti-pyrimidine drugs (such as 5-fluorouracil), antifolate drugs (such as methotrexate), DNA polymerase inhibitors (such as cytarabine), alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin, carboplatin), DNA-damaging antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin), DNA-intercalating drugs that interfere with nucleic acid synthesis (such as epirubicin), drugs that block raw material supply (such as asparaginase), drugs that interfere with tubulin formation (such as paclitaxel), drugs that interfere with ribosome function (such as tadalafil), and drugs that interfere with ribosome function (such as tadalafil). Harringtonine), cytokines (such as IL-1), thymosin, tumor cell proliferation viruses (such as adenovirus ONYX-015), vinca alkaloids (such as vinorelbine), doxorubicin (such as doxorubicin, epirubicin, aclarubicin), tinibs (such as imatinib, gefitinib, erlotinib, dasatinib, sunitinib), monoclonal antibodies (such as trastuzumab, panitumumab, bevacizumab), bortezomib, calcitriol, capecitabine, aminoglutethimide, letrozole, Arimidex, everolimus, fulvestrant, irinotecan, pemetrexed, sirolimus, PD-1, PD-L1, etc.

[0467] In one embodiment of the present invention, the above-mentioned Formula I, Formula I-1, Formula I-IA, Formula I-IB, I-1B-1, I-1B-2, Formula I-2, Formula I-2A, Formula I-2B, I-2B-1, I-2B-2, Formula I-3, Formula I-3A, Formula I-3B, I-3B-1 or I-3B-2 compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation can be administered alone or in combination with other cancer therapeutic agents (or anti-tumor drugs). The combined therapy can be achieved by simultaneous, sequential or separate administration of different cancer therapeutic agents.

[0468] The technical solutions of the present invention will be further described below with reference to specific examples. Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained through conventional commercial means, and the experimental methods used are all conventional methods in the art.

[0469] Example 1: Preparation of Compound 1

[0470] (1) Synthesis route of intermediate 1-1

[0471]

[0472] Under nitrogen protection, 1-1a (20.00 g, 106.36 mmol, 1.0 eq), THF (150 mL), tert-butylsulfenamide (19.31 g, 159.54 mmol, 1.5 eq) and tetraethyl titanate (74.65 g, 327.26 mmol, 3.0 eq) were added to the reaction flask in sequence. After the addition was completed, the temperature was raised to 80°C and stirred for 4 hours. After the reaction system was cooled to room temperature, water (150 mL) was added, and then ethyl acetate (150 mL) was added and extracted twice. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 1-1b (28.0 g); MS: m / z 292.1 [M+H] + .

[0473] Compound 1-1b (28.00 g, 96.19 mmol, 1.0 eq), THF (400 mL), and water (6 mL) were added to the reaction flask in sequence. After cooling to -60 to -50°C, sodium borohydride (6.58 g, 173.14 mmol, 1.8 eq) was slowly added. After the addition was complete, the temperature was raised to -5 to 0°C and stirred for 30 minutes. Water (300 mL) was added to the system to quench the reaction, and ethyl acetate (300 mL) was added and extracted twice. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 1-1c (22.2 g); MS: m / z 294.1 [M+H] + .

[0474] Compound 1-1c (22.20 g, 75.76 mmol, 1.0 eq), dioxane (50 mL), and 4 M hydrochloric acid (40 mL) were added to the reaction flask in sequence. After addition, the mixture was stirred at room temperature for 2 hours. The pH of the system was adjusted to 8-9 with 1 M sodium hydroxide solution, and then ethyl acetate (100 mL) was added for extraction twice. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting solid was slurried with petroleum ether to obtain intermediate 1-1 (10.0 g); MS: m / z 190.1 [M+H] + .

[0475] (2) Synthesis route of intermediate 1-2

[0476]

[0477] Compound 1-2a (10.00 g, 65.76 mmol, 1.0 eq) and acetic anhydride (60 mL) were added to a reaction flask and heated to 70°C for 12 h. After completion, the reaction system was cooled to room temperature, diluted with water (300 mL), and the pH was adjusted to 8-9 with solid sodium carbonate. Ethyl acetate (200 mL) was added and extracted three times. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to dryness to yield compound 1-2b (13.20 g); MS: m / z 195.0 [M+H] + .

[0478] Compound 1-2b (13.20 g, 68.02 mmol, 1.0 eq) and aqueous ammonia (150 ml) were added to a sealed reaction flask and heated to 30°C for overnight reaction. After completion of the reaction, the reaction system was concentrated to dryness to obtain a solid, which was then dried in an oven to afford compound 1-2c (11.03 g); MS: m / z 162.0 [M+H] + .

[0479] Compound 1-2c (1.00 g, 6.21 mmol, 1.0 eq) was added to a reaction flask using acetonitrile (10 ml) as solvent. DIPEA (4.01 g, 31.05 mmol, 5.0 eq) and phosphorus oxychloride (2.86 g, 18.63 mmol, 3.0 eq) were then added to the reaction flask in sequence. The mixture was heated to 85°C under nitrogen for 3 h. After completion of the reaction, the reaction system was concentrated to dryness and then dissolved in ethyl acetate (30 ml). The pH was adjusted to 8-9 with aqueous sodium bicarbonate solution in an ice bath. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and dried by vortexing to obtain compound 1-2 (1.11 g), which was used directly in the next step.

[0480] (3) Synthesis route of compound 1

[0481]

[0482] Compound 1-2 (1.11 g, 6.20 mmol, 1.0 eq), compound 1-1 (1.29 g, 6.82 mmol, 1.1 eq), DIPEA (1.60 g, 12.40 mmol, 2.0 eq), and THF (11 ml) were added to the reaction flask in sequence and allowed to react at room temperature for 3 h. After completion of the reaction, the reaction system was concentrated to dryness and purified by column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain compound 1 (650 mg). 100 mg of the product was further purified by reverse phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 1 (2.50 mg); MS: m / z 333.2 [M+H] + ; 1H-NMR (400MHz, DMSO-d6): δ8.97-8.95(m,1H),8.90-8.88(m,1H),8.74(d,J=7.2Hz,1H),7.71(t,J=7.5Hz,1H),7.54- 7.50 (m, 2H), 7.31 (t, J = 7.7Hz, 1H), 7.26 (t, J = 54.0Hz, 1H), 5.81 (p, J = 7.1Hz, 1H), 2.41 (s, 3H), 1.63 (d, J = 7.0Hz, 3H).

[0483] Example 2: Preparation of Compound 2

[0484]

[0485] Compound 1 (500 mg, 1.43 mmol, 1.0 eq) and potassium nitrate (144 mg, 1.43 mmol, 1.0 eq) were added to a reaction flask, followed by concentrated sulfuric acid (5 ml). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction system was adjusted to pH 8-9 with aqueous sodium carbonate solution in an ice bath, and then extracted five times with ethyl acetate (20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 2 (571 mg). 100 mg of the product was purified by reverse phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 2 (17.87 mg); MS: m / z 378.0 [M+H] + .

[0486] Example 3: Preparation of Compound 3

[0487]

[0488] Under nitrogen protection, compound 5 (50.00 mg, 0.12 mmol, 1.0 eq) and tetrahydrofuran (3 mL) were added to the reaction flask, then cooled to -78 ° C. n-Butyl lithium (0.3 mL, 0.48 mmol, 4.0 eq, 1.6 M) was slowly added dropwise under temperature control. After the addition, the mixture was stirred for 0.5 hours. A mixed solution of N-fluorobisbenzenesulfonamide (57.7 mg, 0.18 mmol, 1.5 eq) and tetrahydrofuran (3 mL) was slowly added dropwise under temperature control. After the addition, the mixture was stirred for 0.5 hours and then naturally warmed to room temperature and stirred overnight. The system was quenched by adding water (10 mL), and the aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined and then washed with water (10 mL) and saturated sodium chloride aqueous solution (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by reverse phase column chromatography (Shim-pack GISC18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 3 (0.85 mg); MS: m / z 351.2 [M+H] + .

[0489] Example 4: Preparation of Compound 4

[0490]

[0491] Compound 4-1a (15.00 g, 65.23 mmol, 1.0 eq) and acetic anhydride (90 mL) were added to the reaction flask in sequence. After the addition was complete, the temperature was raised to 70°C and the reaction was stirred overnight. After the reaction system was cooled to room temperature, water (50 mL) was added and the pH of the system was adjusted to 8-9 with saturated sodium carbonate aqueous solution. Ethyl acetate (500 mL) was added and extracted twice. The organic phases were combined and washed once with water (200 mL) and once with saturated sodium chloride aqueous solution (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 4-1b (9.01 g); MS: m / z 273.0 [M+H] + .

[0492] Compound 4-1b (9.00 g, 33.09 mmol, 1.0 eq) and aqueous ammonia (90 mL) were added to the reaction flask in sequence, the temperature was raised to 30°C, and the reaction was stirred overnight. The reaction system was cooled to room temperature, dried, and then slurried in dichloromethane (100 mL) for 0.5 hours. The mixture was filtered, and the filter cake was washed twice with dichloromethane (50 mL) and dried. Compound 4-1c (6.56 g) was obtained; MS: m / z 240.0 [M+H] + .

[0493] Compound 4-1c (6.07 g, 25.40 mmol, 1.0 eq), acetonitrile (70 mL), N,N-diisopropylethylamine (16.40 g, 127.01 mmol, 5.0 eq), and phosphorus oxychloride (11.68 g, 76.20 mmol, 3.0 eq) were added to the reaction flask in sequence. The temperature was raised to 80°C and the reaction was stirred for 3 hours. The system was spin-dried, ethyl acetate (100 mL) was added, and the pH of the system was adjusted to 8-9 with saturated sodium carbonate aqueous solution under ice bath conditions. The liquids were separated, and the organic phase was washed once with water (50 mL) and once with saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried. Compound 4-1d (6.53 g) was obtained as a crude product; MS: m / z 258.0 [M+H] + .

[0494] Compound 4-1d (6.53 g), 1-1 (7.77 g, 38.10 mmol, 1.5 eq), N,N-diethylethylamine (9.84 g, 76.20 mmol, 3.0 eq) and tetrahydrofuran (70 mL) were added to the reaction flask in sequence and stirred at room temperature overnight. After the system cooled to room temperature, it was spin-dried and then added with water (50 mL). The aqueous phase was extracted twice with ethyl acetate (100 ml). The organic phases were combined and washed once with water (50 ml) and once with saturated sodium chloride aqueous solution (50 ml). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4 (7.0 g). Then, 100 mg of compound 4 was purified by reverse phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain compound 4 (6.11 mg); MS: m / z 411.0 [M+H] + .

[0495] Example 5-9: Preparation of Compound 5-9

[0496] Compounds 5-9 (see Table 1) were synthesized according to procedures substantially similar to those of Example 4.

[0497] Table 1. Structure, mass spectrometry, and H NMR data of compound 9

[0498]

[0499] Example 10: Preparation of Compound 10

[0500]

[0501] Under nitrogen protection, compound 4 (55.00 mg, 0.13 mmol, 1.0 eq), 3-thiopheneboronic acid (25.70 mg, 0.20 mmol, 1.5 eq), sodium carbonate (35.5 mg, 0.34 mmol, 2.5 eq), tetrakis(triphenylphosphine)palladium (31.00 mg, 0.026 mmol, 0.2 eq), 1,4-dioxane (4 ml), and water (1 ml) were added to the reaction flask in sequence. The temperature was raised to 90°C and the reaction was stirred overnight. The system was cooled to room temperature, quenched with water (5 ml), and extracted twice with ethyl acetate (20 ml). The combined organic phases were washed once with water (10 ml) and once with a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by reverse-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 10 (10.3 mg); MS: m / z 415.0 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ9.39(d,J=2.3Hz,1H),9.17(d,J=2.4Hz,1H),8.80(d,J=7.2Hz,1H),8.19-8.14(m,1H),7.83-7.78(m,2H),7.74(t, J=7.5Hz,1H),7.53(t,J=7.1Hz,1H),7.32(t,J=7.7Hz,1H),7.26(t,J=54.0Hz,1H),5.84(p,J=6.9Hz,1H),2.42(s,3H),1.67(d,J=7.0Hz,3H).

[0502] Examples 11-36, 81-82, 85-87, 89, 91-96, 98-99: Preparation of Compounds 11-36, 81-82, 85-87, 89, 91-96, 98-99

[0503] Compounds 11-36, 81-82, 85-87, 89, 91-96, and 98-99 (see Table 2) were synthesized according to procedures substantially similar to those of Example 10.

[0504] Table 2. Structures, mass spectra, and H NMR data of compounds 11-36, 81-82, 85-87, 89, 91-96, and 98-99

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513] Example 37: Preparation of Compound 37

[0514]

[0515] Compound 2 (64 mg, 0.16 mmol, 1.0 eq), ethanol (3 ml), and stannous chloride (153 mg, 0.81 mmol, 5.0 eq) were added to the reaction flask in sequence and heated to 50°C under nitrogen for 4 h. The reaction system was cooled to room temperature and the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution to precipitate a solid. Ethyl acetate (10 ml) was then added, stirred, and filtered. The filtrate was collected and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product. The crude product was first purified by HPLC (developing solvent: dichloromethane / methanol = 10:1) and then by reverse phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid in water / acetonitrile) to obtain pure compound 37 (7.62 mg); MS: m / z 348.0 [M+H] + .

[0516] Example 38: Preparation of Compound 38

[0517]

[0518] Compound 37 (50 mg, 0.144 mmol, 1.0 eq), DCM (2 ml), triethylamine (44 mg, 0.432 mmol, 3.0 eq), and methanesulfonyl chloride (20 mg, 0.173 mmol, 1.2 eq) were added sequentially to a reaction flask and allowed to react at room temperature for 1 h. After completion, the reaction system was diluted with DCM (10 ml) and the pH was adjusted to 8-9 with aqueous sodium bicarbonate. The layers were separated, and the organic phase was retained. The aqueous phase was extracted twice with dichloromethane (10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by reverse-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid in water / acetonitrile) to afford pure compound 38 (7.15 mg); MS: m / z 426.0 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ9.88(s,1H),8.97(dd,J=4.4,1.8Hz,1H),8.90(dd,J=8.3,1.9Hz,1H),8.83(d,J=7.0Hz,1H),7.55-7.50 (m,2H),7.32(dd,J=5.5,2.7Hz,1H),7.26(t,J=54.0Hz,1H),5.73(p,J=7.1Hz,1H),2.95(s,3H),2.42(s,3H),1.63(d,J=7.1Hz,3H).

[0519] Example 39: Preparation of Compound 39

[0520]

[0521] Compound 37 (50 mg, 0.144 mmol, 1.0 eq), 2-fluoroacrylic acid (13 mg, 0.144 mmol, 1.0 eq), N,N-dimethylformamide (3 mL), EDCI (40 mg, 0.21 mmol, 1.5 eq), and HOBt (28 mg, 0.21 mmol, 1.5 eq) were added to a reaction flask in sequence. The mixture was stirred at room temperature for 12 h. Water (4 mL) was then added to the system, followed by extraction with ethyl acetate (4 mL*2). The organic phase was concentrated, and the crude product was purified by reverse-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to afford pure compound 39 (5.23 mg). MS: m / z 420.0 [M+H] + ; 1H-NMR (400MHz, DMSO-d6): δ10.48(s,1H),8.96(dd,J=4.4,1.8Hz,1H),8.91(dd,J=8.3 ,1.9Hz,1H),8.77(d,J=6.8Hz,1H),8.00(dd,J=6.5,2.6Hz,1H),7.93(dd,J=6.0,2.6Hz ,1H),7.53(dd,J=8.2,4.4Hz,1H),7.26(t,J=54.0Hz,1H),5.78-5.74(m,1H),5.69(dd ,J=44.0,3.7Hz,1H),5.43(dd,J=15.5,3.7Hz,1H),2.41(s,3H),1.62(d,J=7.0Hz,3H).

[0522] Example 40-41: Preparation of Compound 40-41

[0523] Compounds 40-41 (see Table 3) were synthesized according to procedures substantially similar to Example 38.

[0524] Table 3. Structures, mass spectra, and H NMR data of compounds 40-41

[0525]

[0526] Example 42: Preparation of Compound 42

[0527]

[0528] Compound 37 (50 mg, 0.144 mmol, 1.0 eq), triethylamine (44 mg, 0.432 mmol, 3.0 eq), dichloromethane (3 mL), and triphosgene (18 mg, 0.06 mmol, 0.4 eq) were added to a reaction flask in sequence. After stirring for 30 minutes, cyclopropylamine (8.2 mg, 0.144 mmol, 1.0 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 6 hours. Water (4 mL) was then added to the system, and extraction was performed three times with ethyl acetate (4 mL). The organic phase was concentrated, and the crude product was purified by reverse phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid in water / acetonitrile) to obtain pure compound 42 (5.23 mg). MS: m / z 431.0 [M+H] + ;

[0529] Example 43: Preparation of Compound 43

[0530] Compound 43 (see Table 4) was synthesized according to procedures substantially similar to those of Example 42.

[0531] Table 4. Structure and mass spectrometry data of compound 43

[0532]

[0533] Example 44: Preparation of Compound 44

[0534]

[0535] Compound 37 (50 mg, 0.144 mmol, 1.0 eq), potassium carbonate (59.6 mg, 0.432 mmol, 3.0 eq), DMF (3 mL), and cyclopentyl bromide (31.3 mg, 0.21 mmol, 1.5 eq) were added to a reaction flask in sequence. The mixture was then heated to 80°C and stirred for 6 h. Water (4 mL) was then added to the system, and extraction was performed three times with ethyl acetate (4 mL). The organic phase was concentrated, and the crude product was purified by reverse phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to obtain pure compound 44 (7.26 mg). MS: m / z 416.1 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ8.48(s,1H),8.23(d,J=7.4Hz,1H),7.68(t,J=7.5Hz,1H),7. 54(d,J=2.8Hz,1H),7.51(t,J=7.4Hz,1H),7.31(t,J=7.7Hz,1H),7.26(t,J=54.0Hz,1H) ,6.31(d,J=7.2Hz,1H),5.81(p,J=7.0Hz,1H),3.97-3.86(m,1H),2.31(s,3H),2.16-2.0 2(m,2H),1.80-1.71(m,2H),1.68-1.59(m,2H),1.63(d,J=7.0Hz,3H),1.56-1.44(m,2H).

[0536] Examples 45-47, 88: Preparation of Compounds 45-47, 88

[0537] Compounds 45-47 and 88 (see Table 5) were synthesized according to procedures substantially similar to Example 44.

[0538] Table 5. Structures, mass spectra, and H NMR data of compounds 45-47 and 88

[0539]

[0540] Example 48: Preparation of Compound 48

[0541]

[0542] Compound 37 (50 mg, 0.144 mmol, 1.0 eq) and concentrated sulfuric acid (2 mL) were added sequentially to a reaction flask. After the system was cooled to 0°C, sodium nitrite (12 mg, 0.17 mmol, 1.2 eq) was added. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 h. Water (5 mL) was then added and stirred for 2 h. The pH of the system was adjusted to 7-8, and the mixture was extracted three times with ethyl acetate (4 mL). The organic phase was concentrated, and the crude product was purified by reverse-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid in water / acetonitrile) to afford pure compound 48 (3.21 mg). MS: m / z 349.2 [M+H] + .

[0543] Example 49: Preparation of Compound 49

[0544]

[0545] Under nitrogen, compound 4 (100 mg, 0.24 mmol, 1.0 eq), tributyl(1-ethoxyvinyl)tin (132.13 mg, 0.37 mmol, 1.5 eq), triethylamine (74.60 mg, 0.73 mmol, 3.0 eq), bis(triphenylphosphine)palladium dichloride (34.00 mg, 0.049 mmol, 0.2 eq), and 1,4-dioxane (4 ml) were added to the reaction flask in sequence. The temperature was raised to 90°C and stirred for 6 hours. The system was cooled to room temperature, quenched with water (10 ml), and extracted twice with ethyl acetate (20 ml). The organic phases were combined and washed once with water (10 ml) and once with saturated sodium chloride aqueous solution (10 ml). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by TLC (DCM / MEOH = 10 / 1) to give 50 mg of the intermediate product. Tetrahydrofuran (4 ml) and 1 M hydrochloric acid (1 ml) were added, and the mixture was stirred at room temperature overnight. The system was then spin-dried. The crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 49 (2.69 mg); MS: m / z 375.0 [M+H] + .

[0546] Example 50: Preparation of Compound 50

[0547]

[0548] Under nitrogen, compound 4 (100.00 mg, 0.24 mmol, 1.0 eq), morpholine (31.90 mg, 0.37 mmol, 1.5 eq), Pd2(dba)3 (55.80 mg, 0.061 mmol, 0.25 eq), xantphos (70.60 mg, 0.12 mmol, 0.5 eq), potassium phosphate (155.30 mg, 0.73 mmol, 3.0 eq), and toluene (4 ml) were added to the reaction flask in sequence. The temperature was raised to 110°C and the reaction was stirred for 6 hours. The system was cooled to room temperature, quenched with water (5 ml), and extracted twice with ethyl acetate (20 ml). The organic phases were combined and washed once with water (10 ml) and once with saturated sodium chloride aqueous solution (10 ml). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 50 (2.29 mg); MS: m / z 418.2 [M+H] + .

[0549] Examples 51-58, 83-84, 90, 97, 100: Preparation of Compounds 51-58, 83-84, 90, 97, 100

[0550] Compounds 51-58, 83-84, 90, 97, and 100 (see Table 6) were synthesized according to procedures substantially similar to Example 50.

[0551] Table 6. Structures, mass spectra, and H NMR data of compounds 51-58, 83-84, 90, 97, and 100

[0552]

[0553]

[0554]

[0555]

[0556] Example 59: Preparation of Compound 59

[0557] (1) Synthesis route of intermediate 59-1

[0558]

[0559] Compound 68-1a (6.00 g, 30.90 mmol, 1.0 eq), acetic acid (36 ml), and nitric acid (18 ml) were added to the reaction flask in sequence and heated to 70°C for 1 h. After completion of the reaction, the reaction system was cooled to room temperature and concentrated to dryness. The crude product was adjusted to pH 7-8 with 5% aqueous sodium hydroxide solution and extracted twice with ethyl acetate (200 ml). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to dryness to yield compound 59-1a (5.82 g); MS: m / z 239.8 [M+H] + .

[0560] Compound 59-1a (5.03 g, 21.03 mmol, 1.0 eq), methanol (50 ml), THF (70 ml), and 10% palladium on carbon (0.50 g) were added to the reaction flask in sequence. The mixture was replaced with hydrogen three times and heated to 30°C under a hydrogen atmosphere for 2 h. After completion of the reaction, the reaction system was filtered, the filtrate was spin-dried, and then washed twice with dichloromethane to obtain compound 59-1b (4.30 g); MS: m / z 209.8 [M+H] + .

[0561] Compound 59-1b (2.00 g, 8.36 mmol, 1.0 eq) and acetic anhydride (20 ml) were added to the reaction flask in sequence and heated to 60°C for 3 h. After completion of the reaction, the reaction system was cooled to room temperature and poured into 100 ml of water. The pH of the system was adjusted to 8-9 with solid sodium carbonate. The solution was then extracted three times with ethyl acetate (50 ml). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to dryness to afford compound 59-1c (2.33 g); MS: m / z 251.8 [M+H] + .

[0562] Compound 59-1c (1.00 g, 3.98 mmol, 1.0 eq) and aqueous ammonia (20 ml) were added sequentially to a sealed reaction flask and heated to 60°C for overnight reaction. After completion of the reaction, the reaction system was concentrated to dryness and purified by column chromatography to obtain compound 59-1d (0.56 g); MS: m / z 218.8 [M+H] + .

[0563] Compound 59-1d (450 mg, 2.06 mmol, 1.0 eq), thionyl chloride (10 ml), and two drops of DMF were added sequentially to the reaction flask. The mixture was heated to 85°C under nitrogen for 3 h. After completion of the reaction, the reaction system was concentrated to dryness, and the crude product was dissolved in ethyl acetate (50 ml). The pH was then adjusted to 8-9 with aqueous sodium bicarbonate solution under an ice bath. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to afford compound 59-1 (0.23 g); MS: m / z 237.0 [M+H] + .

[0564] (2) Synthesis route of compound 59

[0565]

[0566] Compound 59-1 (60 mg, 0.25 mmol, 1.0 eq), compound 1-1 (72 mg, 0.38 mmol, 1.5 eq), DIPEA (98 mg, 0.76 mmol, 3.0 eq), and acetonitrile (3 ml) were added sequentially to a reaction flask. The mixture was heated to 80°C for 2 h. After completion of the reaction, the reaction system was concentrated to dryness and purified by column chromatography, followed by reverse-phase column chromatography (Shim-pack GIS-C18 20*250 nm, 5 μm; 0.01% formic acid-water / acetonitrile) to afford pure compound 59 (0.94 mg); MS: m / z 389.8 [M+H] + .

[0567] Examples 60-67: Preparation of Compounds 60-67

[0568] Compounds 60-67 (see Table 7) were synthesized according to procedures substantially similar to Example 59.

[0569] Table 7. Structures and mass spectrometry data of compounds 60-67

[0570]

[0571]

[0572] Example 68: Preparation of Compound 68

[0573] (1) Synthesis route of intermediate 68-1

[0574]

[0575] Compound 68-1a (10 g, 51.53 mmol, 1.0 eq) and DMF (30 mL) were added to the reaction flask. After cooling to -10°C, a solution of NBS (9.18 g, 51.53 mmol, 1.0 eq) in DMF (30 mL) was slowly added. After the addition was complete, the temperature was raised to 95°C and the reaction was maintained for 3.5 h. The system was then cooled to room temperature and a large amount of ice water was added to precipitate the solid. The filter cake was collected by filtration, washed with water, and dried to obtain the crude product 68-1b, which was directly used in the next step; MS: m / z 273.0 [M+H] + ;

[0576] Under nitrogen protection, the crude product 68-1b (10 g, 36.77 mmol, 1.0 eq), 1,4-dioxane (100 mL), tributyl(1-ethoxyvinyl)tin (16.05 g, 44.12 mmol, 1.2 eq), Pd(dppf)2Cl2 (1.3 g, 1.84 mmol, 0.05 eq) and triethylamine (11.2 g, 110.31 mmol, 3.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 90 ° C. After 6 h of reaction, the system was cooled to room temperature, filtered, and a large amount of water was added to the system. The mixture was extracted three times with EA (100 mL). The organic layers were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude compound 68-1c, which was directly used in the next step; MS: m / z 265.0 [M+H] + ;

[0577] The crude product 68-1c from the previous step, THF (120 mL), and 1N dilute hydrochloric acid (120 mL) were added to the reaction flask in sequence. After stirring at room temperature for 1 h, the reaction product was converted from 68-1c to 68-1d as monitored by TLC and mass spectrometry. The product was diluted with a large amount of water and extracted three times with EA (100 mL). The organic layers were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1-2:1) to obtain compound 68-1d (4.8 g). 68-1a (4.4 g) was recovered; MS: m / z 237.0 [M+H] + ;

[0578] Compound 68-1d (4.8 g, 20.33 mmol, 1.0 eq), anhydrous ethanol (50 mL) and hydrazine hydrate (5.76 g, 91.50 mmol, 4.5 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and reacted for 1.5 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was slurried with methyl tert-butyl ether to give compound 68-1e (3.47 g); MS: m / z 219.0 [M+H] + ;

[0579] Compound 68-1e (3.47 g, 15.91 mmol, 1.0 eq), POCl3 (20 mL), and N,N-diethylaniline (2.45 g, 15.91 mmol, 1.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 105°C and reacted for 3 h. The system was then concentrated under reduced pressure to remove the solvent, and EA (50 mL) was added. The pH was slowly adjusted to 7-8 with a saturated NaHCO3 solution under an ice bath. EA (50 mL) was added and extracted four times. The organic layers were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4:1-1:1) to give compound 68-1 (2.53 g); MS: m / z 237.0 [M+H] + .

[0580] (2) Synthesis route of compound 68

[0581]

[0582] Under nitrogen protection, compound 68-1 (100 mg, 0.42 mmol, 1.0 eq), toluene (12 mL), 1-1 (200 mg, 1.06 mmol, 2.5 eq), Pd(dba)3 (119 mg, 0.13 mmol, 0.3 eq), Xantphos (151.2 mg, 0.26 mmol, 0.6 eq) and tripotassium phosphate (275 mg, 1.3 mmol, 3.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 110°C and reacted for 6.5 h. The solvent was removed by concentration, and water and ethyl acetate were added for extraction and separation. The organic phase was concentrated to dryness, and the crude product was purified by reverse phase column chromatography (Shim-park GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 68 (3.15 mg); MS: m / z 390.2 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ8.25(s,1H),8.07(s,1H),7.59(t,J=7.5Hz,1H),7.51-7.43(m,2H), 7.40-7.31(m,3H),7.28-7.19(m,2H),5.68(p,J=6.9Hz,1H),4.45(s,4H),1.58(d,J=7.0Hz,3H).

[0583] Example 69: Preparation of Compound 69

[0584] Compound 69 was synthesized according to procedures substantially similar to those of Example 68 (see Table 8).

[0585] Table 8. Structure, mass spectrometry, and H NMR data of compound 69

[0586]

[0587] Example 70: Preparation of Compound 70

[0588] (1) Synthesis route of intermediate 70-1

[0589]

[0590] At 0°C, concentrated H2SO4 (80 mL) and compound 70-1a (10.0 g, 45.88 mmol, 1.0 eq) were added sequentially to the reaction flask. Potassium nitrate (4.63 g, 45.88 mmol, 1.0 eq) was then slowly added in portions. The reaction system was allowed to react at 0°C for 1 h. After the reaction was complete, the system was slowly poured into ice water (250 mL) and stirred. After returning to room temperature, the mixture was filtered, the filter cake was rinsed twice with water, and dried to obtain compound 70-1b (11.43 g); MS: m / z 261.8 [MH] - ;

[0591] Compound 70-1b (11.43 g, 43.47 mmol, 1.0 eq), MeOH (100 mL), and concentrated H2SO4 (4.26 g, 43.47 mmol, 1.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 65°C and reacted for 48 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was rinsed twice with water and dried to obtain compound 70-1c (5.94 g); MS: m / z 277.8 [M+H] + ;

[0592] Compound 70-1c (5.50 g, 19.86 mmol, 1.0 eq), DMF (55 mL), DL-alanine methyl ester hydrochloride (4.16 g, 29.79 mmol, 1.5 eq) and triethylamine (5.02 g, 49.65 mmol, 2.5 eq) were added to the reaction flask in sequence. The reaction system was heated to 80°C and reacted for 2 h. The system was then cooled to room temperature, water (200 mL) was added, stirred, and filtered. The filter cake was rinsed twice with water and dried to obtain compound 70-1d (6.40 g); MS: m / z 360.8 [M+H] + ;

[0593] Compound 70-1d (6.40 g, 17.78 mmol, 1.0 eq), anhydrous ethanol (65 mL) and SnCl2 (16.35 g, 88.89 mmol, 5.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and reacted for 2 h. The system was then cooled to room temperature and a saturated NaHCO3 solution was added to adjust the pH to neutral. EA (150 mL) was added, stirred, and filtered. The filter cake was rinsed with EA (50 mL*3). The filtrate was separated, and the organic phase was washed with water and saturated brine in sequence, then dried over anhydrous Na2SO4, filtered, and concentrated to give intermediate 70-1e (2.40 g); MS: m / z 299.0 [M+H] + ;

[0594] Compound 70-1e (2.00 g, 6.71 mmol, 1.0 eq) and DMF (25 mL) were added to the reaction flask in sequence at 0°C. NaH (1.34 g, 33.56 mmol, 5.0 eq) was then slowly added in portions and stirred for 20 minutes. MeI (3.81 g, 26.84 mmol, 4.0 eq) was then added. After reacting for 30 minutes, the system was quenched with water (20 mL) and extracted with EA (50 mL*3). The organic layers were combined and washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give compound 70-1f (1.47 g); MS: m / z 327.0 [M+H] + ;

[0595] Under nitrogen protection, compound 70-1f (1.40 g, 4.30 mmol, 1.0 eq), 1,4-dioxane (15 mL), tributyl(1-ethoxyvinyl)tin (1.86 g, 5.16 mmol, 1.2 eq), Pd(dppf)2Cl2 (0.16 g, 0.22 mmol, 0.05 eq) and triethylamine (1.31 g, 12.90 mmol, 3.0 eq) were added to the reaction flask in sequence, and the reaction system was heated to 90 ° C. After 7 h of reaction, 70-1g was obtained. The system was cooled to room temperature and the pH was adjusted to weak acidity by adding dilute HCl. The reaction product was converted from 70-1g to 70-1h as monitored by TLC and mass spectrometry. EA (30 ml) was added and extracted three times. The organic layers were combined and washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain compound 70-1h (0.67 g); MS: m / z 291.2 [M+H] + ;

[0596] Compound 70-1h (0.67 g, 2.31 mmol, 1.0 eq), anhydrous ethanol (12 mL) and hydrazine hydrate (3.46 g, 6.93 mmol, 3.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and reacted for 2 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was slurried with methyl tert-butyl ether to obtain compound 70-1i (0.47 g); MS: m / z 273.0 [M+H] + ;

[0597] Compound 70-1i (0.44 g, 1.62 mmol, 1.0 eq), POCl3 (4 mL) and N,N-diethylaniline (0.24 g, 1.62 mmol, 1.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 105°C and reacted for 3.5 h. The system was then concentrated under low pressure to remove the solvent, ice water (10 mL) was added, the pH was adjusted to 7-8 with saturated NaHCO3 solution, and EA (10 mL) was added and extracted three times. The organic layers were combined and then washed once with water and saturated brine in sequence. The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1.5) to give compound 70-1 (0.31 g); MS: m / z 291.0 [M+H] + .

[0598] (2) Synthesis route of compound 70

[0599]

[0600] Under nitrogen protection, intermediate 70-1 (20 mg, 0.07 mmol, 1.0 eq), toluene (4 mL), 1-1 (33 mg, 0.17 mmol, 2.5 eq), Pd(dba)3 (40 mg, 0.04 mmol, 0.6 eq), Xantphos (48 mg, 0.08 mmol, 1.2 eq) and tripotassium phosphate (88 mg, 0.41 mmol, 6.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 110°C and reacted for 24 h. The solvent was removed by concentration, and water and ethyl acetate were added for extraction and separation. The organic phase was concentrated to dryness, and the crude product was purified by reverse phase column chromatography (Shim-park GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 70 (2.51 mg); MS: m / z 444.2 [M+H] + .

[0601] Examples 71-73, 107-110: Preparation of Compounds 71-73, 107-110

[0602] Compounds 71-73, 107-110 (see Table 9) were synthesized according to procedures substantially similar to Example 70.

[0603] Table 9. Structures, mass spectra, and H NMR data of compounds 71-73, 107-110

[0604]

[0605]

[0606] Example 74: Preparation of Compound 74

[0607] Synthesis route

[0608]

[0609] Compound 74-1a (10 g, 51.00 mmol, 1.0 eq) and DMF (25 mL) were added to the reaction flask. After cooling to -10°C, a solution of NBS (9.09 g, 51.00 mmol, 1.0 eq) in DMF (25 mL) was slowly added. After the addition was complete, the temperature was raised to 95°C and the reaction was maintained for 3 h. The system was then cooled to room temperature and a large amount of ice water was added to precipitate the solid. The filter cake was collected by filtration, washed with water, and dried to obtain the crude product 74-1b, which was directly used in the next step; MS: m / z 275.1 [M+H] + ;

[0610] Under nitrogen protection, the crude product 74-1b (10 g, 36.50 mmol, 1.0 eq), 1,4-dioxane (100 mL), tributyl(1-ethoxyvinyl)tin (15.94 g, 43.80 mmol, 1.2 eq), Pd(dppf)2Cl2 (1.3 g, 1.83 mmol, 0.05 eq) and triethylamine (11.1 g, 109.50 mmol, 3.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 90 ° C. After 6 h of reaction, the system was cooled to room temperature, filtered, and a large amount of water was added to the system. The mixture was extracted three times with EA (100 mL). The organic layers were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude compound 74-1c, which was directly used in the next step; MS: m / z 267.0 [M+H] + ;

[0611] The crude product 74-1c from the previous step, THF (120 mL), and 1N dilute hydrochloric acid (120 mL) were added to the reaction flask in sequence. After stirring at room temperature for 1 h, the reaction product was converted from 74-1c to 74-1d as monitored by TLC and mass spectrometry. The product was diluted with a large amount of water and extracted three times with EA (100 mL). The organic layers were combined, washed once with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1-2:1) to give compound 74-1d (4.7 g); MS: m / z 239.0 [M+H] + ;

[0612] Compound 74-1d (4.7 g, 19.74 mmol, 1.0 eq), anhydrous ethanol (50 mL) and hydrazine hydrate (5.70 g, 88.83 mmol, 4.5 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and reacted for 1.5 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was slurried with methyl tert-butyl ether to give compound 74-1e (3.40 g); MS: m / z 221.0 [M+H] + ;

[0613] Compound 74-1e (3.4 g, 15.45 mmol, 1.0 eq) and 48% hydrobromic acid (20 mL) solution were added to the reaction flask in sequence. The reaction system was heated to 120°C and reacted for 24 h. The system was then cooled to room temperature and the filter cake was collected by filtration. The filter cake was washed with water and dried to obtain compound 74-1f; MS: m / z 193.0 [M+H] + ;

[0614] Compound 74-1f (3.40 g, 17.70 mmol, 1.0 eq), triethylene glycol di(p-toluenesulfonate) (8.11 g, 17.70 mmol, 1.0 eq), potassium carbonate (7.32 g, 53.10 mmol, 3.0 eq) and DMF (2 mL) were added to the reaction flask in sequence. After stirring at 90° C. for 8 h, the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1-2:1) to obtain compound 74-1g (1.20 g); MS: m / z 307.1 [M+H] + ;

[0615] Compound 74-1g (0.52 g, 1.71 mmol, 1.0 eq), POCl3 (4 mL) and N,N-diethylaniline (0.25 g, 1.71 mmol, 1.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 105°C and reacted for 3.5 h. The system was then concentrated under low pressure to remove the solvent, ice water (10 mL) was added, the pH was adjusted to 7-8 with saturated NaHCO3 solution, and EA (10 mL) was added for extraction three times. The organic layers were combined and washed with water and saturated brine in sequence, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1.5) to give compound 74-1h (0.31 g); MS: m / z 325.1 [M+H] + .

[0616] Under nitrogen protection, intermediate 74-1h (88 mg, 0.27 mmol, 1.0 eq), toluene (4 mL), 1-1 (52 mg, 0.68 mmol, 2.5 eq), Pd(dba)3 (160 mg, 0.16 mmol, 0.6 eq), Xantphos (192 mg, 0.32 mmol, 1.2 eq) and tripotassium phosphate (352 mg, 1.62 mmol, 6.0 eq) were added to the reaction flask in sequence. The reaction system was reacted under microwave (130 ° C, 2 h), concentrated to remove the solvent, and extracted with water and ethyl acetate. The organic phase was separated and concentrated to dryness. The crude product was purified by reverse phase column chromatography (Shim-park GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 74 (12.10 mg); MS: m / z 478.2 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ8.09(s,1H),7.61(t,J=7.4Hz,1H),7.47(d,J=4.3Hz,2H),7.35(d,J=7.1Hz,1H),7.27-7.21(m,1H),7.26( t,J=54.0Hz,1H),5.71(p,J=7.1Hz,1H),4.41-4.34(m,4H),3.86-3.75(m,4H),3.69-3.63(m,4H),2.58(s,3H),1.61(d,J=7.0Hz,3H).

[0617] Examples 75-77, 111: Preparation of Compounds 75-77, 111

[0618] Compounds 75-77 and 111 were synthesized according to procedures substantially similar to Example 74 (see Table 10).

[0619] Table 10. Structures, mass spectra, and H NMR data of compounds 75-77 and 111

[0620]

[0621] Example 78: Preparation of Compound 78

[0622] Synthesis route

[0623]

[0624] Compound 16 (430 mg, 1 mmol, 1.0 eq), m-CPBA (345 mg, 2 mmol, 2.0 eq), and dichloromethane (5 mL) were added to the reaction flask in sequence and stirred at room temperature for 1 h. Water (3 mL) was then added to the system, extracted, and the organic phase was dried and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 78 (50 mg); MS: m / z 463.1 [M+H] + .

[0625] Example 79: Preparation of Compound 79

[0626] Synthesis route

[0627]

[0628] Compound 16 (430 mg, 1 mmol, 1.0 eq), m-CPBA (172 g, 1 mmol, 1.0 eq), and dichloromethane (5 mL) were added sequentially to the reaction flask and stirred at room temperature for 1 h. Water (3 mL) was then added to the system, extracted, and the organic phase was dried and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 79-1a (440 mg); MS: m / z 447.1 [M+H] + .

[0629] Compound 79-1a (440 mg, 2.2 mmol), dimerized rhodium acetate (27 mg, 0.09 mmol), iodophenyl diacetic acid (1060 mg, 3.3 mmol), trifluoroacetamide (497 mg, 4.4 mmol), magnesium oxide (352 mg, 8.8 mmol) and dichloromethane (10 mL) were added to the reaction flask in sequence and stirred at room temperature for 14 h. Water (10 mL) was then added to the system and extracted. The organic phase was dried and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 79-1b (250 mg); MS: m / z 558.1 [M+H] + .

[0630] Compound 79-1b (56 mg, 0.1 mmol), potassium carbonate (69 mg, 0.5 mmol), and methanol (3 mL) were added sequentially to the reaction flask, stirred at room temperature for 1.5 h, and concentrated to dryness. The crude product was purified by reverse-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to afford compound 79 (5.3 mg); MS: m / z 462.2 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ9.09(d,J=2.4Hz,1H),8.88(d,J=2.5Hz,1H),8.80 (d,J=7.2Hz,1H),7.71(t,J=7.4Hz,1H),7.53(t,J=7.0Hz,1H),7.32(t,J=7.7H z,1H),7.26(t,J=54.0Hz,1H),6.26(t,J=4.5Hz,1H),5.82(p,J=7.0Hz,1H),3. 91(s,3H),3.32-3.30(m,1H),3.13(s,2H),2.41(s,3H),1.65(d,J=7.1Hz,3H).

[0631] Example 80: Preparation of Compound 80

[0632]

[0633] Compound 79-1b (56 mg, 0.1 mmol), THF (3 mL), and palladium carbon (6 mg) were added to the reaction flask in sequence and stirred at room temperature for 3 h. Filtered and concentrated to give compound 80-1a (55 mg); MS: m / z 560.1 [M+H] + .

[0634] Compound 80-1a (55 mg, 0.1 mmol), potassium carbonate (69 mg, 0.5 mmol), and methanol (3 mL) were added sequentially to the reaction flask, stirred at room temperature for 1.5 h, and concentrated to dryness. The crude product was purified by reverse-phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to afford compound 80 (5.3 mg); MS: m / z 464.1 [M+H] + .

[0635] Example 101: Preparation of Compound 101

[0636]

[0637] Compound 21 (45.5 mg, 0.1 mmol, 1.0 eq) was dissolved in dichloromethane (0.5 mL) and isopropanol (5 mL), and tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese (30.2 mg, 0.05 mmol, 0.5 eq) and phenylsilane (216.4 mg, 0.2 mmol, 2.0 eq) were added. The mixture was purged with oxygen three times and stirred at room temperature for 24 hours. The mixture was concentrated to dryness and purified by reverse phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 101 (6.03 mg); MS: m / z 474.2 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ9.14(d,J=2.4Hz,1H),8.84(d,J=2.4Hz,1H),8.80(dd,J=7.5,2.7Hz,1H), 7.70(t,J=7.4Hz,1H),7.52(t,J=7.1Hz,1H),7.32(t,J=7.7Hz,1H),7.26(t,J=54.0Hz,1H),5.82(p,J =7.0Hz,1H),5.52(s,1H),4.43(d,J=12.8Hz,1H),3.79(d,J=13.2Hz,1H),3.60-3.47(m,1H),3.07-2. 95(m,1H),2.39(s,3H),2.07(s,3H),2.01-1.95(m,2H),1.80(t,J=12.5Hz,2H),1.64(d,J=7.0Hz,3H).

[0638] Example 102: Preparation of Compound 102

[0639] Compound 102 was synthesized according to procedures substantially similar to Example 101 (see Table 11).

[0640] Table 11. Structure, mass spectrum, and H NMR data of compound 102

[0641]

[0642] Example 103: Preparation of Compound 103

[0643]

[0644] Compound 79 (46.1 mg, 0.1 mmol, 1.0 eq) was dissolved in dichloromethane (0.5 mL), and triethylamine (25.3 mg, 0.25 mmol, 2.5 eq) and acetyl chloride (9.4 mg, 0.12 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, concentrated to dryness, and the system was purified by reverse phase column chromatography (Shim-pack GIS C18 20*250 mm, 5 μm; 0.01% formic acid-water / acetonitrile) to give compound 103 (11.5 mg); MS: m / z 504.2 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ9.12(d,J=2.4Hz,1H),8.90(d,J=2.5Hz,1H),8.82(d,J=7.1Hz,1 H),7.71(t,J=7.4Hz,1H),7.53(t,J=7.1Hz,1H),7.32(t,J=7.7Hz,1H),7.26(t,J=54.0Hz,1 H),6.37-6.29(m,1H),5.82(p,J=7.1Hz,1H),4.49(d,J=17.6Hz,1H),4.33(d,J=17.6Hz,1H) ,3.90-3.78(m,2H),3.20(t,J=6.3Hz,2H),2.41(s,3H),2.00(s,3H),1.65(d,J=7.0Hz,3H).

[0645] Examples 104-106: Preparation of Compounds 104-106

[0646] Compounds 104-106 (see Table 12) were synthesized following procedures substantially similar to those of Example 79.

[0647] Table 12. Structures, mass spectra, and H NMR data of compounds 104-106

[0648]

[0649] Experimental Example 1: KRAS-G12C / SOS1 IC50 Activity Test

[0650] The inhibition rate of KRAS-G12C / SOS1 was detected using the Binding Assay method to evaluate the inhibitory effect of the compounds of the present invention on KRAS-G12C / SOS1.

[0651] 1.1 Experimental Materials

[0652] 1.1.1 Reagents and consumables

[0653] Reagent name Supplier KRAS G12C / SOS Binding kit Cisbio DMSO Sigm 384-well white plate PerkinElmer

[0654] 1.1.2 Instruments

[0655] Centrifuge (manufacturer: Eppendorf, model: 5430 )

[0656] Microplate reader (Manufacturer: Perkin Elmer, Model: Envision )

[0657] Echo 550 (Manufacturer: Labcyte, Model: Echo 550)

[0658] 1.2 Kinase reaction process

[0659] (1) Compound Preparation: Test compound concentration gradients were set at 500 nM, 125 nM, 31.25 nM, 7.81 nM, 1.95 nM, 0.488 nM, 0.122 nM, and 0.03 nM. The test compounds were diluted to 200-fold the final concentration in 100% DMSO in a 384-well plate. An Echo 550 dispenser was used to transfer 50 nL of the compound at 200-fold the final concentration to the target 384-well plate. Negative control wells were treated with 50 nL of 100% DMSO.

[0660] (2) Prepare a Tag1-SOS1 solution with a final concentration of 4 times using dilution buffer.

[0661] (3) Add 2.5 μl of Tag1-SOS1 solution at 4 times the final concentration to a 384-well plate.

[0662] (4) Prepare a Tag2-KRAS-G12C solution with a final concentration of 4 times using dilution buffer.

[0663] (5) Add 2.5 μl of Tag2-KRAS-G12C solution at 4 times the final concentration to the compound wells; add 2.5 μl of dilution buffer to the negative control wells.

[0664] (6) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 15 minutes.

[0665] (7) Prepare 1x final concentration of Anti-Tag1-TB3+ solution and 1x final concentration of Anti-Tag2-XL665 solution using detection buffer. Mix the two solutions and add 5 μl of Mix solution to each well.

[0666] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 120 minutes.

[0667] (9) Read the results using an Envision microplate reader and record the ratio of Em665 to Em620.

[0668] 1.3 Data Analysis

[0669] 1.3.1 Inhibition rate calculation formula

[0670]

[0671] Wherein: Min signal represents the average absorbance of pure DMSO wells; Max signal represents the average absorbance of enzyme, substrate, detection reagent, and DMSO mixture wells; Compound signal represents the average absorbance of sample wells.

[0672] 1.3.2 Fitting the dose-effect curve

[0673] The log value of the compound concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-Variable slope analysis software GraphHPadPrism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity.

[0674] The fitting formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0675] Among them: Top represents the top platform, and the Top standard of the curve is generally between 80% and 120%; Bottom represents the bottom platform, and the Bottom of the curve is generally between -20% and 20%.

[0676] In vitro inhibitory activity test results (IC 50 express)

[0677] Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 <!-- 68 -->]]> 11 36nM 29 15nM 70 6.7nM 92 11nM 12 45nM 30 41nM 71 6.0nM 93 5.6nM 13 30nM 34 21nM 74 4.1nM 94 5.2nM 14 12nM 36 46nM 75 5.3nM 96 4.9nM 15 12nM 44 19nM 79 7.4nM 97 2.1nM 16 22nM 49 53nM 81 11nM 98 5.7nM 17 25nM 52 15nM 82 7.8nM 99 81nM 18 12nM 53 23nM 83 17nM 100 23nM 19 16nM 54 12nM 84 11nM 101 8.4nM 20 53nM 55 7.5nM 85 25nM 102 17nM 22 25nM 56 28nM 86 6.6nM 103 9.2nM 23 32nM 58 52nM 87 5.3nM 104 5.5nM 24 47nM 59 91nM 89 15nM 105 12nM 25 84nM 68 23nM 91 6.5nM 108 16nM

[0678] Experimental Example 2: MIA-PaCa2(3D) cell proliferation inhibitory activity test

[0679] 1.1 Experimental Materials

[0680] 1.1.1 Reagents and consumables

[0681] Reagent name Supplier MIA-PaCa2 ATCC DMEM medium Gibco 96-well Microplate PerkinElmer 3D Cell Viability assay kit Promega PBS buffer Gibco <![CDATA[CO2 Incubator]]> Thermo Scientific Fetal bovine serum Gibco

[0682] 1.1.2 Instruments

[0683] Centrifuge (manufacturer: Eppendorf, model: 5810R )

[0684] Microplate reader (Manufacturer: Perkin Elmer, Model: Envision )

[0685] Echo 550 (Manufacturer: Labcyte, Model: Echo 550)

[0686] 1.2 Experimental Procedure

[0687] MIA-PaCa2 cells in good growth condition were taken and seeded on a 96-well plate (2000 cells / well), and cultured in a 37°C, 5% CO2 cell culture incubator overnight. Different concentrations of compounds were added using a nanoliter pipette. The concentration gradient of the compound was 10 μM, 2.5 μM, 0.625 μM, 0.156 μM, 0.039 μM, 0.0098 μM, 0.0024 μM and 0.0006 μM. Two replicate wells were set for each compound, and a solvent control was set at the same time (0.2% DMSO solution was added to the control well). After drug addition, the cells were cultured in a cell culture incubator for 8 days. The detection reagent (Celltiter Glo Assay kit-3D) was added to the 96-well plate (100 μl / well), shaken in the dark for 30 minutes, incubated in the dark at room temperature for 2 hours, and then the luminescence value was read using an Envision microplate reader.

[0688] 1.3 Data Analysis

[0689] The inhibition rate (IR) of the test compound was calculated using the following formula:

[0690] IR (%) = (1-(RLU 化合物 -RLU 空白对照 ) / (RLU 溶媒对照 -RLU 空白对照 ))*100%

[0691] Of which: RLU 化合物 RLU is the average luminescence value of the sample wells; 空白对照 RLU is the mean luminescence value of the culture medium wells; 溶媒对照 The luminescence value is the mean value of the 0.2% DMSO wells.

[0692] The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition curves were plotted and relevant parameters (including minimum inhibition rate, maximum inhibition rate and IC) were calculated using GraphPad Prism software. 50 ).

[0693] MIA-PaCa2 cell proliferation inhibition activity test results (IC 50 express)

[0694] Compound <![CDATA[IC 50 ]]> 15 381nM 18 475nM 29 186nM 51 442nM 52 107nM 70 325nM 71 368nM 74 122nM 81 251nM 82 127nm 101 264nm 102 103nm

[0695] From the results of the above experimental examples, it can be seen that the compounds of the present invention have excellent in vitro inhibitory activity against KRAS-G12C / SOS1, and also show excellent inhibitory activity against MIA-PaCa2 cell proliferation, making it possible to be used as small molecule SOS1 inhibitors, with the effects of inhibiting cell proliferation and angiogenesis, having good anti-tumor activity, and having good effects on the treatment of tumor diseases in mammals (including humans).

[0696] Although the present invention has been described with reference to the specific examples above, it should not be construed as being limited thereto, but rather as encompassing the general aspects disclosed above and susceptible of various modifications and embodiments without departing from the spirit and scope of the invention.

Claims

1. A compound having the structure of Formula I-3B or a pharmaceutically acceptable salt or stereoisomer thereof: in: Each X is independently CH2 or O; q is 10, 11, 12, or 13; n is 2; each R 1 independently selected from methyl, -CHF2, -CF3, amino, fluoro and cyano; R 2 is selected from hydrogen and methyl; R 6 It is a methyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula I-3B-1 or Formula I-3B-2: in: X, q, n, R 1 、R 2 and R 6 As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: In the formula Selected from the following groups:

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: R 2 For hydrogen.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The fragments were selected from the following structures: Every R 7 are independently hydrogen.

6. The following compounds or pharmaceutically acceptable salts or stereoisomers thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

9. A pharmaceutical preparation prepared from the pharmaceutical composition according to claim 7 or 8.

10. The pharmaceutical preparation according to claim 9, characterized in that The pharmaceutical preparation is a solid preparation for oral administration, a liquid dosage form for oral administration, a dosage form for parenteral injection or a dosage form for topical administration.

11. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 7 or 8, or a pharmaceutical preparation according to claim 9 or 10, in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by SOS1 protein.

12. The use according to claim 11, characterized in that The disease mediated at least in part by the SOS1 protein is cancer.

13. A pharmaceutical combination comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 7 or 8, or a pharmaceutical formulation according to claim 9 or 10, and at least one additional cancer therapeutic agent.

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