CN115536660A - Benzylamino-substituted heteropolycyclic compounds, compositions, formulations and uses thereof - Google Patents

Benzylamino-substituted heteropolycyclic compounds, compositions, formulations and uses thereof Download PDF

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CN115536660A
CN115536660A CN202211320575.2A CN202211320575A CN115536660A CN 115536660 A CN115536660 A CN 115536660A CN 202211320575 A CN202211320575 A CN 202211320575A CN 115536660 A CN115536660 A CN 115536660A
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王书成
黄河
林国良
王岩
刘岩松
耿玉先
敖俊杰
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Beijing Fuyuan Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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    • C07—ORGANIC CHEMISTRY
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    • C07B2200/07—Optical isomers

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a benzylamino-substituted heteropolycyclic compound, and a composition, a preparation and application thereof. Specifically, the general structure of the heterocyclic polycyclic is shown as formula I. The compound has excellent in-vitro inhibitory activity on SOS1, can be used as an SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good antitumor activity, and has good effect on treating mammal (including human) tumor diseases.

Description

Benzylamino-substituted heteropolycyclic compounds, compositions, formulations and uses thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and relates to a series of novel benzylamino-substituted heteropolycyclic compounds, a pharmaceutical composition and a pharmaceutical preparation containing the same, and medical application thereof.
Background
KRAS gene mutations are common in pancreatic, lung adenocarcinoma, colorectal, gall bladder, bile duct and thyroid cancers and are one GTP-binding protein. RAS has two main forms in the body: an inactivated state bound to GDP and an activated state bound to GTP. Its activity is regulated by two proteins, a Guanylate Exchange Factor (GEF) such as SOS1, which promotes the release of GDP from the RAS protein, allowing GTP binding to activate RAS; the GTPase activating protein activates the GTPase activity of the RAS protein, hydrolyzing GTP bound to the RAS protein to GDP, and inactivating the RAS. When in the GTP-binding state, RAS family proteins are active and engage effector proteins (including RAF and PI 3K) to facilitate RAF/MEK/ERK, PI3K/AKT/mTOR, etc. pathways. These pathways affect various cellular processes, such as proliferation, survival, metabolism, and the like.
SOS1 has two binding sites for RAS family proteins: one is a catalytic site that binds to a GDP-bound RAS family protein to facilitate guanine nucleotide exchange, and the other is an ectopic site that binds to a GTP-bound RAS family protein to cause a further increase in the catalytic GEF function of SOS1 (biochem. Pharmacol.,2011,82 (9): 1049-1056). SOS1 is of major involvement in mutant KRAS activation and oncogenic signaling in cancer (nat. Commun.,2012, 3. In tumor cells carrying KRAS mutations, decreasing SOS1 levels can decrease the rate of proliferation of tumor cells, whereas no effect was observed in KRAS wild-type cell lines.
RAS, the first identified oncogene, is the oncogene with the highest mutation rate, and accounts for 25% of human cancers. In recent decades, RAS family protein-SOS 1 protein interactions have gained increasing awareness. Currently, only the SOS1 inhibitor BI1701963 from bergereger berghan enters the clinical phase I study, and no SOS1 inhibitor has been developed on the market. Therefore, the development of new SOS1 inhibitors has great clinical value and broad market prospects.
Disclosure of Invention
Problems to be solved by the invention
In order to develop a novel SOS1 inhibitor, the invention aims to provide a novel benzylamino-substituted heteropolycyclic compound, and a composition, a preparation and application thereof, wherein the derivative has excellent SOS1 inhibition activity, good pharmacodynamic performance and high metabolic stability.
Means for solving the problems
In a first aspect, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof:
Figure BDA0003910195120000011
wherein:
ring A is selected from C 6-10 Aryl, 5-to 10-membered heteroaryl, and 3-to 6-membered heterocyclyl;
u and V are independently N or CR 2 ；
W is N or CR 6 ；
Each R 1 Independently selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, amino, halogen, cyano and nitro;
each R 2 Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, halogen, cyano, -OR 2a and-NR 2a R 2b ；
R 2a And R 2b Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 3-6 A cycloalkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and halogen;
R 4 selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-14 Cycloalkyl radical, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, 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 said cycloalkyl, heterocyclyl, aryl and heteroarylEach of which is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (= O) -C 1-6 Alkyl and-C (= O) O-C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) NH-3-to 14-membered heterocyclyl, -C (= O) -C 6-10 Aryl, -C (= O) -5-to 10-membered heteroaryl, and-S (= O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: amino, halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
R 5 selected from hydrogen, amino, halogen, nitro and-O-C 1-6 An alkyl group;
or, R 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, = CH 2 、＝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 said substituents together with the atoms to which each is attached form a 5-to 8-membered heterocyclyl;
R 5a and R 5b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl;
R 6 selected from hydrogen, amino, halogenElement, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl and-O-C 1-6 An alkyl group;
m is 0,1 or 2;
n is 0,1, 2 or 3;
wherein said heterocyclyl and heteroaryl each contain as ring atoms one or more heteroatoms selected from N, O and S.
In a second aspect, the present invention provides the following non-limiting examples of compounds having the structure of formula I above:
(1) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(2) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-nitropyrido [2,3-d ] pyrimidin-4-amine;
(3) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-fluoro-2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(4) (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(5) (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(6) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6-iodo-2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(7) (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-bromo-2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(8) (R) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) pyrido [2,3-d ] pyrimidin-4-amine;
(9) (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) pyrido [2,3-d ] pyrimidin-4-amine;
(10) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (thiophen-3-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(11) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyridin-3-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(12) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyridin-2-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(13) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyridin-4-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(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;
(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;
(17) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (piperidin-4-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(18) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(19) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1-methylpiperidin-4-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(20) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (thiazol-4-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(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;
(23) (R) -6-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(24) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-phenylpyrido [2,3-d ] pyrimidin-4-amine;
(25) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (2-methoxyphenyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(26) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-methoxyphenyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(27) (R) -6- (2-chlorophenyl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(28) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-fluorophenyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(29) (R) -6- (2-chloropyridin-3-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(30) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (2-methoxypyridin-3-yl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(31) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (naphthalen-2-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(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;
(34) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyrimidin-5-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(36) (R) -6- (3-aminophenyl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(37)(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(38) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) methanesulfonamide;
(39) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -2-fluoroacrylamide;
(40) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) acetamide;
(41) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) benzamide;
(42) (R) -1-cyclopropyl-3- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) urea;
(43) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) morpholine-4-carboxamide;
(44)(R)-N 6 -cyclopentyl-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(45)(R)-N 6 -cyclohexyl-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(46)(R)-N 6 - (cyclohexylmethyl) -N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(47)(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-N 6 - (2-morpholinoethyl) pyrido [2, 3-d)]Pyrimidine-4, 6-diamine;
(48) (R) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-ol;
(49) (R) -1- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) ethan-1-one;
(50) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholinylpyrido [2,3-d ] pyrimidin-4-amine;
(51) N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- ((S) -tetrahydrofuran-3-yloxy) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(53) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (pyrrolin-1-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(54) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (4-methyl-1, 4-diaza-ne
Figure BDA0003910195120000041
-1-yl) pyrido [2,3-d]Pyrimidin-4-amine;
(55) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (4-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(57)(R)-N 4 - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N 6 - ((hexahydro-1H-pyradin-7 a-yl) methyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(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;
(59) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(60) (R) -6-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) - [1,3] dioxolo [4,5-g ] quinazolin-8-amine;
(61) (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methyl- [1,3] dioxolo [4,5-g ] quinazolin-8-amine;
(62) (R) -2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(63) (R) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) -7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(64) (R) -2-methyl-N- (1-phenylethyl) -7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(65) (S) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) -7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(66) (R) -2-methyl-N- (1- (m-tolyl) ethyl) -7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(67) (R) -N- (1- (3-chlorophenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine;
(68) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -9-methyl-2, 3-dihydro- [1,4] dioxino [2,3-g ] phthalazin-6-amine;
(69) (R) -N- (1- (3-amino-5- (difluoromethyl) phenyl) ethyl) -9-methyl-2, 3-dihydro- [1,4] dioxino [2,3-g ] phthalazin-6-amine;
(70) 9- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -1,3,4, 6-tetramethyl-3, 4-dihydropyridazino [4,5-g ] quinoxalin-2 (1H) -one;
(71) (R) -8- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -1,3, 5-tetramethyl-1H-pyrrolo [3,2-g ] phthalazin-2 (3H) -one;
(72) (R) -9- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -1,3, 6-trimethylpyridazo [4,5-g ] quinoxalin-2 (1H) -one;
(73) (R) -6- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -4, 9-dimethyl-2H- [1,4] oxazino [2,3-g ] phthalazin-3 (4H) -one;
(74) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -15-methyl-2, 3,5,6,8, 9-hexahydro- [1,4,7,10] tetraoxacyclododecatrieno [2,3-g ] phthalazin-12-amine;
(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] pentaoxacyclopenta [2,3-g ] phthalazin-15-amine;
(76) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -17-methyl-2, 3,5,6,7,8,10, 11-octahydro- [1,4,7,10] tetraoxacyclotetradecapentaeno [5,6-g ] phthalazin-14-amine;
(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;
(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;
(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-1 lambda 6 -thiopyran 1-oxide;
(80) (R) -4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d]Pyrimidin-6-yl) -1-iminohexahydro-1 lambda 6 -thiopyran 1-oxide;
(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;
(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;
(83) (R) -4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -1-methylpiperazin-2-one;
(84) (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (piperidin-1-yl) pyrido [2,3-d ] pyrimidin-4-amine;
(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;
(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;
(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;
(88) (R) -N- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -N- (methylsulfonyl) methanesulfonamide;
(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;
(90)(R)-N 6 -cycloheptyl-N 4 - (1- (3- (difluoromethyl) methyl)) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d]Pyrimidine-4, 6-diamine;
(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;
(92) (R) -6- (1- (cyclopropylsulfonyl) piperidin-4-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(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;
(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;
(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;
(96) (R) -4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -N, N-dimethylpiperidine-1-carboxamide;
(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;
(98) (R) -cyclobutyl (4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) piperidin-1-yl) methanone;
(99) 4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) cyclohex-3-ene-1-carboxylic acid;
(100) (R) -6- (3-aminoazetidin-1-yl) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine;
(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;
(102) (R) -4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) tetrahydro-2H-pyran-4-ol;
(103) N- (4- (4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2,3-d]Pyrimidin-6-yl) -1-oxo-3, 6-dihydro-2H-1 lambda 6 -thiopyran-1-ylidene) acetamide;
(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-1 lambda 6 -thiopyran 1-oxide;
(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-1 lambda 6 -thiopyran 1-oxide;
(106) (R) -N- (4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -2-methylpyrido [2, 3-d)]Pyrimidin-6-yl) -1-oxo-1 lambda 6 -thiomorpholin-1-ylidene) -2, 2-trifluoroacetamide;
(107) (R) -8- (1- (3-amino-5- (trifluoromethyl) phenyl) ethylamino) -1,3, 5-tetramethyl-1, 3-dihydro-2H-pyrrolo [2,3-g ] phthalazin-2-one;
(108) (R) -1-cyclopropyl-8- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylamino) -3, 5-trimethyl-1, 3-dihydro-2H-pyrrolo [2,3-g ] phthalazin-2-one;
(109) (R) -2-methyl-3- (1- ((1, 3, 5-tetramethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-g ] phthalazin-8-yl) amino) ethyl) benzonitrile;
(110) (R) -8- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethylamino) -1,3, 5-tetramethyl-1, 3-dihydro-2H-pyrrolo [2,3-g ] phthalazin-2-one; and
(111) (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -15-methyl-2, 3,5,6,8, 9-hexahydro- [1,4,7,10] tetraoxacyclododecatrieno [2,3-g ] phthalazin-12-amine.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, as described above, and at least one pharmaceutically acceptable carrier.
Preferably, in the above pharmaceutical composition, the pharmaceutically acceptable carrier includes, but is not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, smelling agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, light-shielding agents (opacifiers), and the like.
In a fourth aspect, the present invention provides a pharmaceutical preparation, which is prepared from the compound having the structure of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans-isomer, isotopic label or prodrug thereof, or a pharmaceutical composition thereof.
In a fifth aspect, the present invention provides a use of the compound having the structure of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or the pharmaceutical composition thereof, or the pharmaceutical preparation thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by the SOS1 protein.
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, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.
In a sixth aspect, the present invention provides a pharmaceutical combination comprising a compound having the structure of formula I as described above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, and at least one additional cancer therapeutic agent.
ADVANTAGEOUS EFFECTS OF INVENTION
The compound of the invention has excellent in vitro inhibitory activity against SOS1 and excellent inhibitory activity against MIA-PaCa2 cell proliferation, so that the compound can be used as an SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good antitumor activity and has good effect on treating mammal (including human) neoplastic diseases.
Detailed Description
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[ definition of terms ]
Unless otherwise indicated, the following terms have the following meanings.
The term "pharmaceutically acceptable salt" refers to salts of compounds having the structure of formula I that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic or organic acid, such salts also being referred to 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 a sulfate or acid sulfate), phosphoric acid (which can form a phosphate or acid phosphate), and the like, and common organic acids include, but are not limited to, trifluoroacetic acid, citric acid (which can form a citrate mono-, di-, or tri-salt), maleic acid (which can form a maleate mono-or di-salt), fumaric acid (which can form a fumarate mono-or di-salt), succinic acid (which can form a succinate mono-or di-salt), tartaric acid (which can form a tartrate mono-or di-salt), oxalic acid (which can form a oxalate mono-or di-salt), malonic acid (which can form a malonate mono-or di-salt), malic acid (which can form a malate mono-or di-salt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
The term "hydrate" refers to a substance formed by the non-covalent intermolecular binding of a compound of the present invention or a pharmaceutically acceptable salt thereof with water. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.
The term "solvate" refers to a substance formed by the binding of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one solvent molecule by non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like. It is to be understood that the present invention encompasses all solvate forms possessing SOS1 inhibitory activity.
The term "isomers" refers to compounds having the same number and type of atoms and thus the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.
The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts comprise asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. Gtoreq.98%,. Gtoreq.95%,. Gtoreq.93%,. Gtoreq.90%,. Gtoreq.88%,. Gtoreq.85% or. Gtoreq.80%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form 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 the 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 present invention.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, 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 invention are within the scope of the invention.
The term "cis-trans isomer" refers to a stereoisomer of an atom (or group) located on both sides of a double bond or ring system, as a result of differing positions relative to a reference plane; in the cis isomer the atom (or group) is located on the same side of the double bond or ring system and in the trans isomer the atom (or group) is located on the opposite side of the double bond or ring system. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present invention are within the scope of the present invention.
The term "isotopic label" refers to a compound formed by replacing a particular atom in a structure with its isotopic atom. Unless otherwise indicated, the present invention is not limited to the examples provided hereinThe compounds include various isotopes of H, C, N, O, F, P, S, 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。
the term "prodrug" refers to a derivatized 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 those that increase the bioavailability of the compounds of the invention when administered to a patient (e.g., more readily absorbed into the blood), or 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 present invention are within the scope of the present invention, and various prodrug forms are well known in the art.
The term "aryl" refers to a monocyclic or fused polycyclic monovalent group having aromatic character whose ring atoms are all C atoms, and may have, for example, 6 to 20, 6 to 14, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3, 4-tetrahydronaphthalene, and the like. The term "C 6-10 Aryl "means an aryl 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 1,2,3, 4-tetrahydronaphthalene, and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic monovalent group having aromatic character, at least one (e.g., 1,2,3 or 4) ring atoms of which are heteroatoms selected from N, O and S, and the remaining ring atoms are C, and may be, for example, 5 to 10-membered rings, especially 5 to 8-membered rings. Non-limiting examples of heteroaryl groups include (but are not limited to)
Figure BDA0003910195120000081
Figure BDA0003910195120000082
Figure BDA0003910195120000083
And so on. 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, and non-limiting examples of 5-to 10-membered heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyridyl, indolyl, quinolyl and the like.
The term "heterocyclyl" refers to a monovalent radical of a fully or partially unsaturated (but not fully unsaturated, e.g. having 1 or 2 double bonds) monocyclic, bridged or spirocyclic ring, at least one (e.g. 1,2,3 or 4) ring atom of which is a heteroatom selected from N, O and S, the remaining ring atoms being C, e.g. may be 3 to 14 membered, even 3 to 6 membered rings. The term "3 to 14-membered heterocyclic group" means a heterocyclic group 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 heterocyclyl groups having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O and S; the term "5-to 15-membered heterocyclic group" means a heterocyclic group having 5 to 15 ring atoms, which may contain 1 to 5 heteroatoms selected from N, O and S.
Non-limiting examples of saturated 3-membered heterocyclic groups include, but are not limited to, oxirane, thiirane, cycloazepane, and the like; non-limiting examples of saturated 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxabutridinyl, thiabutridinyl, and the like; non-limiting examples of saturated 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, 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 derived structures thereof, e.g. of
Figure BDA0003910195120000084
) Cyclopentylsulfonyl, morpholinyl, piperazinyl, 1, 4-thiaxalkyl, 1, 4-dioxanyl, thiomorpholinyl (or derivatives thereof, e.g.
Figure BDA0003910195120000085
)、1,3-dithianyl, 1, 4-dithianyl, and the like; non-limiting examples of saturated 7-membered heterocyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and the like.
Non-limiting examples of partially unsaturated heterocyclyl include (but are not limited to)
Figure BDA0003910195120000086
Figure BDA0003910195120000087
Figure BDA0003910195120000091
Figure BDA0003910195120000092
And so on.
The term "alkyl" refers to a straight or branched chain monovalent hydrocarbon radical, free of unsaturation. The term "C 1-4 Alkyl "refers to an alkyl group having 1 to 4 carbon atoms, the term" C 1-6 Alkyl "means 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 (-CH) 3 ) Ethyl (-CH) 2 CH 3 ) N-propyl (-CH) 2 CH 2 CH 3 ) Isopropyl group (-CH (CH)) 3 ) 2 ) N-butyl (-CH) 2 CH 2 CH 2 CH 3 ) Sec-butyl (-CH (CH) 3 )CH 2 CH 3 ) Isobutyl group (-CH) 2 CH(CH 3 ) 2 ) T-butyl (-C (CH)) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) Neo-pentyl (-CH) 2 C(CH 3 ) 3 ) And the like.
The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more carbon-carbon double bonds, and may have, for example, from 2 to 20 carbon atoms. The term "C 2-6 Alkenyl "means alkenyl having 2 to 6 carbon atoms; the term "C 2-4 Alkenyl "means having 2 to 4 carbon atomsAlkenyl groups of (a). C 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.
The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more carbon-carbon triple bonds, and may have, for example, from 2 to 20 carbon atoms. The term "C 2-6 Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms; the term "C 2-4 Alkynyl "refers to alkynyl groups having 2 to 4 carbon atoms. C 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.
The term "haloalkyl" refers to a straight or branched chain monovalent radical formed by the replacement of at least one hydrogen atom in an alkyl group with a halogen atom, containing no unsaturation. The term "C 1-6 Haloalkyl "refers to haloalkyl having 1 to 6 carbon atoms; the term "C 1-4 Haloalkyl "refers to haloalkyl having 1 to 4 carbon atoms. C 1-6 Non-limiting examples of haloalkyl include, but are not limited to, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 And the like.
The term "cycloalkyl" refers to a monovalent cyclic hydrocarbon group of a fully saturated monocyclic or polycyclic (e.g., spiro, fused, or bridged) ring, for example, and may have 3 to 20, 3 to 12,3 to 6, or 5 to 6 carbon atoms. The term "C 3-14 Cycloalkyl "refers to cycloalkyl groups having 3 to 14 carbon atoms; the term "C 3-6 Cycloalkyl "refers to cycloalkyl groups having 3 to 6 carbon atoms. Monocyclic C 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.
The term "cycloalkenyl" means having a radicalA mono-or polycyclic (e.g., spiro, fused, or bridged, but not aromatic) monovalent cyclic hydrocarbon group of one or more carbon-carbon double bonds, for example, may have 3 to 20, 3 to 12,3 to 6, or 5 to 6 carbon atoms. The term "C 3-14 Cycloalkenyl refers to cycloalkenyl 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.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in main group VII of the periodic Table of the elements.
The term "hydroxy" refers to an-OH group.
The term "amino" refers to-NH 2 The radical, in some cases, amino may also represent at least one H atom in the structure further substituted by an alkyl group (e.g. C) 1-6 Alkyl) to the monovalent radical formed.
The term "nitro" means-NO 2 A group.
The term "cyano" refers to the group — CN.
The term "single bond" refers to a chemical bond between atoms for mutual connection or interaction, such as an ionic bond, covalent bond, coordination bond, and the like; in the molecular structure of an organic compound, a single bond is usually a covalent bond.
The term "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, a heterocyclyl group "optionally" substituted with halo "means that the heterocyclyl group may be unsubstituted, mono-, poly-, or fully substituted with halo atoms. It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
[ benzylamino-substituted heteropolycyclic Compound ]
The present invention provides a series of novel benzylamino-substituted heteropolycyclic compounds or pharmaceutically acceptable forms thereof, which may be, for example, salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels, or prodrugs of such compounds.
In a first class of embodiments of the present invention, the structure of the compound is shown in formula I:
Figure BDA0003910195120000101
wherein:
ring A is selected from C 6-10 Aryl, 5-to 10-membered heteroaryl, and 3-to 6-membered heterocyclyl;
u and V are independently N or CR 2 ；
W is N or CR 6 ；
Each R 1 Is independently selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, amino, halogen, cyano and nitro;
each R 2 Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, halogen, cyano, -OR 2a and-NR 2a R 2b ；
R 2a And R 2b Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 3-6 A cycloalkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and halogen;
R 4 selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-14 Cycloalkyl radical, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, 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 said cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more substituentsGeneration; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (= O) -C 1-6 Alkyl and-C (= O) O-C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) NH-3-to 14-membered heterocyclyl, -C (= O) -C 6-10 Aryl, -C (= O) -5-to 10-membered heteroaryl and-S (= O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: amino, halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
R 5 selected from hydrogen, amino, halogen, nitro and-O-C 1-6 An alkyl group;
or, R 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, = CH 2 、＝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 said substituents together with the atoms to which each is attached form a 5-to 8-membered heterocyclyl;
R 5a and R 5b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl;
R 6 selected from hydrogen, amino, halogen, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl and-O-C 1-6 An alkyl group;
m is 0,1 or 2;
n is 0,1, 2 or 3;
wherein said heterocyclyl and heteroaryl each contain as ring atoms one or more heteroatoms selected from N, O and S.
In one embodiment of the invention, ring A in formula I is selected from C 6-10 Aryl and 5 to 10 membered heteroaryl.
In a preferred embodiment of the invention, ring A in formula I is C 6-10 And (4) an aryl group.
In a more preferred embodiment of the invention, ring a in formula I is selected from phenyl and naphthyl, preferably phenyl.
In one embodiment of the invention, n in formula I is 0,1 or 2, preferably n is 1 or 2, more preferably n is 2.
In a preferred embodiment of the invention, n in formula I is 0, i.e. ring A is not substituted by R 1 And (4) substituent substitution.
In another preferred embodiment of the invention, n in formula I is 1, i.e. ring A is substituted by 1R 1 Is substituted by a substituent, and the R 1 The substituent is substituted at any substitutable position on ring A.
In a further preferred embodiment of the invention, n in formula I is 2, i.e. ring A is substituted by 2R which are identical to or different from one another 1 Substituted by a substituent, and the 2R 1 The substituents are independently substituted at any substitutable position on ring a.
In one embodiment of the invention, each R in formula I 1 Is independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, amino, halogen, cyano and nitro.
In a preferred embodiment of the invention, each R in formula I 1 Is independently selected from C 1-4 Alkyl radical, C 1-4 Haloalkyl, amino, halogen and cyano.
In a preferred embodiment of the present inventionIn selected embodiments, each R in formula I 1 Independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Amino, fluoro, chloro, bromo, iodo and cyano.
In an even more preferred embodiment of the invention, each R in formula I 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano.
In one embodiment of the invention, each R in formula I 2 Independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Haloalkyl, preferably hydrogen and C 1-4 An alkyl group.
In a preferred embodiment of the invention, each R in formula I 2 Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 and-CH 2 CH 2 CF 3 Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl are preferred.
In a more preferred embodiment of the invention, each R in formula I 2 Independently selected from hydrogen and methyl.
In one embodiment of the invention, R in formula I 3 Selected from hydrogen, C 1-4 Alkyl and C 1-4 A haloalkyl group.
In a preferred embodiment of the invention, R in formula I 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 and-CH 2 CH 2 CF 3 。
In a more preferred embodiment of the invention, R in formula I 3 Is hydrogen.
In one embodiment of the invention, R in formula I 4 Selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, 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 said cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (= O) -C 1-6 Alkyl and-C (= O) O-C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) NH-3-to 14-membered heterocyclyl, -C (= O) -C 6-10 Aryl, -C (= O) -5-to 10-membered heteroaryl, and-S (= O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: amino, halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl.
In a preferred embodiment of the invention, R in the formula I 4 Selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -C (= O) R 4a 、-OR 4a and-NR 4a R 4b Wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl and-C (= O) -C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) -C 6-10 Aryl and-S (= O) m -C 1-6 An alkyl group, wherein the alkyl and alkenyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl.
In a more preferred embodiment of the invention, R in formula I 4 Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, 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), furyl, oxazolyl, isoxazolyl, thienyl (e.g., thiophen-2-yl or thiophen-3-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl or thiazol-5-yl), isothiazolyl, dihydropyrrolyl (e.g., 2, 5-dihydro-1H-pyrrol-3-yl), dihydrofuranyl, dihydrothienyl, pyrrolinyl (e.g., pyrrolin-1-yl, pyrrolin-2-yl, or pyrrolin-3-yl), tetrahydrofuranyl, tetrahydrothienyl, 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), piperidinyl (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), thiochromanyl (e.g., 3, 6-dihydro-2H-thiopyran-4-yl), thiochromanyl oxide (e.g., 1-oxo)3, 6-dihydro-2H-thiopyran-4-yl), thiochromanyl dioxide (e.g., 1-dioxido-3, 6-dihydro-2H-thiopyran-4-yl), thiochromanyl iminooxide (e.g., 1-imino-1-oxide-3, 6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyran base (e.g., tetrahydro-2H-thiopyran-4-yl), tetrahydrothiopyran oxide (e.g., 1-oxide-tetrahydro-2H-thiopyran-4-yl), tetrahydrothiopyran dioxide (e.g., 1-dioxido-tetrahydro-2H-thiopyran-4-yl), tetrahydrothiopyran iminooxide (e.g., 1-imino-1-oxide-tetrahydro-2H-thiopyran-4-yl), piperazinyl (e.g., piperazin-1-yl), 1, 4-diaza-1-thiopyran-4-yl), thiopyran oxide (e.g., 1, 4-diaza-1, 4-oxide-thiopyran-yl), or a salt thereof
Figure BDA0003910195120000121
Radical (e.g. 1, 4-dinitrogen)
Figure BDA0003910195120000122
-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-benzodioxinyl (e.g., 2, 3-dihydro-1, 4-benzodioxin-5-yl or 2, 3-dihydro-1, 4-benzodioxin-6-yl), formyl, acetyl, and propionyl;
wherein said phenyl, naphthyl, anthracenyl, phenanthryl, pyrrolyl, imidazolyl, pyrazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, pyrimidinyl, pyridyl, pyranyl, thiopyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 1, 4-diazepin
Figure BDA0003910195120000123
Each of which is optionally substituted with one substituent; if present, theThe substituents are selected from the following groups: = O, = NH, amino, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, acetyl, and propionyl.
In another preferred embodiment of the invention, R in formula I 4 Is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group.
In another more preferred embodiment of the invention, R in formula I 4 Selected from tetrahydropyridinyl (e.g., 1,2,3, 6-tetrahydropyridin-4-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-4-yl), thiochromanyl (e.g., 3, 6-dihydro-2H-thiopyran-4-yl), thiochromanyl iminooxide (e.g., 1-imino-1-oxy-3, 6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyran (e.g., tetrahydro-2H-thiopyran-4-yl), tetrahydrothiopyran iminooxide (e.g., 1-imino-1-oxy-tetrahydro-2H-thiopyran-4-yl), piperazinyl (e.g., piperazin-1-yl), 1, 4-diazepin
Figure BDA0003910195120000124
Radical (e.g. 1, 4-dinitrogen)
Figure BDA0003910195120000125
-1-yl) and 2-oxa-6-azaspiro [3.3]Heptyl (e.g. 2-oxa-6-azaspiro [3.3]]Hept-6-yl);
wherein said tetrahydropyridinyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl and 1, 4-diaza
Figure BDA0003910195120000126
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl.
In another more preferred embodiment of the invention, R in formula I 4 is-OR 4a ，R 4a Selected from hydrogen, methyl, ethyl, n-propylIsopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, pyrrolinyl, tetrahydrofuryl (e.g., tetrahydrofuran-3-yl), tetrahydrothienyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, piperazinyl, and morpholinyl.
In another more preferred embodiment of the invention, R in formula I 4 is-NR 4a R 4b ，R 4a And R 4b Independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 3 to 14 membered heterocyclic group, acetyl, propionyl, acryloyl, crotonyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, piperidine-1-formyl, piperazine-1-formyl, morpholine-4-formyl, benzoyl, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl and isopropylbenzenesulfonyl, wherein each of said methyl, ethyl, n-propyl, isopropyl, acryloyl and crotonyl is optionally substituted by one substituent; if present, the substituents are selected from the following groups: fluorine, chlorine, bromine, iodine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl.
In one embodiment of the invention, R in formula I 5 Selected from the group consisting of hydrogen, amino, halogen and nitro.
In a preferred embodiment of the invention, R in formula I 5 Selected from hydrogen and halogen.
In a more preferred embodiment of the invention, R in formula I 5 Is hydrogen.
In one embodiment of the invention, R in formula I 4 And R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, = O, = CH 2 、＝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 An alkyl group.
In a preferred embodiment of the invention, R in formula I 4 And R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and = O.
In a more preferred embodiment of the invention, R in formula I 4 And R 5 Together with the atom to which each is attached, form a 5,6, 9, 12, 14, or 15 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and = O, preferably methyl, cyclopropyl and = O.
In one embodiment of the invention, R in formula I 6 Selected from hydrogen, C 1-4 Alkyl and-O-C 1-5 An alkyl group.
In a preferred embodiment of the invention, R in formula I 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy.
In a more preferred embodiment of the invention, R in formula I 6 Is methyl.
In one embodiment of the invention, U in formula I is CR 2 V is N, W is N, and the structure of the compound of formula I is shown as formula I-1:
Figure BDA0003910195120000131
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above.
In a more preferred embodiment of the present invention, in formula I-1,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, of the formula I-1
Figure BDA0003910195120000132
Selected from the following groups:
Figure BDA0003910195120000133
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiopyranyl iminooxide, thiopyranyl tetrahydroxide, thiopyranyl iminooxide, piperazinyl, 1, 4-diaza-nyl
Figure BDA0003910195120000141
Radicals and 2-oxa-6-azaspiro [3.3]Heptyl, wherein the tetrahydropyridyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl, and 1, 4-diazepam
Figure BDA0003910195120000142
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl;
R 5 is hydrogen;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
In a preferred embodiment of the present invention, the compound of formula I-1 has the structure shown in formula I-1A:
Figure BDA0003910195120000143
wherein: n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above.
In a more preferred embodiment of the present invention, in formula I-1A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1A
Figure BDA0003910195120000144
Selected from the following groups:
Figure BDA0003910195120000145
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiochromanyl, iminooxathiopyranyl, tetrahydrothiopyranyl, iminooxathiopyranyl, piperazinyl, 1, 4-diaza
Figure BDA0003910195120000146
Radicals and 2-oxa-6-azaspiro [3.3]]Heptyl, wherein the tetrahydropyridyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl, and 1, 4-diazepam
Figure BDA0003910195120000147
Each of which is optionally substituted with one substituent; if there is anyWherein the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl;
R 5 is hydrogen;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
In a more preferred embodiment of the invention, the compounds of formula I-1A have the structure shown in formula I-1B (especially formula I-1B-1 or formula I-1B-2):
Figure BDA0003910195120000151
wherein: n, R 1 、R 2 And R 4 As defined above.
In a more preferred embodiment of the present invention, in formula I-1B (especially formula I-1B-1 or formula I-1B-2),
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1B (especially of formula I-1B-1 or of formula I-1B-2)
Figure BDA0003910195120000152
Selected from the following groups:
Figure BDA0003910195120000153
R 2 selected from hydrogen and methyl, preferably methyl;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiochromanyl, iminooxathiopyranyl, tetrahydrothiopyranyl, iminooxathiopyranyl, piperazinyl, 1, 4-diaza
Figure BDA0003910195120000154
Radical and 2-oxygenHetero-6-azaspiro [3.3]]Heptyl wherein the tetrahydropyridinyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl and 1, 4-diazanyl are present
Figure BDA0003910195120000155
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
In one embodiment of the invention, U in formula I is CR 2 V is CR 2 And W is N, and the structure of the compound of the formula I is shown as a formula I-2:
Figure BDA0003910195120000156
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above.
In a more preferred embodiment of the present invention, in formula I-2,
ring A is phenyl;
n is 1 or 2, preferably 1;
each R 1 Is independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably-CHF 2 、-CF 3 Amino, fluoro, chloro and nitro groups;
each R 2 Independently selected from hydrogen and methyl;
R 3 is hydrogen;
R 4 and R 5 Together with the atoms to which each is attached, form a 5-to 8-membered heterocyclic group containing one or more heteroatoms selected from N, O and S as ring atoms;
but does not include
Figure BDA0003910195120000161
In a preferred embodiment of the present invention, the compound of formula I-2 has the structure shown in formula I-2A:
Figure BDA0003910195120000162
wherein:
ring B is a 5-to 15-membered, preferably 5-to 8-membered heterocyclic group containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O and S as ring atoms;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
p is 0,1, 2,3,4, 5 or 6;
n、R 1 and R 2 As defined above.
In a more preferred embodiment of the present invention, in formula I-2A,
n is 1 or 2, preferably 1;
each R 1 Independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably-CHF 2 、-CF 3 Amino, fluoro, chloro and nitro;
each R 2 Independently selected from hydrogen and methyl;
ring B is a 5-to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms;
but does not include
Figure BDA0003910195120000163
Preferably, in the above-mentioned compounds of formula I-2A, ring B is a 5-or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms, preferably 1 or 2 heteroatoms selected from N, O and S as ring atoms, more preferably 2O atoms as ring atoms.
In one aspect of the inventionIn embodiments, U in formula I is N and V is CR 2 W is CR 6 When the structure of the compound of formula I is shown as formula I-3:
Figure BDA0003910195120000171
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined above.
In a more preferred embodiment of the present invention, in formula I-3,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in formula I-3
Figure BDA0003910195120000172
Selected from the following groups:
Figure BDA0003910195120000173
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 3 is hydrogen;
R 4 and R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and = O, more preferably methyl, cyclopropyl and = O;
R 6 is methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
In a preferred embodiment of the present invention, the compound of formula I-3 has the structure shown in formula I-3A:
Figure BDA0003910195120000174
wherein:
ring B is a 5-to 15-membered heterocyclic group containing 1 to 5 heteroatoms selected from N, O and S;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
p is 0,1, 2,3,4, 5 or 6;
n、R 1 、R 2 and R 6 As defined above.
Preferably, in the above-mentioned compounds of formula I-3A, ring B is a 5-, 6-, 9-, 12-, 14-or 15-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms, preferably 1 or 2 heteroatoms selected from N, O and S as ring atoms, more preferably 1 or 2 heteroatoms selected from N and O as ring atoms.
Preferably, in the above-mentioned compounds of formula I-3A, each R is 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl and 3-to 14-membered heterocyclyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 。
More preferably, in the above-described compounds of formula I-3A, each R is 7 Independently selected from C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O.
Even more preferably, in the above-described compounds of formula I-3A, each R is 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O.
Preferably, in the compounds of formula I-3A above, p is 0,1, 2,3 or 4.
More preferably, in the above compound of formula I-3A, p is 1,2,3 or 4.
Even more preferably, in the above compound of formula I-3A, p is 2,3 or 4.
In a more preferred embodiment of the present invention, in formula I-3A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in the formula I-3A
Figure BDA0003910195120000181
Selected from the following groups:
Figure BDA0003910195120000182
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O;
rings B and p are as defined above.
In a more preferred embodiment of the invention, the compounds of formula I-3A have the structure shown in formula I-3B (especially formula I-3B-1 or formula I-3B-2):
Figure BDA0003910195120000183
wherein:
each X is independently C (R) 7 ) 2 、NR 7 O or S;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
q is 3,4, 5,6,7,8, 9, 10,11, 12 or 13;
n、R 1 、R 2 and R 6 As defined aboveAnd (5) defining.
Preferably, in the compounds of formula I-3B (especially of formula I-3B-1 or formula I-3B-2) above, each X is independently C (R) 7 ) 2 、NR 7 Or O.
More preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), each X is independently C (R) 7 ) 2 Or NR 7 。
Alternatively, more preferably, in the compounds of formula I-3B (especially of formula I-3B-1 or formula I-3B-2) above, each X is independently C (R) 7 ) 2 Or O.
Preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), each R is 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl and 3-to 14-membered heterocyclyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 。
Preferably, in the compounds of formula I-3B (especially of formula I-3B-1 or formula I-3B-2) above, each R is 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O.
Preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), q is 3,4, 7,8, 9, 10,11, 12 or 13.
More preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), q is 3,4, 7,10, 12 or 13.
Even more preferably, in the compounds of formula I-3B above (especially formula I-3B-1 or formula I-3B-2), q is 3.
Alternatively, even more preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), q is 4.
Alternatively, even more preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), q is 7.
Alternatively, even more preferably, in the compounds of formula I-3B above (especially formula I-3B-1 or formula I-3B-2), q is 10.
Alternatively, even more preferably, in the compounds of formula I-3B above (especially formula I-3B-1 or formula I-3B-2), q is 12.
Alternatively, even more preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), q is 13.
In a more preferred embodiment of the present invention, in formula I-3B (especially formula I-3B-1 or formula I-3B-2),
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-3B (especially of formula I-3B-1 or of formula I-3B-2)
Figure BDA0003910195120000191
Selected from the following groups:
Figure BDA0003910195120000192
each X is independently C (R) 7 ) 2 、NR 7 Or O;
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O;
q is as defined above.
Further preferably, in the compounds of the formula I-3B described above (in particular of the formula I-3B-1 or of the formula I-3B-2),
Figure BDA0003910195120000193
the fragment is selected from the following structures:
Figure BDA0003910195120000194
Figure BDA0003910195120000201
Figure BDA0003910195120000202
preferably, the first and second electrodes are formed of a metal,
Figure BDA0003910195120000203
the fragment is selected from the following structures:
Figure BDA0003910195120000204
each R 7 Independently selected from hydrogen, C 1-6 Alkyl (preferably methyl) and C 3-14 Cycloalkyl (preferably cyclopropyl), or, any two R's attached to the same ring atom 7 Form = O.
Alternatively, in a second class of embodiments of the invention, in the compounds of formula I,
ring A is C 6-10 Aryl, preferably phenyl;
u and V are independently N or CR 2 ；
W is N or CR 6 ；
Each R 1 Is independently selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, amino, halogen, cyano and nitro, preferably methyl, difluoromethyl, trifluoromethyl, amino, fluoro, chloro, cyano and nitro;
each R 2 Independently selected from hydrogen and C 1-6 Alkyl, preferably hydrogen and methyl;
R 3 is hydrogen;
R 4 selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl radical, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -C (= O) R 4a 、-OR 4a and-NR 4a R 4b Wherein the cycloalkenyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, hydroxy, carboxy, C 1-6 Alkyl, -O-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) m -C 1-6 Alkyl and-S (= O) m -C 3-14 A cycloalkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) -C 6-10 Aryl and-S (= O) m -C 1-6 An alkyl group, wherein the alkyl and alkenyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
R 5 selected from hydrogen and-O-C 1-6 An alkyl group;
or, R 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O;
R 6 is C 1-6 Alkyl, preferably methyl;
each m is independently 0,1 or 2, preferably 2;
n is 0,1, 2 or 3, preferably 0,1 or 2, more preferably 1 or 2, further preferably 2;
wherein said heterocyclyl and heteroaryl each contain as ring atoms one or more heteroatoms selected from N, O and S.
In a preferred embodiment of the invention, R in formula I 4 Is a 3-to 14-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 A cycloalkyl group;
R 4a and R 4b Independently is C 1-6 Alkyl, preferably methyl.
In a more preferred embodiment of the invention, R in formula I 4 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), thiochromanyl (e.g., 3, 6-dihydro-2H-thiopyran-4-yl), iminooxidothiopyranyl (e.g., 1-imino-1-oxido-3, 6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), iminooxidothiopyranyl (e.g., 1-imino-1-oxido-tetrahydro-2H-thiopyran-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), and iminooxidothiomorpholinyl (e.g., 1-iminooxido-1-4-thiomorpholinyl);
wherein said azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminothiopyranyl, tetrahydrothiopyranyl, iminothiopyranyl, thiomorpholinyl, and iminothiomorpholinyl oxide are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, hydroxy, 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 (CH) (= O) -cyclopropyl, -C (= O) -cyclobutyl, -C (= O) -cyclopentyl, -C (= O) - (tetrahydropyran-4-yl) 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -cyclopropyl.
In a preferred embodiment of the invention, R in formula I 5 Selected from hydrogen and methoxy.
In a more preferred embodiment of the invention, R in formula I 5 Is hydrogen.
In another preferred embodiment of the invention, R in formula I 4 And R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, = O, = CH 2 、＝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 An alkyl group.
In a preferred embodiment of the invention, R in formula I 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: methyl, cyclopropyl and = O.
Alternatively, in another embodiment of the present invention, in the compounds of formula I-1, ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above.
In a preferred embodiment of the present invention, in formula I-1,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, of the formula I-1
Figure BDA0003910195120000211
Selected from the following groups:
Figure BDA0003910195120000212
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 A cycloalkyl group;
R 4a and R 4b Independently selected from C 1-6 Alkyl, preferably methyl;
R 5 is hydrogen;
wherein said heterocyclyl and heteroaryl each independently contain as ring atoms one or more heteroatoms selected from N, O and S.
Alternatively, in another embodiment of the present invention, in the compounds of formula I-1A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above.
In a preferred embodiment of the present invention, in formula I-1A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1A
Figure BDA0003910195120000221
Selected from the following groups:
Figure BDA0003910195120000222
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 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-pyranyl)Pyran-4-yl), thiochromanyl (e.g., 3, 6-dihydro-2H-thiopyran-4-yl), iminothiolanyl (e.g., 1-imino-1-oxy-3, 6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyran (e.g., tetrahydro-2H-thiopyran-4-yl), iminothiolanyl (e.g., 1-imino-1-oxy-tetrahydro-2H-thiopyran-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), and iminothiolalinyl (e.g., 1-imino-1-oxy-thiomorpholin-4-yl);
wherein said azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminooxathiopyranyl, tetrahydrothiopyranyl, iminooxatetrahydrothiopyranyl, thiomorpholinyl, and iminooxathiomorpholinyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, hydroxy, 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 (CH) (= O) -cyclopropyl, -C (= O) -cyclobutyl, -C (= O) -cyclopentyl, -C (= O) - (tetrahydropyran-4-yl) 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -a cyclopropyl group;
R 5 is hydrogen.
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.
In a preferred embodiment of the present invention, in formula I-1B (especially formula I-1B-1 or formula I-1B-2),
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1B (especially of formula I-1B-1 or of formula I-1B-2)
Figure BDA0003910195120000223
Selected from the following groups:
Figure BDA0003910195120000224
R 2 selected from hydrogen and methyl, preferably methyl;
R 4 selected from the group consisting of thiopyranyl (e.g., 3, 6-dihydro-2H-thiopyran-4-yl), iminooxathiopyranyl (e.g., 1-imino-1-oxo-3, 6-dihydro-2H-thiopyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydro-2H-thiopyran-4-yl), and iminooxathiopyranyl (e.g., 1-imino-1-oxo-tetrahydro-2H-thiopyran-4-yl);
wherein the thiochromanyl and tetrahydrothiopyranyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 (CH) (= O) -N 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -cyclopropyl.
Alternatively, in another embodiment of the invention, in the compounds of formula I-3, ring A, n, R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined above.
In a preferred embodiment of the present invention, in formula I-3,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in formula I-3
Figure BDA0003910195120000231
Selected from the following groups:
Figure BDA0003910195120000232
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 3 is hydrogen;
R 4 and R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with oneOr substituted by a plurality of substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O, preferably methyl, cyclopropyl and = O;
R 6 is methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
Alternatively, in another embodiment of the present invention, in the compound of formula I-3A,
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;
each R 7 Independently selected from C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O;
p is 0,1, 2,3,4, 5 or 6;
n、R 1 、R 2 and R 6 As defined above.
Preferably, in the above-mentioned 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.
Preferably, in the compounds of formula I-3A above, each R 7 Independently selected from methyl and cyclopropyl, or, any two R attached to the same ring atom 7 Form = O.
Preferably, in the compounds of formula I-3A above, p is 0,1, 2,3,4 or 5.
More preferably, in the above compound of formula I-3A, p is 1,2,3,4 or 5.
Even more preferably, in the above compound of formula I-3A, p is 2,3,4 or 5.
In a preferred embodiment of the present invention, in the formula I-3A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in the formula I-3A
Figure BDA0003910195120000233
Selected from the following groups:
Figure BDA0003910195120000234
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O;
rings B and p are as defined above.
Alternatively, in another embodiment of the present invention, in formula I-3B (especially formula I-3B-1 or formula I-3B-2),
each X is independently CH 2 、NR 7 O or S, preferably CH 2 、NR 7 Or O;
each R 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O;
q is 3,4, 5,6,7,8, 9, 10,11, 12 or 13;
n、R 1 、R 2 and R 6 As defined above.
Preferably, in the compounds of formula I-3B (especially of formula I-3B-1 or formula I-3B-2) above, each X is independently C (R) 7 ) 2 、NR 7 Or O.
More preferably, in the compounds of formula I-3B above (especially of formula I-3B-1 or formula I-3B-2), each X is independently C (R) 7 ) 2 Or NR 7 。
Alternatively, more preferably, in the compounds of formula I-3B (especially of formula I-3B-1 or formula I-3B-2) above, each X is independently C (R) 7 ) 2 Or O.
In a preferred embodiment of the present invention, in formula I-3B (especially formula I-3B-1 or formula I-3B-2),
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluorine and cyanogenA group; preferably of formula I-3B (especially of formula I-3B-1 or of formula I-3B-2)
Figure BDA0003910195120000241
Selected from the following groups:
Figure BDA0003910195120000242
each X is independently CH 2 、NR 7 Or O;
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O;
q is as defined above.
Further preferably, in the above-mentioned compounds of formula I-3B (especially of formula I-3B-1 or of formula I-3B-2),
Figure BDA0003910195120000243
the fragment is selected from the following structures:
Figure BDA0003910195120000244
each R 7 Independently selected from hydrogen, methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O.
Specifically, benzylamino-substituted heteropolycyclic compounds of the present invention include, but are not limited to, the following:
Figure BDA0003910195120000245
Figure BDA0003910195120000251
Figure BDA0003910195120000261
Figure BDA0003910195120000271
Figure BDA0003910195120000281
Figure BDA0003910195120000291
[ pharmaceutical composition ]
The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, one or more diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, co-solvents, surfactants, light-shielding agents (opacifiers), and the like.
The invention provides a pharmaceutical composition comprising a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1, or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, as described above.
In one embodiment of the present invention, the above pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
[ pharmaceutical preparations ]
The term "pharmaceutical formulation" refers to a finished pharmaceutical product prepared in a form suitable for administration to a patient.
The invention provides a pharmaceutical preparation, which is prepared from the pharmaceutical composition.
In one embodiment of the present invention, the above pharmaceutical preparation is a solid preparation for oral administration, including (but not limited to) pharmaceutically acceptable capsules, tablets, pills, powders, granules, and the like. The solid dosage forms may 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 may comprise an opacifying agent and the active ingredient therein may be released in a delayed manner in a portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. In addition, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned carriers.
In another embodiment of the present invention, the above pharmaceutical formulation is a liquid dosage form for oral administration, including (but not limited to) pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.
In yet another embodiment of the present invention, the above pharmaceutical formulation is a dosage form for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.
In still another embodiment of the present invention, the above pharmaceutical preparation is a dosage form for topical administration, including (but not limited to) ointment, powder, suppository, drop, spray, inhalant, etc.
[ medicinal use ]
Whether a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1, or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition thereof, or a pharmaceutical formulation thereof, is capable of exhibiting inhibitory activity against SOS1, the invention therefore provides the use of a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-2A, formula I-2B, formula I-3A or formula I-3B as defined above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans-isomer, isotopic label or prodrug thereof, or of a pharmaceutical composition as defined above or of a pharmaceutical formulation as defined above, for the preparation of a medicament for the prophylaxis and/or treatment of a disease which is mediated at least in part by the SOS1 protein.
The invention provides application of the compound of the formula I, the formula 1-1, the formula I-IA, the formula I-IB, the formula I-1B-1, the formula I-1B-2, the formula I-2A, the formula I-2B-1, the formula I-2B-2, the formula I-3A, the formula I-3B-1 or the formula I-3B-2 or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope marker or prodrug thereof, or the pharmaceutical composition or the pharmaceutical preparation in preparing a medicament for preventing and/or treating cancer.
The term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth at an ectopic site. Non-limiting examples of cancer include, but are not limited to, pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, 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.
The invention also provides a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1 or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition or formulation thereof, as defined above, for use in the prevention and/or treatment of a disease (particularly cancer) mediated at least in part by the SOS1 protein.
The present invention also provides a method for the prevention and/or treatment of a disease mediated at least in part by the SOS1 protein, in particular cancer, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1, or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans-isomer, isotopic label or prodrug thereof, or a pharmaceutical composition thereof, or a pharmaceutical formulation thereof, as described above.
[ combination drug ]
The present invention provides a pharmaceutical combination comprising a compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1, or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition or formulation thereof, as described above, and at least one additional cancer therapeutic agent.
The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical formulation that is effective in controlling and/or combating cancer. Common cancer therapeutic agents include, but are not limited to, anti-purines (e.g., pentostatin, etc.), anti-pyrimidines (e.g., 5-fluorouracil), antifolates (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum complexes (e.g., cisplatin, carboplatin), DNA damaging antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecin), intercalating DNA interfering nucleic acid synthesizers (e.g., epirubicin), preventing raw material supply (e.g., asparaginase), interfering tubulin formation drugs (e.g., paclitaxel), interfering with ribosomal function (e.g., cephalotaxin), and the like cytokines (e.g., IL-1), thymosin, tumor cell proliferating viruses (e.g., adenovirus ONYX-015), vinca alkaloids (e.g., vinorelbine), doxorubicin (e.g., doxorubicin, epirubicin, aclacinomycin), tinib (e.g., imatinib, gefitinib, erlotinib, dasatinib, sunitinib), mabs (e.g., trastuzumab, panitumumab, bevacizumab), bortezomib, calcitriol, capecitabine, aminoglutethimide, letrozole, runing, everolimus, fulvestrant, irinotecan, pemetrexed, sirolimus, PD-1, PD-L1, and the like.
In one embodiment of the present invention, the compound of formula I, formula 1-1, formula I-IA, formula I-IB, formula I-1B-1, formula I-1B-2, formula I-2A, formula I-2B-1, formula I-2B-2, formula I-3A, formula I-3B-1, or formula I-3B-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or the pharmaceutical composition or formulation thereof, can be administered alone or in combination with other cancer therapeutic agents (or antineoplastic agents). The combination therapy can be achieved by administering the different cancer therapeutic agents simultaneously, sequentially, or separately.
The technical solution of the present invention will be further described with reference to specific examples. Unless otherwise indicated, reagents, materials, instruments and the like used in the following examples are commercially available in a conventional manner, and the experimental methods used are conventional in the art.
Example 1: preparation of Compound 1
(1) Intermediate 1-1 synthetic route
Figure BDA0003910195120000311
Under the protection of nitrogen, 1-1a (20.00g, 106.36mmol, 1.0eq), THF (150 mL), tert-butylsulfinamide (19.31g, 159.54mmol, 1.5eq) and tetraethyltitanate (74.65g, 327.26mmol, 3.0eq) are added into a reaction flask in turn, and after the addition, the temperature is raised to 80 ℃, and the reaction is stirred for 4 hours. After the reaction system was cooled to room temperature, water (150 mL) was added, followed by extraction with ethyl acetate (150 mL) for 2 times, and 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[ deg. ] M + H] + 。
Adding the compound 1-1b (28.00g, 96.19mmol and 1.0eq), THF (400 mL) and water (6 mL) into a reaction bottle in sequence, cooling to-60-50 ℃, slowly adding sodium borohydride (6.58g, 173.14mmol and 1.8eq), and after the addition, heating to-5-0 ℃ and continuously stirring for 30 minutes at the controlled temperature. The reaction was quenched by adding water (300 mL), extracted 2 times with ethyl acetate (300 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to give compound 1-1c (22.2 g); MS m/z 294.1[ deg. ] M + H] + 。
To a reaction flask were added compound 1-1c (22.20g, 75.76mmol, 1.0eq), dioxane (50 mL) and 4M hydrochloric acid (40 mL) in this order, and the mixture was stirred at room temperature for 2 hours. Adjusting the pH value of the system to 8-9 by using 1M sodium hydroxide solution, adding ethyl acetate for extraction (100 mL) for 2 times, drying an organic phase by using anhydrous sodium sulfate, concentrating, and pulping the obtained solid by using petroleum ether to obtain an intermediate 1-1 (10.0 g); MS m/z 190.1[ 2 ], [ M ] +H] + 。
(2) Intermediate 1-2 synthetic route
Figure BDA0003910195120000321
To a reaction flask were added compound 1-2a (10.00g, 65.76mmol,1.0 eq), acetic anhydride (60 mL), and the mixture was heated to 70 ℃ for 12 hours. After the reaction, the reaction system was cooled to room temperature, diluted with water (300 ml), and the pH of the system was adjusted to 8 to 9 with sodium carbonate solid, and extracted 3 times with ethyl acetate (200 ml). Drying the ethyl acetate phase with anhydrous sodium sulfate, and concentrating to obtain compound 1-2b (13.20 g); MS m/z 195.0[ m ] +H] + 。
Compound 1-2b (13.20g, 68.02mmol, 1.0eq) and ammonia (150 ml) were charged into a closed-tube reaction flask, and the flask was heated to 30 ℃ to react overnight. After the reaction is finished, concentrating and drying the reaction system to obtain a solid, and drying the solid in an oven to obtain a compound 1-2c (11.03 g); MS m/z 162.0[ m ] +H] + 。
Adding the compound 1-2c (1.00g, 6.21mmol and 1.0eq) into a reaction bottle, using acetonitrile (10 ml) as a solvent, sequentially adding DIPEA (4.01g, 31.05mmol and 5.0eq) and phosphorus oxychloride (2.86g, 18.63mmol and 3.0eq) into the reaction bottle, and heating to 85 ℃ under the protection of nitrogen to react for 3 hours after the addition is finished. After the reaction, the reaction system was concentrated to dryness, then dissolved in ethyl acetate (30 ml), adjusted to pH 8-9 with an aqueous sodium bicarbonate solution in an ice bath, separated, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give compound 1-2 (1.11 g), which was used directly in the next step.
(3) Synthetic route to Compound 1
Figure BDA0003910195120000322
To a reaction flask were added compounds 1 to 2 (1.11g, 6.20mmol, 1.0eq), compounds 1 to 1 (1.29g, 6.82mmol, 1.1eq), DIPEA (1.60g, 12.40mmol, 2.0eq), and THF (11 ml) in this order, and after the addition, the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was concentrated to dryness, and purified by column chromatography (eluent: dichloromethane/methanol =30: 1) to obtain compound 1 (650 mg), and 100mg was taken and subjected to reverse phase column chromatography purification (Shim-pack GIS-C18 × 250nm,5 μm;0.01% formic acid-water/acetonitrile) to obtain pure compound 1 (2.50 mg); MS m/z 333.2[ m ] +H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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)。
Example 2: preparation of Compound 2
Figure BDA0003910195120000323
Compound 1 (500mg, 1.43mmol,1.0 eq) and potassium nitrate (144mg, 1.43mmol,1.0 eq) were added to a reaction flask, followed by concentrated sulfuric acid (5 ml), and the reaction was stirred at room temperature for 1 hour. After the reaction is finished, regulating the pH of the reaction system to 8-9 by using a sodium carbonate aqueous solution in an ice bath, extracting for 5 times by using ethyl acetate (20 ml), combining organic phases, drying by using anhydrous sodium sulfate, concentrating to dryness to obtain a compound 2 (571 mg), and taking 100mg for reverse reactionPurification by column chromatography (Shim-pack GIS-C18 20 x 250nm,5 μm;0.01% formic acid-water/acetonitrile) to give pure compound 2 (17.87 mg); MS m/z 378.0[ m ] +H] + 。
Example 3: preparation of Compound 3
Figure BDA0003910195120000331
Adding the compound 5 (50.00mg, 0.12mmol, 1.0eq) and tetrahydrofuran (3 mL) into a reaction bottle under the condition of nitrogen protection, then cooling to-78 ℃, slowly dropwise adding N-butyllithium (0.3mL, 0.48mmol,4.0eq, 1.6M) at controlled temperature, keeping the temperature and stirring for 0.5 hour after dropwise adding, slowly dropwise adding a mixed solution of N-fluorobis (benzenesulfonamide) (57.7mg, 0.18mmol, 1.5eq) and tetrahydrofuran (3 mL) at controlled temperature, keeping the temperature and stirring for 0.5 hour after dropwise adding, naturally heating to room temperature and stirring overnight. The system was quenched with water (10 mL), then the aqueous phase was extracted 2 times with ethyl acetate (20 mL), the organic phases were combined and then washed successively with water (10 mL) and saturated aqueous sodium chloride (10 mL), the organic phase was dried over anhydrous sodium sulphate and spun dry. The crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 3 (0.85 mg); MS m/z 351.2[ m ] +H] + 。
Example 4: preparation of Compound 4
Figure BDA0003910195120000332
The compound 4-1a (15.00g, 65.23mmol,1.0 eq) and acetic anhydride (90 mL) were added to a reaction flask in this order, and after the addition, the temperature was raised to 70 ℃ and the reaction was stirred overnight. Cooling the reaction system to room temperature, adding water (50 mL), adjusting the pH of the system to 8-9 by using a saturated sodium carbonate aqueous solution, adding ethyl acetate (500 mL) for extraction for 2 times, combining organic phases, washing the organic phases once by using water (200 mL) and washing the organic phases once by using a saturated sodium chloride aqueous solution (200 mL), drying the organic phases with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain a compound 4-1b (9.01 g); MS m/z 273.0[ M + H ]] + 。
Compound 4-1b (9.00g, 33.09mmol, 1.0eq) and ammonia (90 mL) were added in this order to a reaction flask, and the reaction was stirred overnight at 30 ℃. The reaction system is cooled to room temperature, is dried by spinning, is added with dichloromethane (100 mL) and is pulped for 0.5 hour, is filtered, and a filter cake is washed by dichloromethane (50 mL) for 2 times and is dried. Compound 4-1c (6.56 g) was obtained; MS m/z 240.0[ deg. ] M + H] + 。
The reaction flask was charged with the compounds 4-1c (6.07g, 25.40mmol, 1.0eq), acetonitrile (70 mL), N-diisopropylethylamine (16.40g, 127.01mmol, 5.0eq) and phosphorus oxychloride (11.68g, 76.20mmol, 3.0eq) in this order, heated to 80 ℃ and stirred for 3 hours. And (3) spin-drying the system, adding ethyl acetate (100 mL), adjusting the pH of the system to 8-9 by using a saturated sodium carbonate aqueous solution under an ice bath condition, separating the solution, washing an organic phase once by using water (50 mL) and a saturated sodium chloride aqueous solution (50 mL), drying the organic phase by using anhydrous sodium sulfate, and spin-drying. To obtain crude compound 4-1d (6.53 g); MS m/z 258.0[ deg. ] M + H] + 。
The reaction flask was charged with the compounds 4 to 1d (6.53 g), 1 to 1 (7.77g, 38.10mmol,1.5 eq), N, N-diethylethylamine (9.84g, 76.20mmol,3.0 eq) and tetrahydrofuran (70 mL) in this order, and the mixture was stirred at room temperature overnight. After the system was cooled to room temperature, spin-dried, followed by addition of water (50 mL), extraction of the aqueous phase with ethyl acetate (100 mL) for 2 times, combination of the organic phases and washing with water (50 mL) once, saturated aqueous sodium chloride solution (50 mL) once, drying of the organic phase with anhydrous sodium sulfate, spin-drying, and purification by column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to give compound 4 (7.0 g). Then 100mg of Compound 4 was purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give Compound 4 (6.11 mg); MS m/z 411.0[ m ] +H] + 。
Examples 5 to 9: preparation of Compounds 5-9
Compounds 5-9 (see Table 1) were synthesized in a procedure substantially similar to example 4.
TABLE 1 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compound-9
Figure BDA0003910195120000341
Example 10: preparation of Compound 10
Figure BDA0003910195120000342
Under the protection of nitrogen, compound 4 (55.00mg, 0.13mmol, 1.0eq), 3-thiopheneboronic acid (25.70mg, 0.20mmol, 1.5eq), sodium carbonate (35.5mg, 0.34mmol, 2.5eq), tetrakis (triphenylphosphine) palladium (31.00mg, 0.026mmol, 0.2eq), 1, 4-dioxane (4 ml) and water (1 ml) were sequentially added to a reaction flask. The temperature was raised to 90 ℃ and the reaction was stirred overnight. The system was cooled to room temperature, quenched with water (5 ml), extracted 2 times with ethyl acetate (20 ml), the organic phases combined and washed once with water (10 ml), once with saturated aqueous sodium chloride (10 ml), the organic phase dried over anhydrous sodium sulfate, spun dry, and the crude product purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,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-d 6 ):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)。
Examples 11 to 36, 81 to 82, 85 to 87, 89, 91 to 96, 98 to 99: preparation of Compounds 11-36, 81-82, 85-87, 89, 91-96, 98-99
Compounds 11-36, 81-82, 85-87, 89, 91-96, 98-99 (see Table 2) were synthesized according to a procedure substantially similar to example 10.
TABLE 2 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 11-36, 81-82, 85-87, 89, 91-96, 98-99
Figure BDA0003910195120000351
Figure BDA0003910195120000361
Figure BDA0003910195120000371
Figure BDA0003910195120000381
Figure BDA0003910195120000391
Figure BDA0003910195120000401
Figure BDA0003910195120000411
Figure BDA0003910195120000421
Example 37: preparation of Compound 37
Figure BDA0003910195120000422
The compound 2 (64mg, 0.16mmol, 1.0eq), ethanol (3 ml), stannous chloride (153mg, 0.81mmol, 5.0eq) were added in sequence to a reaction flask, and heated to 50 ℃ under nitrogen protection for 4h. Cooling the reaction system to room temperature, adjusting the pH value to 8-9 with sodium bicarbonate aqueous solution, precipitating a solid, adding ethyl acetate (10 ml), stirring and filtering, collecting filtrate, separating out an organic phase, extracting a water phase for 3 times with ethyl acetate (10 ml), combining the organic phases, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, purifying the crude product by climbing a large plate (a developing agent: dichloromethane/methanol = 10)Acetonitrile) to give pure compound 37 (7.62 mg); MS m/z 348.0[ m ] +H] + 。
Example 38: preparation of Compound 38
Figure BDA0003910195120000423
To a reaction flask were added compound 37 (50mg, 0.144mmol, 1.0eq), DCM (2 ml), triethylamine (44mg, 0.432mmol, 3.0eq), and methanesulfonyl chloride (20mg, 0.173mmol, 1.2eq) in that order, and the reaction was carried out at room temperature for 1 hour. After the reaction, the reaction system was diluted with DCM (10 ml), adjusted pH to 8-9 with aqueous sodium bicarbonate solution, separated, the organic phase retained, the aqueous phase extracted 2 times with dichloromethane (10 ml), the organic phases combined, dried with anhydrous sodium sulfate, concentrated to dryness, and the crude product purified by reverse phase column chromatography (Shim-pack GIS-C18 20 250nm,5 μm;0.01% formic acid-water/acetonitrile) to give pure compound 38 (7.15 mg); MS m/z 426.0[ m ] +H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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)。
Example 39: preparation of Compound 39
Figure BDA0003910195120000431
Compound 37 (50mg, 0.144mmol, 1.0eq), 2-fluoroacrylic acid (13mg, 0.144mmol, 1.0eq), N-dimethylformamide (3 mL), EDCI (40mg, 0.21mmol, 1.5eq), and HOBt (28mg, 0.21mmol, 1.5eq) were added to the reaction flask in this order, and the reaction was stirred at room temperature for 12 hours, then water (4 mL) was added to the system, ethyl acetate (4mL. Multidot.2) was added thereto for extraction, the organic phase was concentrated, and the crude product was purified by reverse phase column chromatography (Shim-pack GIS-C18: 250nm,5 μm;0.01% formic acid-water/acetonitrile) to give pure compound 39 (5.23 mg). MS m/z 420.0[ m ] +H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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)。
Examples 40 to 41: preparation of Compounds 40-41
Compounds 40-41 (see Table 3) were synthesized in a procedure substantially similar to example 38.
TABLE 3 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 40-41
Figure BDA0003910195120000432
Example 42: preparation of Compound 42
Figure BDA0003910195120000441
Compound 37 (50mg, 0.144mmol, 1.0eq), triethylamine (44mg, 0.432mmol, 3.0eq), dichloromethane (3 mL), and triphosgene (18mg, 0.06mmol, 0.4eq) were sequentially added to a reaction flask, and after stirring for 30 minutes, cyclopropylammonia (8.2mg, 0.144mmol, 1.0eq) was added, and after completion, stirring was performed at room temperature for 6 hours, then water (4 mL) was added to the system, ethyl acetate was added thereto and extracted (4 mL) 3 times, the organic phase was concentrated, and the crude product was purified by reverse phase column chromatography (Shim-pack GIS-C18 20X 250nm,5 μm;0.01% formic acid-water/acetonitrile) to give pure compound 42 (5.23 mg). MS m/z 431.0[ m ] +H] + ；
Example 43: preparation of Compound 43
Compound 43 (see table 4) was synthesized in a procedure substantially similar to example 42.
TABLE 4 Structure and Mass Spectrometry data for Compound 43
Figure BDA0003910195120000442
Example 44: preparation of Compound 44
Figure BDA0003910195120000443
Compound 37 (50mg, 0.144mmol, 1.0eq), potassium carbonate (59.6mg, 0.432mmol, 3.0eq), DMF (3 mL), and cyclopentyl bromide (31.3mg, 0.21mmol, 1.5eq) were added to a reaction flask in this order, and then the mixture was heated to 80 ℃ and stirred for 6 hours, then water (4 mL) was added to the system, followed by addition of ethyl acetate for extraction (4 mL) 3 times, the organic phase was concentrated, and the crude product was purified by reverse phase column chromatography (Shim-pack GIS-C18 20X 250nm,5 μm;0.01% formic acid-water/acetonitrile) to give pure compound 44 (7.26 mg). MS m/z 416.1[ deg. ] M + H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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),2.16-2.02(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)。
Examples 45-47, 88: preparation of Compounds 45-47, 88
Compounds 45-47, 88 (see Table 5) were synthesized in a procedure substantially similar to example 44.
TABLE 5 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 45-47, 88
Figure BDA0003910195120000451
Example 48: preparation of Compound 48
Figure BDA0003910195120000452
Adding compound 37 (50mg, 0.144mmol, 1.0eq) and concentrated sulfuric acid (2 mL) into a reaction bottle in sequence, cooling the system to 0 ℃, adding sodium nitrite (12mg, 0.17mmol, 1.2eq), naturally heating to room temperature after the addition is finished, continuing stirring for 1h, and then adding the mixture into water (5 m)L), continuously stirring for 2 hours, adjusting the pH value of the system to 7-8, adding ethyl acetate (4 mL) for extraction for 3 times, concentrating an organic phase, and purifying a crude product by reverse phase column chromatography (Shim-pack GIS-C18 20X 250nm,5 mu m;0.01% formic acid-water/acetonitrile) to give pure compound 48 (3.21 mg). MS m/z 349.2[ m ] +H] + 。
Example 49: preparation of Compound 49
Figure BDA0003910195120000461
Under the protection of nitrogen gas, compound 4 (100mg, 0.24mmol, 1.0eq), tributyl (1-ethoxyvinyl) tin (132.13mg, 0.37mmol, 1.5eq), triethylamine (74.60mg, 0.73mmol, 3.0eq), bis (triphenylphosphine) palladium dichloride (34.00mg, 0.049mmol, 0.2eq) and 1, 4-dioxane (4 ml) were sequentially added into a reaction flask, heated to 90 ℃, and stirred for reaction for 6 hours. The system was cooled to room temperature, quenched with water (10 ml), extracted 2 times with ethyl acetate (20 ml), the organic phases combined and washed once with water (10 ml), once with saturated aqueous sodium chloride (10 ml), the organic phase dried over anhydrous sodium sulfate and spin dried. The crude product was purified by TLC (DCM/MEOH = 10/1) to give 50mg of intermediate product, tetrahydrofuran (4 ml) and 1M hydrochloric acid (1 ml) were added, stirred overnight at room temperature, the system was spun dry and the crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,5 μ M;0.01% formic acid-water/acetonitrile) to give compound 49 (2.69 mg); MS m/z 375.0[ m ] +H] + 。
Example 50: preparation of Compound 50
Figure BDA0003910195120000462
Under the protection of nitrogen, compound 4 (100.00mg, 0.24mmol, 1.0eq), morpholine (31.90mg, 0.37mmol, 1.5eq) and Pd were sequentially added into a reaction bottle 2 (dba) 3 (55.80mg, 0.061mmol, 0.25eq), xanthphos (70.60mg, 0.12mmol, 0.5eq), potassium phosphate (155.30mg, 0.73mmol, 3.0eq) and toluene (4 ml). The temperature is raised to 110 ℃, and the reaction is stirred for 6 hours. The system was cooled to room temperature and quenched with water (5 ml)Ethyl acetate (20 ml) was added and extracted 2 times, the organic phases were combined and washed once with water (10 ml), once with saturated aqueous sodium chloride solution (10 ml), and 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 with 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 50 (2.29 mg); MS m/z 418.2[ m ] +H] + 。
Examples 51 to 58, 83 to 84, 90, 97, 100: preparation of Compounds 51-58, 83-84, 90, 97, 100
Compounds 51-58, 83-84, 90, 97, 100 (see Table 6) were synthesized in a procedure substantially similar to example 50.
TABLE 6 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 51-58, 83-84, 90, 97, 100
Figure BDA0003910195120000463
Figure BDA0003910195120000471
Figure BDA0003910195120000481
Figure BDA0003910195120000491
Example 59: preparation of Compound 59
(1) Intermediate 59-1 synthetic route
Figure BDA0003910195120000492
To a reaction flask were added in this order 68-1a (6.00g, 30.90mmol, 1.0eq), acetic acid (36 ml), and nitric acid (18 ml), and the mixture was heated to 70 ℃ to react for 1 hour. After the reaction is finished, cooling the reaction system to room temperature and concentrating to dry, and adjusting the crude product by using 5% sodium hydroxide aqueous solutionThe pH was adjusted to 7 to 8, and ethyl acetate (200 ml) was added thereto for extraction 2 times. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to give 59-1a (5.82 g); MS m/z 239.8[ deg. ] M + H] + 。
To a reaction flask were added successively 59-1a (5.03g, 21.03mmol, 1.0eq), methanol (50 ml), THF (70 ml), and 10% palladium on carbon (0.50 g), and the mixture was subjected to hydrogen substitution 3 times, followed by heating to 30 ℃ under a hydrogen atmosphere for 2 hours. After the reaction, the reaction system is filtered, the filtrate is dried in a spinning mode, and then dichloromethane is used for carrying for 2 times to obtain a compound 59-1b (4.30 g); MS m/z 209.8[ deg. ] M + H] + 。
To a reaction flask were added successively 59-1b (2.00g, 8.36mmol, 1.0eq) and acetic anhydride (20 ml), and the mixture was heated to 60 ℃ to react for 3 hours. After the reaction is finished, cooling the reaction system to room temperature, pouring the reaction system into 100ml of water, adjusting the pH value of the system to 8-9 by using sodium carbonate solid, extracting the system for 3 times by using ethyl acetate (50 ml), drying an ethyl acetate phase by using anhydrous sodium sulfate, and concentrating the dried ethyl acetate phase to obtain a compound 59-1c (2.33 g); MS m/z 251.8[ deg. ] M + H] + 。
The compound 59-1c (1.00g, 3.98mmol, 1.0eq) and ammonia (20 ml) were added in this order to a reaction flask with a sealed tube, and the mixture was heated to 60 ℃ to react overnight. After the reaction is finished, concentrating and drying the reaction system, and purifying by column chromatography to obtain a compound 59-1d (0.56 g); MS m/z 218.8[ deg. ] M + H] + 。
The compound 59-1d (450mg, 2.06mmol,1.0 eq), thionyl chloride (10 ml) and two drops of DMF were added in sequence to a reaction flask, and heated to 85 ℃ under nitrogen protection for reaction for 3h. After the reaction is finished, concentrating and drying the reaction system, dissolving the crude product by using ethyl acetate (50 ml), adjusting the pH value to 8-9 by using a sodium bicarbonate aqueous solution in an ice bath, separating an organic phase, drying by using anhydrous sodium sulfate, concentrating and drying to obtain the crude product, and purifying the crude product by using column chromatography to obtain a compound 59-1 (0.23 g); MS m/z 237.0[ m ] +H] + 。
(2) Synthetic route to compound 59
Figure BDA0003910195120000493
Compound 59-1 (60mg, 0.25mmol,1.0 eq), 1-1 (72mg, 0.38mmol,1.5 eq), DIPEA (98mg, 0.76mmol, 3.0eq), acetonitrile (3 ml), after addition, heating to 80 ℃ for 2h. After the reaction, the reaction system was concentrated to dryness, purified by column chromatography, and then purified by reverse phase column chromatography (Shim-pack GIS-C18 × 250nm,5 μm;0.01% formic acid-water/acetonitrile) to obtain pure compound 59 (0.94 mg); MS m/z 389.8[ 2 ], [ M ] +H ]] + 。
Examples 60 to 67: preparation of Compounds 60-67
Compounds 60-67 (see Table 7) were synthesized according to a procedure substantially similar to example 59.
TABLE 7 Structure and Mass Spectrometry data for Compounds 60-67
Figure BDA0003910195120000501
Figure BDA0003910195120000511
Example 68: preparation of Compound 68
(1) Intermediate 68-1 synthetic route
Figure BDA0003910195120000512
Adding 68-1a (10g, 51.53mmol, 1.0eq) and DMF (30 mL) into a reaction bottle, cooling to-10 ℃, slowly adding a DMF (30 mL) solution of NBS (9.18g, 51.53mmol, 1.0eq) into the reaction bottle, after the addition is finished, heating to 95 ℃ and keeping the reaction for 3.5 hours, cooling the system to room temperature, adding a large amount of ice water to precipitate solids, filtering and collecting a filter cake, washing the filter cake with water, drying to obtain a 68-1b crude product, and directly putting the crude product into the next step; MS m/z 273.0[ m ] +H] + ；
Under the protection of nitrogen, the crude product 68-1b (10g, 36.77mmol, 1.0eq) from the previous step, 1, 4-dioxane (100 mL), tributyl (1-ethoxyvinyl) tin (16.05g, 44.12mmol, 1.2eq) and Pd (dppf) are sequentially added into a reaction bottle 2 Cl 2 (1.3g, 1.84mmol, 0.05eq) and triethylamine (11.2g, 1. Sup. St10.31mmol, 3.0eq) reaction system is heated to 90 ℃, after reaction for 6 hours, the system is cooled to room temperature, filtration is carried out, a large amount of water is added into the system, EA (100 mL) is used for extraction for 3 times, organic layers are combined, saturated salt water is used for washing once, and anhydrous Na is added 2 SO 4 Drying, filtering and concentrating to obtain a crude product of the compound 68-1c, and directly putting the crude product into the next step; MS m/z 265.0[ m ] +H] + ；
Adding the crude product 68-1c, THF (120 mL) and 1N diluted hydrochloric acid (120 mL) into a reaction flask in sequence, stirring at room temperature for reaction for 1h, monitoring the conversion of the reaction product from 68-1c to 68-1d by TLC and mass spectrometry, adding a large amount of water for dilution, extracting with EA (100 mL) for 3 times, combining organic layers, washing with saturated common salt water once, adding anhydrous Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (eluent: petroleum ether/ethyl acetate =10 = 1-2) to give compound 68-1d (4.8 g) which was recovered to 68-1a (4.4 g); MS m/z 237.0[ deg. ] M + H] + ；
Adding a compound 68-1d (4.8g, 20.33mmol and 1.0eq), absolute ethyl alcohol (50 mL) and hydrazine hydrate (5.76g, 91.50mmol and 4.5eq) into a reaction bottle in sequence, heating a reaction system to 95 ℃, reacting for 1.5h, cooling the system to room temperature, concentrating to remove most of a solvent, filtering, and pulping the obtained solid with methyl tert-butyl ether to obtain a compound 68-1e (3.47 g); MS m/z 219.0[ m ] +H] + ；
To a reaction flask were added in this order 68-1e (3.47g, 15.91mmol, 1.0eq) and POCl 3 (20 mL) and N, N-diethylaniline (2.45g, 15.91mmol, 1.0eq), after the reaction system is heated to 105 ℃, the reaction is carried out for 3h, the system is decompressed and concentrated to remove the solvent, EA (50 mL) is added, and saturated NaHCO is used for ice bath 3 Slowly adjusting the pH value of the solution to 7-8, adding EA (50 mL) for extraction for 4 times, combining organic layers, washing with saturated salt water once, and adding anhydrous Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (eluent: petroleum ether/ethyl acetate =4 = 1-1) to give compound 68-1 (2.53 g); MS m/z 237.0[ m ] +H] + 。
(2) Synthetic route to compound 68
Figure BDA0003910195120000521
Under the protection of nitrogen, the compound 68-1 (100mg, 0.42mmol, 1.0eq), toluene (12 mL), 1-1 (200mg, 1.06mmol, 2.5eq), pd (dba) were added in sequence to a reaction flask 3 (119mg, 0.13mmol, 0.3eq), xantphos (151.2mg, 0.26mmol, 0.6eq) and tripotassium phosphate (275mg, 1.3mmol, 3.0eq), heating the reaction system to 110 ℃, reacting for 6.5h, concentrating to remove the solvent, adding water and ethyl acetate for extraction, separating, concentrating the organic phase to dryness, and purifying the crude product by reverse column chromatography (Shim-park GIS C18 20 250mm,5 mu m;0.01% formic acid-water/acetonitrile) to obtain a compound 68 (3.15 mg); MS m/z 390.2[ m ] +H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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)。
Example 69: preparation of Compound 69
Compound 69 (see table 8) was synthesized in a procedure substantially similar to example 68.
TABLE 8 Structure and Mass Spectrometry of Compound 69 NMR Hydrogen Spectroscopy data
Figure BDA0003910195120000522
Example 70: preparation of Compound 70
(1) Intermediate 70-1 synthetic route
Figure BDA0003910195120000523
Adding concentrated H into the reaction bottle at 0 DEG C 2 SO 4 (80 mL) and compound 70-1a (10.0 g,45.88mmol,1.0 eq), followed by slow addition of potassium nitrate (4.63g, 45.88mmol,1.0 eq) in portions, and after the addition, the reaction system was reacted at 0 ℃ for 1 hour. After the reaction is finished, slowly pouring the system into ice water (250 mL), stirring, after the room temperature is recovered, filtering, leaching a filter cake twice by using water, and drying to obtain a compound 70-1b (11.43 g); mS:m/z 261.8[M-H] - ；
To a reaction flask were added compound 70-1b (11.43g, 43.47mmol, 1.0eq), meOH (100 mL), and concentrated H in that order 2 SO 4 (4.26g, 43.47mmol and 1.0eq), heating the reaction system to 65 ℃, reacting for 48 hours, cooling the system to room temperature, concentrating to remove most of the solvent, filtering, leaching the obtained solid twice with water, and drying to obtain a compound 70-1c (5.94 g); MS m/z 277.8[ alpha ], [ M + H ]] + ；
Adding a compound 70-1c (5.50g, 19.86mmol, 1.0eq), DMF (55 mL), DL-alanine methyl ester hydrochloride (4.16g, 29.79mmol, 1.5eq) and triethylamine (5.02g, 49.65mmol, 2.5eq) into a reaction bottle in sequence, heating a reaction system to 80 ℃, reacting for 2 hours, cooling the system to room temperature, adding water (200 mL), stirring, filtering, leaching a filter cake twice with water, and drying to obtain a compound 70-1d (6.40 g); MS m/z 360.8[ deg. ] M + H] + ；
To a reaction flask were added compound 70-1d (6.40g, 17.78mmol, 1.0eq), anhydrous ethanol (65 mL) and SnCl in that order 2 (16.35g, 88.89mmol, 5.0eq), heating the reaction system to 95 ℃, reacting for 2 hours, cooling the system to room temperature, adding saturated NaHCO 3 Adjusting pH of the solution to neutral, adding EA (150 mL), stirring, filtering, rinsing the filter cake with EA (50mL. Multidot.3), separating the filtrates, washing the organic phase with water and saturated brine, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain intermediate 70-1e (2.40 g); MS m/z 299.0[ m ] +H] + ；
Adding compound 70-1e (2.00g, 6.71mmol, 1.0eq) and DMF (25 mL) into a reaction bottle at 0 ℃, then adding NaH (1.34g, 33.56mmol, 5.0eq) slowly in batches, stirring for 20 min, then adding MeI (3.81g, 26.84mmol, 4.0eq), reacting for 30min, adding water (20 mL) into the system, quenching, adding EA (50mL, 3) for extraction, combining several layers, washing the organic layer with water and saturated brine in turn, adding Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (eluent: petroleum ether/ethyl acetate =3: 1) to give compound 70-1f (1.47 g); MS m/z 327.0[ deg. ] M + H] + ；
Under the protection of nitrogen, sequentially adding into a reaction bottleCompounds 70-1f (1.40g, 4.30mmol, 1.0eq), 1, 4-dioxane (15 mL), tributyl (1-ethoxyvinyl) tin (1.86g, 5.16mmol, 1.2eq), pd (dppf) 2 Cl 2 (0.16g, 0.22mmol, 0.05eq) and triethylamine (1.31g, 12.90mmol, 3.0eq), heating the reaction system to 90 ℃, reacting for 7 hours to obtain 70-1g, cooling the system to room temperature, adding dilute HCl to adjust the pH to weak acidity, monitoring the conversion of a reaction product from 70-1g to 70-1h by TLC and mass spectrometry, adding EA (30 ml) to extract for 3 times, combining organic layers, washing the organic phase with water and saturated salt once in turn, adding anhydrous Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (eluent: petroleum ether/ethyl acetate = 1) to give compound 70-1h (0.67 g); MS m/z 291.2[ m ] +H] + ；
Adding the compound 70-1h (0.67g, 2.31mmol and 1.0eq), absolute ethyl alcohol (12 mL) and hydrazine hydrate (3.46g, 6.93mmol and 3.0eq) into a reaction bottle in sequence, heating a reaction system to 95 ℃, reacting for 2h, cooling the system to room temperature, concentrating to remove most of the solvent, filtering, pulping the obtained solid by methyl tert-butyl ether to obtain a compound 70-1i (0.47 g); MS m/z 273.0[ m ] +H] + ；
The compound 70-1i (0.44g, 1.62mmol, 1.0eq) and POCl were added to the reaction flask in this order 3 (4 mL) and N, N-diethylaniline (0.24g, 1.62mmol, 1.0eq), the reaction system was warmed to 105 ℃ and reacted for 3.5h, then the system was concentrated under low pressure to remove the solvent, ice water (10 mL) was added, and saturated NaHCO was used 3 Adjusting the pH of the solution to 7-8, adding EA (10 mL) for extraction for 3 times, combining organic layers, washing with water and saturated saline solution in sequence, and adding anhydrous Na 2 SO 4 Drying, filtering, concentrating, column chromatography purification (eluent: petroleum ether/ethyl acetate = 1.5) to give compound 70-1 (0.31 g); MS m/z 291.0[ m ] +H] + 。
(2) Synthetic route to compound 70
Figure BDA0003910195120000531
Under the protection of nitrogen, the intermediate 70-1 (20) is added into a reaction bottle in sequencemg,0.07mmol, 1.0eq), toluene (4 mL), 1-1 (33mg, 0.17mmol, 2.5eq), pd (dba) 3 (40mg, 0.04mmol, 0.6eq), xantphos (48mg, 0.08mmol, 1.2eq) and tripotassium phosphate (88mg, 0.41mmol,6.0 eq), heating the reaction system to 110 ℃, reacting for 24h, concentrating to remove the solvent, adding water and ethyl acetate for extraction, separating, concentrating the organic phase to dryness, and purifying the crude product by reverse column chromatography (Shim-park GIS C18 20X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to obtain compound 70 (2.51 mg); MS: m/z 444.2[ m ] +H] + 。
Examples 71-73, 107-110: preparation of Compounds 71-73, 107-110
Compounds 71-73, 107-110 (see Table 9) were synthesized according to a procedure substantially similar to example 70.
TABLE 9 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 71-73, 107-110
Figure BDA0003910195120000541
Figure BDA0003910195120000551
Example 74: preparation of Compound 74
Synthetic route
Figure BDA0003910195120000552
Adding a compound 74-1a (10g, 51.00mmol, 1.0eq) and DMF (25 mL) into a reaction bottle, cooling to-10 ℃, slowly adding a DMF (25 mL) solution of NBS (9.09g, 51.00mmol, 1.0eq) into the reaction bottle, after the addition is finished, heating to 95 ℃ and keeping the reaction for 3 hours, cooling the system to room temperature, adding a large amount of ice water to precipitate a solid, filtering and collecting a filter cake, washing the filter cake with water, drying to obtain a crude product 74-1b, and directly putting the crude product into the next step; MS m/z 275.1[ m ] +H] + ；
Under the protection of nitrogen, the crude product 74-1b (10g, 36.50mmol, 1.0eq) and 1, 4-dioxygen are added into the reaction bottle in turnHexacyclic ring (100 mL), tributyl (1-ethoxyvinyl) tin (15.94g, 43.80mmol, 1.2eq), pd (dppf) 2 Cl 2 (1.3 g,1.83mmol, 0.05eq) and triethylamine (11.1g, 109.50mmol, 3.0eq), the reaction system was warmed to 90 ℃ and reacted for 6 hours, then the system was cooled to room temperature, filtered, and a large amount of water was added to the system, extracted with EA (100 mL) for 3 times, the organic layers were combined, washed once with saturated brine, and anhydrous Na was added 2 SO 4 Drying, filtering and concentrating to obtain a crude product of the compound 74-1c, and directly putting the crude product into the next step; MS m/z 267.0[ m ] +H] + ；
Adding the crude product 74-1c, THF (120 mL) and 1N diluted hydrochloric acid (120 mL) into a reaction bottle in sequence, stirring at room temperature for reaction for 1h, monitoring the conversion of the reaction product from 74-1c to 74-1d by TLC and mass spectrometry, adding a large amount of water for dilution, extracting with EA (100 mL) for 3 times, combining organic layers, washing with saturated common salt water once, adding anhydrous Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (eluent: petroleum ether/ethyl acetate =10 = 1-2) to give compound 74-1d (4.7 g); MS m/z 239.0[ m ] +H] + ；
Adding a compound 74-1d (4.7g, 19.74mmol, 1.0eq), absolute ethyl alcohol (50 mL) and hydrazine hydrate (5.70g, 88.83mmol, 4.5eq) into a reaction bottle in sequence, heating a reaction system to 95 ℃, reacting for 1.5h, cooling the system to room temperature, concentrating to remove most of a solvent, filtering, and pulping the obtained solid by methyl tert-butyl ether to obtain a compound 74-1e (3.40 g); MS m/z 221.0[ deg. ] M + H] + ；
Adding a compound 74-1e (3.4g, 15.45mmol, 1.0eq) and a 48% hydrobromic acid (20 mL) solution into a reaction bottle in sequence, heating a reaction system to 120 ℃, reacting for 24 hours, cooling the system to room temperature, filtering and collecting a filter cake, washing the filter cake with water, and drying to obtain a compound 74-1f; MS m/z 193.0[ m ] +H] + ；
After compounds 74-1f (3.40g, 17.70mmol, 1.0eq), triethylene glycol di (p-toluenesulfonate) (8.11g, 17.70mmol, 1.0eq), potassium carbonate (7.32g, 53.10mmol, 3.0eq) and DMF (2 mL) were added to a reaction flask in this order, and stirred at 90 ℃ for 8 hours, the reaction solution was concentrated under reduced pressure, and column chromatography purification (eluent: petroleum ether/ethyl acetate =101g(1.20g)；MS:m/z 307.1[M+H] + ；
To a reaction flask were added 74-1g (0.52g, 1.71mmol, 1.0eq) of the compound and POCl in this order 3 (4 mL) and N, N-diethylaniline (0.25g, 1.71mmol, 1.0eq), the reaction system was heated to 105 deg.C, after reaction for 3.5h, the system was concentrated under low pressure to remove the solvent, ice water (10 mL) was added, saturated NaHCO was used 3 Adjusting the pH of the solution to 7-8, adding EA (10 mL) for extraction for 3 times, combining organic layers, washing with water and saturated saline solution in sequence, and adding anhydrous Na 2 SO 4 Drying, filtering, concentrating, column chromatography purification (eluent: petroleum ether/ethyl acetate = 1.5) to afford compound 74-1h (0.31 g); MS m/z 325.1[ deg. ] M + H] + 。
Under the protection of nitrogen, the intermediate 74-1h (88mg, 0.27mmol, 1.0eq), toluene (4 mL), 1-1 (52mg, 0.68mmol, 2.5eq), pd (dba) are added into a reaction bottle in sequence 3 (160mg, 0.16mmol, 0.6eq), xanthphos (192mg, 0.32mmol, 1.2eq) and tripotassium phosphate (352mg, 1.62mmol, 6.0eq), subjecting the reaction system to microwave reaction (130 ℃,2 h), concentrating to remove the solvent, adding water and ethyl acetate for extraction, separating, concentrating the organic phase to dryness, and purifying the crude product by reverse phase column chromatography (Shim-park GIS C18 20 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to obtain a compound 74 (12.10 mg); MS m/z 478.2[ deg. ] M + H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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)。
Examples 75-77, 111: preparation of Compounds 75-77, 111
Compounds 75-77, 111 (see Table 10) were synthesized according to a procedure substantially similar to example 74.
TABLE 10 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 75-77, 111
Figure BDA0003910195120000561
Example 78: preparation of Compound 78
Synthetic route
Figure BDA0003910195120000571
Compound 16 (430mg, 1mmol,1.0 eq), m-CPBA (345mg, 2mmol,2.0 eq) and methylene chloride (5 mL) were added to a reaction flask in this order, and the reaction was stirred at room temperature for 1 hour. Then, water (3 mL) was added to the system, extracted, the organic phase was spin-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] + 。
Example 79: preparation of Compound 79
Synthetic route
Figure BDA0003910195120000572
Compound 16 (430mg, 1mmol,1.0 eq), m-CPBA (172g, 1mmol,1.0 eq) and methylene chloride (5 mL) were added to the reaction flask in this order, and the reaction was stirred at room temperature for 1 hour. Then, water (3 mL) was added to the system, extracted, the organic phase was spin-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[ alpha ], [ M ] +H ]] + 。
To a reaction flask were added compound 79-1a (440mg, 2.2 mmol), rhodium diacetate (27mg, 0.09mmol), iodobenzene diacetate (1060mg, 3.3mmol), trifluoroacetamide (497mg, 4.4 mmol), magnesium oxide (352mg, 8.8 mmol), and dichloromethane (10 mL) in this order, and the reaction was stirred at room temperature for 14 hours. Then, water (10 mL) was added to the system, extracted, the organic phase was spin-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[ alpha ], [ M ] +H ]] + 。
To a reaction flask, compound 79-1b (56mg, 0.1mmol), potassium carbonate (69mg, 0.5mmol) and methanol (3 mL) were added in this order, and the mixture was stirred at room temperature for 1.5 hours and concentrated to dryness. The crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 79 (5.3 mg); MS m/z 462.2[ m ]+H] + ； 1 H-NMR(400MHz,DMSO-d 6 ):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＝7.7Hz,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)。
Example 80: preparation of Compound 80
Figure BDA0003910195120000581
To a reaction flask were added successively 79-1b (56mg, 0.1mmol), THF (3 mL) and palladium on carbon (6 mg), and the reaction was stirred at room temperature for 3h. Filtration and concentration gave compound 80-1a (55 mg); MS m/z 560.1[ deg. ] M + H] + 。
The compound 80-1a (55mg, 0.1mmol), potassium carbonate (69mg, 0.5mmol) and methanol (3 mL) were added in this order to a reaction flask, and the mixture was stirred at room temperature for 1.5 hours and concentrated to dryness. The crude product was purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 80 (5.3 mg); MS m/z 464.1[ deg. ] M + H] + 。
Example 101: preparation of Compound 101
Figure BDA0003910195120000582
Compound 21 (45.5mg, 0.1mmol, 1.0eq) was dissolved in methylene chloride (0.5 mL) and isopropanol (5 mL), tris (2, 6-tetramethyl-3, 5-heptenoic acid) manganese (30.2mg, 0.05mmol, 0.5eq) and phenylsilane (216.4mg, 0.2mmol, 2.0eq) were added, oxygen was replaced three times, the reaction was stirred at room temperature for 24 hours, concentrated to dryness, and the system was purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,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-d 6 ):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)。
Example 102: preparation of Compound 102
Compound 102 was synthesized in substantially the same procedure as in example 101 (see table 11).
TABLE 11 Structure and Mass Spectrometry of Compound 102, NMR Hydrogen Spectroscopy data
Figure BDA0003910195120000583
Example 103: preparation of Compound 103
Figure BDA0003910195120000591
Compound 79 (46.1mg, 0.1mmol, 1.0eq) was dissolved in methylene chloride (0.5 mL), triethylamine (25.3mg, 0.25mmol, 2.5eq) and acetyl chloride (9.4mg, 0.12mmol, 1.2eq) were added, the reaction 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 20X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 103 (11.5 mg); MS M/z504.2[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ9.12(d,J＝2.4Hz,1H),8.90(d,J＝2.5Hz,1H),8.82(d,J＝7.1Hz,1H),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,1H),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)。
Examples 104 to 106: preparation of Compounds 104-106
Compounds 104-106 (see Table 12) were synthesized by essentially similar procedures as in example 79.
TABLE 12 Structure and Mass Spectroscopy, NMR Hydrogen Spectroscopy data for Compounds 104-106
Figure BDA0003910195120000592
Experimental example 1: KRAS-G12C/SOS1 IC50 Activity assay
The inhibition rate of the compound of the invention on KRAS-G12C/SOS1 is detected by using Binding Assay method to evaluate the inhibition effect of the compound on KRAS-G12C/SOS 1.
1.1 Experimental materials
1.1.1 reagents and consumables
Name of reagent Suppliers of goods
KRAS G12C/SOS Binding kit Cisbio
DMSO Sigm
384-well white plate PerkinElmer
1.1.2 Instrument
Centrifuge (manufacturer: eppendorf, model 5430)
Enzyme-linked immunosorbent assay (manufacturer: perkin Elmer, model: envision)
Echo 550 (manufacturer: labcyte, model: echo 550)
1.2 kinase reaction Processes
(1) Preparation of the compound: test compounds were graded at 500nm, 125nm, 31.25nm, 7.81nm, 1.95nm, 0.488nm, 0.122nm and 0.03nm, and tested in duplicate wells, diluted 200-fold into 100% dmso solution at final concentration in 384-well plates. A50nl 200-fold final concentration of compound was transferred to a 384-well plate of interest using a knockout Echo 550. Negative control wells plus 50nl in dmso 100%.
(2) A4-fold final concentration of Tag1-SOS1 solution was prepared in dilution buffer.
(3) To a 384 well plate, 2.5. Mu.l of a 4-fold final concentration solution of Tag1-SOS1 was added.
(4) The final concentration of the solution of Tag2-KRAS-G12C was 4 times that of the diluted buffer solution.
(5) Add 2.5. Mu.l of Tag2-KRAS-G12C solution at 4 times final concentration to the compound well; add 2.5. Mu.l of dilution buffer to the negative control wells.
(6) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated for 15 minutes at room temperature.
(7) Preparing a 1-time final concentration of Anti-Tag1-TB3+ solution and a 1-time final concentration of Anti-Tag2-XL665 solution by using a detection buffer solution, mixing the two solutions uniformly, and adding 5 mu l of Mix solution into each well.
(8) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated for 120 minutes at room temperature.
(9) The reading was taken with an Envision microplate reader and recorded as Em665/620.
1.3 data analysis
1.3.1 formula for calculating inhibition ratio
Figure BDA0003910195120000601
Wherein: min signal represents the absorbance mean of pure DMSO wells; max signal represents the absorbance mean value of the enzyme, the substrate, the detection reagent and the DMSO mixture well; compound signal represents the absorbance mean of the sample well.
1.3.2 fitting dose-response curves
The log values of the compound concentrations were taken as the X-axis and the percent inhibition as the Y-axis, and the log (inhibitor) vs. response-Variable slope of the analytical software GrapHPad Prism 5 was used to fit the dose-effect curves, thereby obtaining the IC50 values of each compound for the enzyme activity.
The fitting formula is: y = Bottom + (Top-Bottom)/(1 +10^ ((LogicC 50-X) > HillSlope))
Wherein: top represents the Top platform, and the Top standard of the curve is generally 80-120%; bottom plateau is represented by Bottom, and Bottom of the curve is generally between-20% and 20%.
In vitro inhibitory Activity test results (in IC) 50 Is shown)
Compound (I) IC 50 Compound (I) IC 50 Compound (I) IC 50 Compound (I) IC 50
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
Experimental example 2: MIA-PaCa2 (3D) cell proliferation inhibitory Activity assay
1.1 Experimental materials
1.1.1 reagents and consumables
Name of reagent Suppliers of goods
MIA-PaCa2 ATCC
DMEM medium Gibco
96-well Microplate PerkinElmer
3D Cell Viability assay kit Promega
PBS buffer Gibco
CO 2 Cell culture box Thermo Scientific
Fetal bovine serum Gibco
1.1.2 instruments
Centrifuge (manufacturer: eppendorf, model: 5810R)
Enzyme-linked immunosorbent assay (manufacturer: perkin Elmer, model: envision)
Echo 550 (manufacturer: labcyte, model: echo 550)
1.2 Experimental procedures
Taking the MIA-PaCa2 cells in good growth state, inoculating the cells in a 96-well plate (2000 cells/well), standing at 37 ℃,5% 2 Culturing overnight in a cell incubator, loading different concentrations of compounds with a nanoliter loader, wherein the concentration gradient of the compounds is 10 μm, 2.5 μm, 0.625 μm, 0.156 μm, 0.039 μm, 0.0098 μm, 0.0024 μm and 0.0006 μm, each compound is provided with two multiple wells, simultaneously a solvent control is arranged (0.2 DMSO solution is added into the control well), culturing is continued for 8 days in the cell incubator after adding the reagents (Celltiter Glo Assay kit-3D) into a 96-well plate (100 μ l/well), shaking for 30 minutes in the dark, incubating for 2 hours in the dark at room temperature, and then reading the luminescence value by an Envision microplate reader.
1.3 data analysis
The Inhibition Rate (IR) of the test compound was calculated by the following formula:
IR(％)＝(1-(RLU compound (I) -RLU Blank control )/(RLU Vehicle control -RLU Blank control ))*100％
Wherein: RLU Compound (I) Is the average value of the luminosity of the sample hole; RLU Blank control The average value of the luminosity of the culture medium hole is obtained; RLU Vehicle control To 0.2% of the mean value of the DMSO well luminosity.
Calculating the inhibition rate of the compound with different concentrations in Excel, and then using GraphPad Prism software to make an inhibition curve graph and calculate related parameters (including minimum inhibition rate, maximum inhibition rate and IC) 50 )。
Results of the MIA-PaCa2 cell proliferation inhibitory Activity assay (as IC) 50 Is shown)
Compound (I) 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
From the results of the above experimental examples, it is clear that the compound of the present invention has excellent in vitro inhibitory activity against KRAS-G12C/SOS1 and excellent inhibitory activity against MIA-PaCa2 cell proliferation, so that it can be used as a small molecule SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good antitumor activity, and has good effects on treating neoplastic diseases in mammals (including humans).
While the invention has been illustrated by the foregoing specific examples, it is not to be construed as limited thereby, but that the invention encompasses the general aspects disclosed above and many modifications and embodiments may be made without departing from the spirit and scope of the invention.

Claims (47)

1. A compound having the structure of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof:
Figure FDA0003910195110000011
wherein:
ring A is selected from C 6-10 Aryl, 5-to 10-membered heteroaryl, and 3-to 6-membered heterocyclyl;
u and V are independently N or CR 2 ；
W is N or CR 6 ；
Each R 1 Independently selected from C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, amino, halogen, cyano and nitro;
each R 2 Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, halogen, cyano, -OR 2a and-NR 2a R 2b ；
R 2a And R 2b Independently selected from hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 3-6 A cycloalkyl group;
R 3 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and halogen;
R 4 selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-14 Cycloalkyl radical, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, 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 said cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (= O) -C 1-6 Alkyl and-C (= O) O-C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) NH-3-to 14-membered heterocyclyl, -C (= O) -C 6-10 Aryl, -C (= O) -5-to 10-membered heteroaryl, and-S (= O) m -C 1-6 Alkyl, wherein the alkyl, alkenyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: amino, halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
R 5 selected from hydrogen, amino, halogen, nitro and-O-C 1-6 An alkyl group;
alternatively, the first and second electrodes may be,R 4 and R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, = CH 2 、＝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 said substituents together with the atoms to which each is attached form a 5-to 8-membered heterocyclyl;
R 5a and R 5b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl;
R 6 selected from hydrogen, amino, halogen, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl and-O-C 1-6 An alkyl group;
m is 0,1 or 2;
n is 0,1, 2 or 3;
wherein said heterocyclyl and heteroaryl each contain as ring atoms one or more heteroatoms selected from N, O and S.
2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
ring A is selected from C 6-10 Aryl and 5-to 10-membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl and naphthyl.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
n is 0,1 or 2, preferably 1 or 2.
4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, characterized in that,
each R 1 Independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, amino, halogen, cyano and nitro;
preferably, each R 1 Independently selected from C 1-4 Alkyl radical, C 1-4 Haloalkyl, amino, halogen and cyano;
more preferably, each R 1 Independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Amino, fluoro, chloro, bromo, iodo and cyano;
further preferably, each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
each R 2 Independently selected from hydrogen, C 1-4 Alkyl and C 1-4 A haloalkyl group;
preferably, each R 2 Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 and-CH 2 CH 2 CF 3 ；
More preferably, each R 2 Independently selected from hydrogen and methyl.
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
R 3 selected from hydrogen, C 1-4 Alkyl and C 1-4 A haloalkyl group;
preferably, R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 and-CH 2 CH 2 CF 3 ；
More preferably, R 3 Is hydrogen.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
R 4 selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -C (= O) R 4a 、-OR 4a and-NR 4a R 4b Wherein said heterocyclyl, aryl and heteroaryl are each optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, amino, halogen, C 1-6 Alkyl, -O-C 1-6 Alkyl and-C (= O) -C 1-6 An alkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= O) -C 6-10 Aryl and-S (= O) m -C 1-6 An alkyl group, wherein the alkyl and alkenyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
preferably, R 4 Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, pyrimidinyl, pyridyl, pyranyl, thiopyranyl, dihydropyridinyl, tetrahydropyridyl, piperidyl, dihydropyranyl, tetrahydropyranyl, thiochromanyl oxide, thiochromanyl dioxide, thiochromanyl iminooxide, tetrahydrothiopyranyl oxide, tetrahydrothiopyranyl dioxide, tetrahydrothiopyranyl iminooxide, tetrahydrothiopyranyl oxide, piperazinyl, 1, 4-dinitrogen, thiopyranyl, cyclopentyl, piperazinyl, and the like
Figure FDA0003910195110000021
3, 8-diazabicyclo [3.2.1] radicals]Octyl, 2-oxa-6-azaspiro [3.3]]Heptyl, morpholinyl, indolyl, indazolyl, 2, 3-dihydro-1, 4-benzodioxinyl, formyl, acetyl and propionyl; wherein said phenyl, naphthyl, anthracyl, phenanthryl, pyrrolyl, imidazolyl, pyrazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, dihydropyrrolyl, dihydrofuryl, thienyl, etc dihydrothienyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, pyrimidinyl, pyridyl, pyranyl, thiopyranyl, dihydropyridinyl, tetrahydropyranyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridylThiopyranyl, tetrahydrothiopyranyl, piperazinyl, 1, 4-diaza
Figure FDA0003910195110000032
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: amino, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, acetyl and propionyl.
8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
R 5 selected from hydrogen, amino, halogen and nitro, preferably hydrogen and halogen, more preferably hydrogen.
9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
R 4 and R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl group, = O, = CH 2 、＝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 An alkyl group;
preferably, R 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl, = O and = CH 2 ；
More preferably, R 4 And R 5 Together with the atom to which each is attached, form a 5,6, 9, 12, 14 or 15 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, = O and = CH 2 。
10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, characterized in that,
R 6 selected from hydrogen, C 1-4 Alkyl and-O-C 1-5 An alkyl group;
preferably, R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy;
more preferably, R 6 Is methyl.
11. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
the structure of the compound is shown as a formula I-1:
Figure FDA0003910195110000031
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined in claim 1;
preferably, in the formula I-1,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluorineAnd a cyano group; preferably, of the formula I-1
Figure FDA0003910195110000041
Selected from the following groups:
Figure FDA0003910195110000042
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiochromanyl, iminooxathiopyranyl, tetrahydrothiopyranyl, iminooxathiopyranyl, piperazinyl, 1, 4-diaza
Figure FDA0003910195110000046
Radicals and 2-oxa-6-azaspiro [3.3]Heptyl wherein the tetrahydropyridinyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl and 1, 4-diazanyl are present
Figure FDA0003910195110000047
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl;
R 5 is hydrogen;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
12. The compound of claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
the structure of the compound is shown as a formula I-1A:
Figure FDA0003910195110000043
wherein: n, R 1 、R 2 、R 3 、R 4 And R 5 As defined in claim 11;
preferably, in formula I-1A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1A
Figure FDA0003910195110000044
Selected from the following groups:
Figure FDA0003910195110000045
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiopyranyl iminooxide, thiopyranyl tetrahydroxide, thiopyranyl iminooxide, piperazinyl, 1, 4-diaza-nyl
Figure FDA0003910195110000048
Radicals and 2-oxa-6-azaspiro [3.3]Heptyl, wherein the tetrahydropyridyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl, and 1, 4-diazepam
Figure FDA0003910195110000049
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl andisopropyl, preferably = O, = NH and methyl;
R 5 is hydrogen;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
13. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
the structure of the compound is shown as formula I-1B, formula I-1B-1 or formula I-1B-2:
Figure FDA0003910195110000051
wherein: n, R 1 、R 2 And R 4 As defined in claim 12;
preferably, in formula I-1B, formula I-1B-1 or formula I-1B-2,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1B, formula I-1B-1 or formula I-1B-2
Figure FDA0003910195110000052
Selected from the following groups:
Figure FDA0003910195110000053
R 2 selected from hydrogen and methyl, preferably methyl;
R 4 is a 3-to 14-membered heterocyclyl, which heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH and C 1-6 An alkyl group; preferably, R 4 Selected from tetrahydropyridinyl, piperidinyl, thiopyranyl iminooxide, thiopyranyl tetrahydroxide, thiopyranyl iminooxide, piperazinyl, 1, 4-diaza-nyl
Figure FDA0003910195110000055
Radicals and 2-oxa-6-azaspiro [3.3]]Heptyl, wherein the tetrahydropyridyl, piperidinyl, thiochromanyl, tetrahydrothiopyranyl, piperazinyl, and 1, 4-diazepam
Figure FDA0003910195110000056
Each of which is optionally substituted with one substituent; if present, the substituents are selected from the following groups: = O, = NH, methyl, ethyl, n-propyl, and isopropyl, preferably = O, = NH, and methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
14. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
the structure of the compound is shown as a formula I-2:
Figure FDA0003910195110000054
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined in claim 1;
preferably, in the formula I-2,
ring A is phenyl;
n is 1 or 2, preferably 1;
each R 1 Is independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably-CHF 2 、-CF 3 Amino, fluoro, chloro and nitro groups;
each R 2 Independently selected from hydrogen and methyl;
R 3 is hydrogen;
R 4 and R 5 Together with each being attached toThe atoms taken together form a 5-to 8-membered heterocyclic group containing one or more heteroatoms selected from N, O and S as ring atoms;
but do not comprise
Figure FDA0003910195110000061
15. The compound of claim 14, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
the structure of the compound is shown as a formula I-2A:
Figure FDA0003910195110000062
wherein:
ring B is a 5-to 15-membered, preferably 5-to 8-membered heterocyclic group containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O and S as ring atoms;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
p is 0,1, 2,3,4, 5 or 6;
n、R 1 and R 2 As defined in claim 14;
preferably, in formula I-2A,
n is 1 or 2, preferably 1;
each R 1 Independently selected from C 1-6 Haloalkyl, amino, halogen and nitro, preferably-CHF 2 、-CF 3 Amino, fluoro, chloro and nitro;
each R 2 Independently selected from hydrogen and methyl;
ring B is a 5-to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms;
but do not comprise
Figure FDA0003910195110000063
16. The compound of claim 15, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
ring B is a 5-, 6-, 9-, 12-, 14-or 15-membered, preferably 5-or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms;
preferably, ring B is a 5-, 6-, 9-, 12-, 14-or 15-membered, preferably 5-or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S as ring atoms;
more preferably, ring B is a 5,6, 9, 12, 14 or 15 membered, preferably 5 or 6 membered heterocyclyl containing 2O atoms as ring atoms.
17. The compound according to claim 15 or 16, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
preferably, each R 7 Independently selected from hydrogen, halogen and C 1-6 An alkyl group;
more preferably, R 7 Is hydrogen.
18. The compound according to any one of claims 15 to 17, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
p is 0,1, 2,3 or 4, preferably 0,1 or 2, more preferably 0 or 1.
19. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
the structure of the compound is shown as a formula I-3:
Figure FDA0003910195110000071
wherein: ring A, n, R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined in claim 1;
preferably, in the formula I-3,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in formula I-3
Figure FDA0003910195110000072
Selected from the following groups:
Figure FDA0003910195110000073
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 3 is hydrogen;
R 4 and R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and = O, more preferably methyl, cyclopropyl and = O;
R 6 is methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
20. The compound of claim 19, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
the structure of the compound is shown as a formula I-3A:
Figure FDA0003910195110000081
wherein:
ring B is a 5-to 15-membered heterocyclic group containing 1 to 5 heteroatoms selected from N, O and S;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
p is 0,1, 2,3,4, 5 or 6;
n、R 1 、R 2 and R 6 As defined in claim 19;
preferably, in formula I-3A,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in the formula I-3A
Figure FDA0003910195110000082
Selected from the following groups:
Figure FDA0003910195110000083
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O;
rings B and p are as defined above.
21. The compound of claim 20, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
ring B is a 5-, 6-, 9-, 12-, 14-or 15-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S as ring atoms;
preferably, ring B is a 5,6, 9, 12, 14 or 15 membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S as ring atoms;
more preferably, ring B is a 5,6, 9, 12, 14 or 15 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O as ring atoms.
22. The compound according to claim 20 or 21, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl and 3-to 14-membered heterocyclyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
Preferably, each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
More preferably, each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 。
23. The compound of any one of claims 20 to 22, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
p is 0,1, 2,3 or 4, preferably 1,2,3 or 4, more preferably 2,3 or 4.
24. The compound of claim 20, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
the structure of the compound is shown as formula I-3B, formula I-3B-1 or formula I-3B-2:
Figure FDA0003910195110000091
wherein:
each X is independently C (R) 7 ) 2 、NR 7 O or S;
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
q is 3,4, 5,6,7,8, 9, 10,11, 12 or 13;
n、R 1 、R 2 and R 6 As defined in claim 20;
preferably, in formula I-3B, formula I-3B-1 or formula I-3B-2,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-3B, formula I-3B-1 or formula I-3B-2
Figure FDA0003910195110000092
Selected from the following groups:
Figure FDA0003910195110000093
each X is independently C (R) 7 ) 2 、NR 7 Or O;
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O;
q is as defined above.
25. The compound of claim 24, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
each X is independently C (R) 7 ) 2 、NR 7 Or O;
preferably, each X is independently C (R) 7 ) 2 Or NR 7 Or, each X is independently NR 7 Or O;
more preferably, X is O, or X is NR 7 。
26. The compound of claim 24 or 25, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl and 3-to 14-membered heterocyclyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
Preferably, each R 7 Independently selected from hydrogen, halogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 ；
More preferably, each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 。
27. The compound of any one of claims 24 to 26, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
q is 3,4, 7,8, 9, 10,11, 12 or 13, preferably 3,4, 7,10, 12 or 13.
28. The compound of any one of claims 24 to 27, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
Figure FDA0003910195110000101
the fragment is selected from the following structures:
Figure FDA0003910195110000102
preferably, the first and second electrodes are formed of a metal,
Figure FDA0003910195110000111
the fragment is selected from the following structures:
Figure FDA0003910195110000112
each R 7 Independently selected from hydrogen, C 1-6 Alkyl and C 3-14 Cycloalkyl, or, any two R attached to the same ring atom 7 Form = O or = CH 2 。
29. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
ring A is C 6-10 Aryl, preferably phenyl;
u and V are independently N or CR 2 ；
W is N or CR 6 ；
Each R 1 Independently selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, amino, halogen, cyano and nitro, preferably methyl, difluoromethyl, trifluoromethyl, amino, fluoro, chloro, cyano and nitro;
each R 2 Independently selected from hydrogen and C 1-6 Alkyl, preferably hydrogen and methyl;
R 3 is hydrogen;
R 4 selected from hydrogen, halogen, nitro, C 3-14 Cycloalkyl radical, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, -C (= O) R 4a 、-OR 4a and-NR 4a R 4b Wherein the cycloalkenyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, halogen, hydroxy, carboxy, C 1-6 Alkyl, -O-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) m -C 1-6 Alkyl and-S (= O) m -C 3-14 A cycloalkyl group;
R 4a and R 4b Independently selected from hydrogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, 3-to 14-membered heterocyclyl, -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 heterocyclyl, -C (= C =)O)-C 6-10 Aryl and-S (= O) m -C 1-6 An alkyl group, wherein the alkyl and alkenyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclyl;
R 5 selected from hydrogen and-O-C 1-6 An alkyl group;
or, R 4 And R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O;
R 6 is C 1-6 Alkyl, preferably methyl;
each m is independently 0,1 or 2, preferably 2;
n is 0,1, 2 or 3, preferably 0,1 or 2, more preferably 1 or 2, further preferably 2;
wherein said heterocyclyl and heteroaryl each contain as ring atoms one or more heteroatoms selected from N, O and S.
30. The compound of claim 29, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof,
R 4 is a 3-to 14-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 A cycloalkyl group; r is 4a And R 4b Independently is C 1-6 Alkyl, preferably methyl;
preferably, R 4 Selected from the group consisting of azetidinyl, piperazinyl, tetrahydropyridyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminothiopyranyl, tetrahydrothiopyranyl, iminothiopyranyl, thiomorpholinyl, and iminothiomorpholinyl; wherein said azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminothiopyranyl, tetrahydrothiopyranyl, iminothiopyranyl, thiomorpholinyl, and iminothiomorpholinyl oxide are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = O, = NH, amino, hydroxy, 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 (CH) (= O) -cyclopropyl, -C (= O) -cyclobutyl, -C (= O) -cyclopentyl, -C (= O) - (tetrahydropyran-4-yl) 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -a cyclopropyl group.
31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
R 5 selected from hydrogen and methoxy, preferably hydrogen.
32. The compound of claim 29, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
R 4 and R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 3-14 Cycloalkyl, = O, = CH 2 、＝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 An alkyl group;
preferably, R 4 And R 5 Together with the atoms to which each is attached, form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: methyl, cyclopropyl and = O.
33. The compound of claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
in the formula I-1, the compound of formula I,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, of the formula I-1
Figure FDA0003910195110000121
Selected from the following groups:
Figure FDA0003910195110000122
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 is a 3-to 14-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 A cycloalkyl group;
R 4a and R 4b Is independently selected from C 1-6 Alkyl, preferably methyl;
R 5 is hydrogen;
wherein said heterocyclyl and heteroaryl each independently contain one or more heteroatoms selected from N, O and S as ring atoms.
34. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
in the formula I-1A, the compound of formula I,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1A
Figure FDA0003910195110000131
Selected from the following groups:
Figure FDA0003910195110000132
R 2 selected from hydrogen and methyl, preferably methyl;
R 3 is hydrogen;
R 4 selected from the group consisting of azetidinyl, piperazinyl, tetrahydropyridyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminothiopyranyl, tetrahydrothiopyranyl, iminothiopyranyl, thiomorpholinyl, and iminothiomorpholinyl; wherein said azetidinyl, piperazinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, thiochromanyl, iminooxathiopyranyl, tetrahydrothiopyranyl, iminooxatetrahydrothiopyranyl, thiomorpholinyl, and iminooxathiomorpholinyl are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: (= O) -methyl, -C (= O) -ethyl, -C (= O) -isopropyl, -C (= O) -trifluoromethyl, -C (= O) -cyclopropylAlkyl, -C (= O) -cyclobutyl, -C (= O) -cyclopentyl, -C (= O) - (tetrahydropyran-4-yl), -C (= O) - (furan-3-yl), -C (= O) -N (CH) 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -a cyclopropyl group;
R 5 is hydrogen.
35. The compound of claim 13, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
in formula I-1B, formula I-1B-1 or formula I-1B-2,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-1B, formula I-1B-1 or formula I-1B-2
Figure FDA0003910195110000133
Selected from the following groups:
Figure FDA0003910195110000134
R 2 selected from hydrogen and methyl, preferably methyl;
R 4 selected from the group consisting of thiopyranyl, iminothiolanyl, tetrahydrothiopyranyl, and iminothiolanyl; wherein the thiochromanyl and tetrahydrothiopyranyl groups are each optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: = 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 (CH) (= O) -N 3 ) 2 、-S(＝O) 2 -methyl and-S (= O) 2 -cyclopropyl.
36. The compound of claim 19, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
in the formula I-3, the compound of formula I,
ring A is phenyl; n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in formula I-3
Figure FDA0003910195110000135
Selected from the following groups:
Figure FDA0003910195110000136
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 3 is hydrogen;
R 4 and R 5 Together with the atoms to which each is attached form a 5-to 15-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents; each of said substituents, if present, is independently selected from the group consisting of: c 1-6 Alkyl radical, C 3-14 Cycloalkyl and = O, preferably methyl, cyclopropyl and = O;
R 6 is methyl;
wherein said heterocyclic group contains one or more heteroatoms selected from N, O and S as ring atoms.
37. The compound of claim 20, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
in the formula I-3A, the compound has the following structure,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably, in the formula I-3A
Figure FDA0003910195110000141
Selected from the following groups:
Figure FDA0003910195110000142
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O;
rings B and p are as defined above.
38. The compound of claim 24, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, wherein,
in formula I-3B, formula I-3B-1 or formula I-3B-2,
n is 2; each R 1 Independently selected from methyl, -CHF 2 、-CF 3 Amino, fluoro and cyano; preferably of formula I-3B, formula I-3B-1 or formula I-3B-2
Figure FDA0003910195110000143
Selected from the following groups:
Figure FDA0003910195110000144
each X is independently CH 2 、NR 7 Or O;
R 2 selected from hydrogen and methyl, preferably hydrogen;
R 6 is methyl;
each R 7 Independently selected from methyl and cyclopropyl, or, any two R's attached to the same ring atom 7 Form = O;
q is as defined above.
39. The compound of claim 38, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof,
Figure FDA0003910195110000145
the fragment is selected from the following structures:
Figure FDA0003910195110000146
Figure FDA0003910195110000151
each R 7 Independently selected from hydrogen, methyl and cyclopropyl, or, any two R attached to the same ring atom 7 Form = O.
40. The following compounds, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof:
Figure FDA0003910195110000152
Figure FDA0003910195110000161
Figure FDA0003910195110000171
Figure FDA0003910195110000181
Figure FDA0003910195110000191
Figure FDA0003910195110000201
41. a pharmaceutical composition comprising a compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof.
42. The pharmaceutical composition of claim 41,
the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
43. A pharmaceutical formulation made from the pharmaceutical composition of claim 41 or 42;
preferably, the pharmaceutical formulation is a solid formulation for oral administration, a liquid formulation for oral administration, a formulation for parenteral injection or a formulation for topical administration.
44. Use of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition according to claim 41 or 42 or a pharmaceutical formulation according to claim 43, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by the SOS1 protein;
preferably, the disease mediated at least in part by the SOS1 protein is cancer.
45. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition according to claim 41 or 42 or a pharmaceutical formulation according to claim 43, for use in the prevention and/or treatment of a disease mediated at least in part by the SOS1 protein;
preferably, the disease mediated at least in part by the SOS1 protein is cancer.
46. A method for the prevention and/or treatment of a disease mediated at least in part by SOS1 protein, comprising administering to an individual in need thereof a prophylactically and/or therapeutically effective amount of a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition according to claim 41 or 42, or a pharmaceutical formulation according to claim 43;
preferably, the disease mediated at least in part by the SOS1 protein is cancer.
47. A pharmaceutical combination comprising a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition according to claim 41 or 42 or a pharmaceutical formulation according to claim 43, and at least one additional cancer therapeutic agent.
CN202211320575.2A 2021-11-04 2022-10-26 Benzylamino-substituted heteropolycyclic compounds, compositions, formulations and uses thereof Pending CN115536660A (en)

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