CN115246841B - Benzylamino-substituted pyrimidopyrone derivatives, compositions, formulations and uses thereof - Google Patents
Benzylamino-substituted pyrimidopyrone derivatives, compositions, formulations and uses thereof Download PDFInfo
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- CN115246841B CN115246841B CN202211049471.2A CN202211049471A CN115246841B CN 115246841 B CN115246841 B CN 115246841B CN 202211049471 A CN202211049471 A CN 202211049471A CN 115246841 B CN115246841 B CN 115246841B
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- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
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- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
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- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
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- 125000005981 pentynyl group Chemical group 0.000 description 1
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- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
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Classifications
-
- 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
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a benzylamino substituted pyrimidopyrone derivative, a composition, a preparation and application thereof. Specifically, the general structure of the derivative is shown as formula I. The compound provided by the invention has excellent in-vitro inhibition activity on SOS1, can be used as an SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good anti-tumor activity, and has good effect on treating mammal (including human) tumor diseases.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a series of novel benzylamino substituted pyrimidopyrone derivatives, a pharmaceutical composition and a pharmaceutical preparation containing the same, and medical application of the same.
Background
KRAS gene mutations are common in pancreatic, lung, colorectal, gall bladder, bile duct and thyroid cancers, and are a GTP binding protein. The RAS has two main forms in the body: an inactive state in which GDP binds and an active state in which GTP binds. Its activity is regulated by two proteins, guanylate Exchange Factor (GEF) such as SOS1, which promotes release of GDP from RAS proteins, allowing GTP binding to activate RAS; the GTPase activating protein activates the GTPase activity of the RAS protein, hydrolyzes GTP bound to the RAS protein to GDP, and deactivates the RAS. When in the GTP-bound state, RAS family proteins are active and bind effector proteins (including RAF and PI 3K) to promote RAF/MEK/ERK, PI3K/AKT/mTOR, and the like pathways. These pathways affect a variety of cellular processes, such as proliferation, survival, metabolism, etc.
SOS1 has two binding sites for RAS family proteins: one is a catalytic site that binds to GDP-bound RAS family proteins to promote guanine nucleotide exchange, and the other is an ectosite that binds to GTP-bound RAS family proteins to cause a further increase in catalytic GEF function of SOS1 (biochem. Pharmacol.,2011,82 (9): 1049-1056). SOS1 has an important role in mutant KRAS activation and oncogenic signaling in cancer (Nat. Commun.,2012, 3:1168). In tumor cells carrying KRAS mutations, decreasing SOS1 content can decrease the proliferation rate of tumor cells, whereas no effect is observed in KRAS wild-type cell lines.
RAS, the first oncogene identified, is the most mutated oncogene, accounting for 25% of human cancers. Over the last decades, RAS family protein-SOS 1 protein interactions have gained increasing knowledge. Currently, only the SOS1 inhibitor BI1701963 of bolin invahn enters clinical phase I studies, and no SOS1 inhibitors have been developed on the market. Therefore, the development of new SOS1 inhibitors has great clinical value and broad market prospect.
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 pyrimidopyrone derivative, and a composition, a preparation and application thereof, wherein the derivative has excellent SOS1 inhibitor activity, good pharmacodynamic performance and high metabolic stability.
Solution for solving the problem
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:
wherein:
a is selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, and 3 to 6 membered heterocyclyl;
n is selected from 1, 2 and 3;
each R is 1 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, 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, -C 1-6 alkylene-OH, -C 1-6 haloalkylene-OH, amino, halogen, cyano and nitro;
R 2 selected from hydrogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, halogen, cyano, -NR 2a R 2b and-OR 2a ;
R 2a And R is 2b Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;
R 3 selected from hydrogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and halogen;
m is selected from 1 and 2;
each R is 4 Selected from hydroxy, cyano, nitro, halogen, -N (R) 4d ) 2 and-R 4d ;
Each R is 4d Independently selected from hydrogen and the following groups optionally substituted with one or more substituents: c (C) 1-6 Alkyl, -C 1-6 alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl; each of the substituents, if present, is independently selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, =o, =c 1-6 Alkyl, =c 1-6 Haloalkyl, =c 3-6 Cycloalkyl, halogen, cyano, -OR 4a 、-C(=O)R 4a 、-C(=O)OR 4a 、-SO 2 R 4a 、-C(=O)NR 4b R 4c 、-NR 4b C(=O)R 4c and-NR 4b R 4c ;
R 4a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -C (=o) R 4b 、C 3-6 Cycloalkyl and C 6-10 An aryl group;
R 4b and R is 4c Independently selected from hydrogen and C 1-6 An alkyl group;
when m=1, L 1 Selected from single bonds, - (CH) 2 ) p -、-C(=CH 2 )O-、-C(=O)-、-C(=O)O-、-O-、-S-、-S(=O)-、-S(=O) 2 -、-NR L1a C(=O)-、-NR L1a S(=O) q -and-NR L1a C (=s) S-; when m=2, L 1 Selected from the group consisting of
p is selected from 1, 2,3, 4, 5 and 6;
q is selected from 1 and 2;
R L1a selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl and C 6-10 Aryl groups.
In a second aspect, the present invention provides the following non-limiting examples of the above-described compounds having the structure of formula I:
(1) (R) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(2) (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2, 5-dimethyl-7H-pyrano [2,3-d ] pyrimidin-7-one;
(3) (R) -2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid methyl ester;
(4) (R) -2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid methyl ester;
(5) (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid methyl ester;
(6) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid methyl ester;
(7) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid methyl ester;
(8) (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6-benzoyl-2-methyl-7H-pyrano [2,3-d ] pyrimidin-7-one;
(9) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid ethyl ester;
(10) (R) -2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid;
(11) (R) -6-bromo-2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(12) (R) -2, 5-dimethyl-6- (pyridin-3-yl) -4- (1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(13) (R) -2, 5-dimethyl-6- (thiophen-3-yl) -4- (1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(14) (R) -2, 5-dimethyl-6- (1, 2,3, 6-tetrahydropyridin-4-yl) -4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(15) (R) -6- (3, 6-dihydro-2H-pyran-4-yl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(16) (R) -6- (3, 6-dihydro-2H-thiopyran-4-yl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(17) (R) -6- (2, 5-dihydro-1H-pyrrol-3-yl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(18) (R) -6- (4, 5-dihydro-1H-pyrrol-3-yl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(19) (R) -6- (1-acetyl-1, 2,3, 6-tetrahydropyridin-4-yl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(20) (R) -2-methyl-6- (morpholine-4-carbonyl) -4- (1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(21) (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -N, 2-trimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(22) Methyl (R) -2- (2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide) acetate;
(23) (R) -N- (2-methoxyphenyl) -2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(24) (R) -N, 2-dimethyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(25) (R) -4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- (4-methylpiperazine-1-carbonyl) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(26) (R) -2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(27) 2-methyl-7-oxo-N- ((S) -tetrahydrofuran-3-yl) -4- ((R) -1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(28) 4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-7-oxo-N- ((S) -tetrahydrofuran-3-yl) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(29) (R) -N, N-bis (2-hydroxyethyl) -2-methyl-7-oxo-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidine-6-carboxamide;
(30) (R) -6- (1-ethoxyvinyl) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(31) (R) -6- (diethylamino) -2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(32) (R) -6-acetyl-2, 5-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(33) (R) -6-acetyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(34) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-6-nitro-7H-pyrano [2,3-d ] pyrimidin-7-one;
(35) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6-nitro-7H-pyrano [2,3-d ] pyrimidin-7-one;
(36) (R) -6-amino-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7H-pyrano [2,3-d ] pyrimidin-7-one;
(37) (R) -6-amino-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(38) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) acetamide;
(39) 4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -6- (hydroxy (phenyl) methyl) -2-methyl-7H-pyrano [2,3-d ] pyrimidin-7-one;
(40) 4- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6- ((methylamino) (phenyl) methyl) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(41) (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) -3-methylurea;
(42) (R) -1-cyclopropyl-3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) urea;
(43) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid isopropyl ester;
(44) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid benzyl ester;
(45) 4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid (S) -1-phenylethyl ester;
(46) 4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidine-6-carboxylic acid (R) -1-phenylethyl ester;
(47) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) methanesulfonamide;
(48) (R) - (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) dithiocarbamic acid methyl ester;
(49) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) -2-methoxybenzenesulfonamide;
(50) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) cyclopropanecarboxamide;
(51) (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-6- (1-methyl-1H-pyrazol-4-yl) -7H-pyrano [2,3-d ] pyrimidin-7-one;
(52) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) acrylamide;
(53) (R) -N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) benzo [ d ] [1,3] dioxole-5-carboxamide; and
(54) (R) -2-amino-N- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2, 5-dimethyl-7-oxo-7H-pyrano [2,3-d ] pyrimidin-6-yl) -4-fluorobenzamide.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, 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, co-solvents, surfactants, opacifiers (opacifiers), and the like.
In a fourth aspect, the present invention provides a pharmaceutical formulation made from a compound having the structure of formula I above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or from a pharmaceutical composition as described above.
In a fifth aspect, the present invention provides the use of 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, in the manufacture of a medicament for the prophylaxis and/or treatment of a disease mediated at least in part by SOS1 protein.
Preferably, in the above use, the disease mediated at least in part by 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 above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition, or a pharmaceutical formulation, as described above, and at least one additional cancer therapeutic agent.
ADVANTAGEOUS EFFECTS OF INVENTION
The compound provided by the invention has excellent in-vitro inhibition activity on SOS1, can be used as an SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good anti-tumor activity, and has good effect on treating mammal (including human) tumor 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 from the compounds of the present invention by reaction with pharmaceutically acceptable inorganic or organic acids, 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 may form sulfate or acid sulfate), phosphoric acid (which may form phosphate or acid phosphate), and the like, and common organic acids include, but are not limited to, trifluoroacetic acid, citric acid (which may form citric acid mono-, di-, or tri-salt), maleic acid (which may form maleic acid mono-or di-salt), fumaric acid (which may form fumaric acid mono-or di-salt), succinic acid (which may form succinic acid mono-or di-salt), tartaric acid (which may form tartaric acid mono-or di-salt), oxalic acid (which may form oxalic acid mono-or di-salt), malonic acid (which may form malonic acid mono-or di-salt), malic acid (which may form oxalic acid 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 association of a compound of the invention or a pharmaceutically acceptable salt thereof with water by non-covalent intermolecular forces. 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 association of a compound of the invention, or a pharmaceutically acceptable salt thereof, with 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 "isomer" refers to compounds having the same number and type of atoms and thus the same molecular weight, but different spatial arrangements or configurations of atoms.
The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular plane of asymmetry due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby enabling rotation of plane polarized light. The present invention also includes stereoisomers and mixtures thereof, due to the presence of asymmetric centers and other chemical structures in the compounds of the present invention which may lead to stereoisomers. Since the compounds of the present invention and salts thereof include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can 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 below, individual stereoisomers of the compounds are prepared synthetically from optically active starting materials containing the desired chiral centers 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 enantiomers on chiral chromatographic columns. Starting compounds having specific stereochemistry are either commercially available or prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-overlapping mirror images of each other. The term "diastereoisomer" 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 portions of individual enantiomers. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation, amide-imine alcohol isomerisation, 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 stereoisomers formed by atoms (or groups) located on either side of a double bond or ring system due to different positions relative to a reference plane; in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system. All cis and trans isomeric forms of the compounds of the present invention are within the scope of the present invention unless otherwise indicated.
The term "isotopic label" refers to a compound formed by substituting a specific atom in a structure with its isotopic atom. Unless otherwise indicated, the compounds of the invention include various isotopes of H, C, N, O, F, P, S, cl, e.g 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 derivative compound that is capable of providing a compound of the invention directly or indirectly after administration to a patient. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, may increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood) or promote delivery of the parent compound to the site of action (e.g., the lymphatic system). All prodrug forms of the compounds of the invention are within the scope of the invention unless otherwise indicated, and the various prodrug forms are well known in the art.
The term "aryl" refers to a monovalent group having a single ring or a condensed multiple ring of aromaticity, the ring atoms of which 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-tetrahydrochyseneNaphthalene, and the like. The term "C 6-10 Aryl "means aryl 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, among others.
The term "heteroaryl" refers to a monovalent group having a single or fused multiple rings of aromatic character, at least one (e.g., 1,2,3, or 4) of which is a heteroatom selected from N, O and S, the remaining ring atoms being C, which may be, for example, a 5 to 10 membered ring, especially a 5 to 8 membered ring. Non-limiting examples of heteroaryl groups include (but are not limited to) Etc. The term "5-to 10-membered heteroaryl" refers to heteroaryl groups having 5 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O and S, non-limiting examples of 5-to 10-membered heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyridyl, indolyl, quinolinyl, and the like.
The term "heterocyclyl" refers to a monovalent radical that is a single, bridged or spiro ring, either fully saturated or partially unsaturated (but not fully unsaturated, e.g., having 1 or 2 double bonds), at least one (e.g., 1, 2, 3 or 4) of which is a heteroatom selected from N, O and S, the remaining ring atoms being C, e.g., can be a 3 to 14 membered ring, or even a 3 to 6 membered ring. The term "3 to 14 membered heterocyclyl" refers to heterocyclyl having 3 to 14 ring atoms which may contain 1 to 4 heteroatoms selected from N, O and S; the term "3-to 6-membered heterocyclyl" refers to a heterocyclyl having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O and S.
Non-limiting examples of saturated 3-membered heterocyclyl groups include, but are not limited to, oxiranyl, mercaptoethyl, cyclic aminoethyl, and the like; non-limiting examples of saturated 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, and the like; non-limiting examples of saturated 5-membered heterocyclyl 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 heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxalkyl, 1, 4-dioxane, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and the like; non-limiting examples of saturated 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl, and the like.
Non-limiting examples of partially unsaturated heterocyclyl groups include (but are not limited to) Etc.
The term "alkyl" refers to a straight or branched monovalent hydrocarbon radical, free of unsaturation. 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 (-CH (CH) 3 ) 2 ) N-butyl (-CH) 2 CH 2 CH 2 CH 3 ) Sec-butyl (-CH (CH) 3 )CH 2 CH 3 ) Isobutyl (-CH) 2 CH(CH 3 ) 2 ) Tert-butyl (-C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) Neopentyl (-CH) 2 C(CH 3 ) 3 ) Etc.
The term "alkylene" refers to a straight or branched divalent hydrocarbon radical formed by further substitution of one hydrogen atom of an alkyl radical, without unsaturation. The term "C 1-6 Alkylene "means an alkylene group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 (-), ethylene (e.g. -CH) 2 -CH 2 (-), propylene (e.g. -CH) 2 -CH 2 -CH 2 -) butylene (e.g. -CH 2 -CH 2 -CH 2 -CH 2 (-), etc.
The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more carbon-carbon double bonds, e.g., may have from 2 to 20 carbon atoms. The term "C 2-6 Alkenyl "refers to alkenyl groups having 2 to 6 carbon atoms; the term "C 2-4 Alkenyl "refers to alkenyl groups having 2 to 4 carbon atoms. C (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 monovalent hydrocarbon radical having one or more carbon-carbon triple bonds, e.g., may have 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 (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 from the substitution of at least one hydrogen atom in an alkyl group with a halogen atom, free of 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 groups having 1 to 4 carbon atoms. C (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 Etc.
The term "haloalkylene" refers to a straight or branched divalent hydrocarbon radical formed by further substitution of one hydrogen atom of a haloalkyl group, free of unsaturation. The term "C 1-6 Haloalkylene "means a haloalkylene having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of haloalkenes include, but are not limited to, CHF-, -CF 2 -、-CH 2 CHF-、-CH 2 CF 2 -、-CH 2 CH 2 CHF、-CH 2 CH 2 CF 2 -、-CH 2 CF 2 CF 2 -and the like.
The term "cycloalkyl" refers to a monovalent cyclic hydrocarbon group that is fully saturated, monocyclic or polycyclic (e.g., spiro, fused or bridged), and may have, for example, 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" refers to a monovalent cyclic hydrocarbon group of a single or multiple ring (e.g., spiro, fused or bridged, but not aromatic) having one or more carbon-carbon double bonds, e.g., may have 3 to 20, 3 to 12, 3 to 6, or 5 to 6 carbon atoms. The term "C 3-14 Cycloalkenyl "means 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 A group, in some cases amino, may also represent at least one H atom in the structure further substituted with an alkyl group (e.g., C 1-6 Alkyl) to replace the monovalent groups formed.
The term "nitro" refers to-NO 2 A group.
The term "cyano" refers to a-CN group.
The term "single bond" refers to a chemical bond between atoms for interconnection or interaction, such as an ionic bond, covalent bond, coordination bond, and the like; in the molecular structure of organic compounds, single bonds are typically covalent bonds.
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, R 4d "optionally" substituted with halogen means R 4d May be unsubstituted, monosubstituted, polysubstituted or fully substituted by halogen atoms. It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
[ benzylamino-substituted pyrimidopyrone derivatives ]
The present invention provides a series of novel benzylamino-substituted pyrimidopyrone derivatives or pharmaceutically acceptable forms thereof, such as salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs of the compounds.
In one embodiment of the invention, the structure of the compound is shown as a formula I:
wherein:
a is selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, and 3 to 6 membered heterocyclyl;
n is selected from 1, 2 and 3;
each R is 1 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, 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, -C 1-6 alkylene-OH, -C 1-6 haloalkylene-OH, amino, halogen, cyano and nitro;
R 2 selected from hydrogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, halogen, cyano, -NR 2a R 2b and-OR 2a ;
R 2a And R is 2b Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;
R 3 selected from hydrogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and halogen;
m is selected from 1 and 2;
each R is 4 Independently selected from hydroxy, cyano, nitro, halogen, -N (R) 4d ) 2 and-R 4d ;
Each R is 4d Independently selected from hydrogen and the following groups optionally substituted with one or more substituents: c (C) 1-6 Alkyl, -C 1-6 alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-14 Cycloalkyl, C 3-14 Cycloalkenyl, 3-to 14-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl; each of the substituents, if present, is independently selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, =o, =c 1-6 Alkyl, =c 1-6 Haloalkyl, =c 3-6 Cycloalkyl, halogen, cyano, -OR 4a 、-C(=O)R 4a 、-C(=O)OR 4a 、-SO 2 R 4a 、-C(=O)NR 4b R 4c 、-NR 4b C(=O)R 4c and-NR 4b R 4c ;
R 4a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -C (=o) R 4b 、C 3-6 Cycloalkyl and C 6-10 An aryl group;
R 4b and R is 4c Independently selected from hydrogen and C 1-6 An alkyl group;
when m=1, L 1 Selected from single bonds, - (CH) 2 ) p -、-C(=CH 2 )O-、-C(=O)-、-C(=O)O-、-O-、-S-、-S(=O)-、-S(=O) 2 -、-NR L1a C(=O)-、-NR L1a S(=O) q -and-NR L1a C (=s) S-; when m=2, L 1 Selected from the group consisting of
p is selected from 1, 2, 3, 4, 5 and 6;
q is selected from 1 and 2;
R L1a selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl and C 6-10 Aryl groups.
In a preferred embodiment of the invention, A in formula I is selected from C 6-10 Aryl and 5 to 10 membered heteroaryl.
In a more preferred embodiment of the invention, A in formula I is C 6-10 Aryl groups.
In an even more preferred embodiment of the invention, a in formula I is selected from phenyl and naphthyl.
In a preferred embodiment of the invention, n in formula I is selected from 1 and 2.
In a more preferred embodiment of the invention, n in formula I is 1, i.e. the A fragment is substituted by 1R 1 Substituted with a substituent, and R is 1 The substituents are substituted at any substitutable site on the A fragment.
In a further preferred embodiment of the invention, n in formula I is 2, i.e. the A fragment is substituted by 2R 1 Substituted with a substituent, and the 2R 1 The substituents are independently substituted at any substitutable site on the A fragment.
In a preferred embodiment of the invention, the formulaEach R in I 1 Independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 haloalkylene-OH, amino, halogen, cyano and nitro.
In a more preferred embodiment of the invention, each R in formula I 1 Independently selected from C 1-4 Haloalkyl, amino, halogen and nitro.
In another more preferred embodiment of the present invention, each R in formula I 1 Independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl, propenyl, propargyl, propynyl, -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 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CH 2 CH 2 CH 2 OH、-CHFCH 2 OH、-CHFCH 2 CH 2 OH、-CH 2 CHFCH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, fluoro, chloro, bromo, cyano and nitro.
In an even more preferred embodiment of the invention, each R in formula I 1 Independently selected from-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 and nitro, preferably-CHF 2 、-CF 3 Amino, fluoro, and nitro.
In a preferred embodiment of the invention, R in formula I 2 Selected from hydrogen, C 1-6 Alkyl and C 1-4 Halogenated compoundsAn alkyl group.
In another preferred embodiment of the present invention R in formula I 2 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 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, cyano, amino, methylamino, dimethylamino, ethylamino, diethylamino, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, -OCH 2 F、-OCHF 2 、-OCF 3 and-OCH 2 CF 3 。
In a more preferred embodiment of the invention, R in formula I 2 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, preferably hydrogen and methyl.
In a preferred embodiment of the invention, R in formula I 3 Selected from hydrogen, C 1-6 Alkyl and C 1-4 A haloalkyl group.
In another preferred embodiment of the present 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 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro and bromo.
In a more preferred embodiment of the invention, R in formula I 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, preferably hydrogen and methyl.
In a preferred embodiment of the invention, m in formula I is 1, i.e.the parent nucleus structure is represented by L 1 Fragment ligation of 1R 4 A substituent, and R is 4 Substituent and L 1 Any of the ligatable sites of the fragments are ligated.
In another preferred embodiment of the invention, m in formula I is 2, i.e. the parent nucleus structure is represented by L 1 Fragment ligation of 2R 4 Substituents, and the 2R 4 The substituents being independently from L 1 Any of the ligatable sites of the fragments are ligated.
In a preferred embodiment of the invention, each R in formula I 4 Independently selected from hydroxy, cyano, nitro, halogen, -N (R) 4d ) 2 and-R 4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein each R 4d Independently selected from hydrogen and the following groups optionally substituted with one or more substituents: c (C) 1-6 Alkyl, -C 1-6 alkylene-OH, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl; each of the substituents, if present, is independently selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, =o, halogen, -OR 4a 、-C(=O)R 4a 、-C(=O)OR 4a and-NR 4b R 4c ;R 4a Selected from C 1-6 An alkyl group; r is R 4b And R is 4c Independently selected from hydrogen and C 1-6 An alkyl group.
In a more preferred embodiment of the invention, each R in formula I 4 Independently selected from hydroxy, nitro, halogen, -N (R) 4d ) 2 and-R 4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein each R 4d Independently selected from hydrogen and the following groups optionally substituted with one or more substituents: c (C) 1-6 Alkyl, -C 1-6 alkylene-OH, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 Aryl and 5 to 10 membered heteroaryl; each of the substituents, if present, is independently selected from the group consisting of: c (C) 1-6 Alkyl, C 6-10 Aryl, =o, halogen, -OR 4a 、-C(=O)R 4a 、-C(=O)OR 4a and-NR 4b R 4c ;R 4a Selected from C 1-6 An alkyl group; r is R 4b And R is 4c Independently selected from hydrogen.
In an even more preferred embodiment of the invention, each R in formula I 4 Independently selected from hydroxy, nitro, fluoro, chloro, bromo, -N (R) 4d ) 2 and-R 4d The method comprises the steps of carrying out a first treatment on the surface of the Wherein each R 4d Independently selected from hydrogen and the following groups optionally substituted with one or more substituents: methyl, ethyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 6-tetrahydropyridin-4-yl, 3, 6-dihydro-2H-pyran-4-yl, 3, 6-dihydro-2H-thiopyran-4-yl, 2, 5-dihydro-1H-pyrrol-3-yl, 4, 5-dihydro-1H-pyrrol-3-yl, morpholin-4-yl, piperazin-1-yl, tetrahydrofuran-3-yl, phenyl, pyridinyl-3-yl, 1H-pyrazol-4-yl, benzo [ d ] ][1,3]Dioxol-5-yl and thiophen-3-yl; each of the substituents, if present, is independently selected from the group consisting of: methyl, ethyl, phenyl, =o, fluoro, methoxy, ethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl and amino.
In a preferred embodiment of the invention, m=1 in formula I, and L 1 Selected from single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-C(=CH 2 )O-、-C(=O)-、-C(=O)O-、-NHC(=O)-、-NHS(=O)-、-NHS(=O) 2 -and-NHC (=s) S-.
In a more preferred embodiment of the present invention, m=1 in formula I, and L 1 Selected from single bonds, -C (=ch 2 )O-、-C(=O)-、-C(=O)O-、-NHC(=O)-、-NHS(=O) 2 -and-NHC (=s) S-.
In another preferred embodiment of the present invention, m=2 in formula I, and L 1 Selected from the group consisting of
In a preferred embodiment of the invention, m=1 in formula I, and-L 1 -R 4 Selected from the group consisting of/>
In another preferred embodiment of the present invention, m=2 in formula I, and-L 1 -(R 4 ) 2 Selected from the group consisting of
In a preferred embodiment of the present invention, the structure of the benzylamino-substituted pyrimidopyrone derivatives of the present invention is as shown in formula IA, formula IA-1 or formula IA-2:
wherein R is 1 、R 2 、R 3 、R 4 、L 1 N and m are as defined in formula I.
In another preferred embodiment of the present invention, the structure of the benzylamino-substituted pyrimidopyrone derivatives of the present invention is as shown in formula IB, formula IB-1, or formula IB-2:
wherein R is 1 、R 2 、R 3 And n is as defined in formula I; r is R 4 Selected from hydrogen and C 1-6 Alkyl, wherein C 1-6 Alkyl optionally substituted with one or more C 6-10 Aryl substitution.
In a more preferred embodiment of the present invention, R in formula IB, formula IB-1 or formula IB-2 4 Independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, benzyl and 1-phenylethyl.
In another preferred embodiment of the present invention, the benzylamino-substituted pyrimidopyrone derivatives of the present invention have the structure of formula IC, formula IC-1, or formula IC-2:
wherein R is 1 、R 2 、R 3 And n is as defined in formula I.
In particular, benzylamino-substituted pyrimidopyrone derivatives of the present invention include (but are not limited to) the following compounds:
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[ 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 pharmaceutical excipients that are compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, one or more of diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, preservatives, antioxidants, pH adjusting agents, solvents, co-solvents, surfactants, opacifiers, and the like.
The present invention provides a pharmaceutical composition comprising a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2 described above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof.
In one embodiment of the present invention, the above pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
[ pharmaceutical preparation ]
The term "pharmaceutical formulation" refers to a finished pharmaceutical product prepared in a form that is ready for use by 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 formulation is a solid formulation for oral administration, including (but not limited to) pharmaceutically acceptable capsules, tablets, pills, powders, granules, and the like. The solid formulation 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 contain an opacifying agent and wherein the active ingredient is capable of being released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. Alternatively, the active ingredient may be in the form of microcapsules with one or more of the carriers described above.
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 yet another embodiment of the present invention, the above pharmaceutical formulation is a dosage form for topical administration, including (but not limited to) ointments, powders, suppositories, drops, sprays, inhalants and the like.
[ medical use ]
Whether a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2, 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, is capable of exhibiting inhibitory activity against SOS1, the present invention thus provides the use of a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2, 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, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by SOS1 protein.
The invention provides application of the compound shown in the formula I, the formula IA-1, the formula IA-2, the formula IB-1 or the formula IB-2 or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs thereof or the pharmaceutical composition or the pharmaceutical preparation thereof in preparing medicines for preventing and/or treating cancers.
The term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, an ability to inappropriately invade surrounding tissues, and/or an ability to establish new growth in ectopic sites. Non-limiting examples of cancers 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 sarcomas.
The invention also provides a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or a pharmaceutical composition or pharmaceutical preparation thereof, for use in the prevention and/or treatment of a disease (particularly cancer) mediated at least in part by SOS1 protein.
The present invention also provides a method for preventing and/or treating a disease mediated at least in part by SOS1 protein, in particular cancer, comprising administering to a subject in need thereof a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2 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.
[ Combined drug administration ]
The present invention provides a pharmaceutical combination comprising a compound of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2 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.
The term "cancer therapeutic" 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-purine agents (e.g., pranopetadine, etc.), anti-pyrimidine agents (e.g., 5-fluorouracil), antifolate agents (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum complexes (e.g., cisplatin, carboplatin), DNA-disrupting antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecins), intercalating DNA interfering nucleic acid synthetic agents (e.g., epirubicin), drug delivery inhibitors (e.g., asparaginase), microtubule-forming agents (e.g., paclitaxel), ribosome-interfering agents (e.g., cephalotaxine), topoisomerase inhibitors (e.g., camptothecin) cytokines (e.g., IL-1), thymulin, tumor cell proliferation viruses (e.g., adenovirus ONYX-015), vinblastines (e.g., vinorelbine), doxorubicin (e.g., doxorubicin, epirubicin, aclacinomycin), tenidines (e.g., imatinib, gefitinib, erlotinib, dasatinib, sunitinib), monoclonal antibodies (e.g., trastuzumab, panitumumab, bevacizumab), bortezomib, calcitriol, capecitabine, aminoglutethimide, letrozole, lanindac, everolimus, fulvestrant, irinotecan, pemetrexed, sirolimus, PD-1, PD-L1, and the like.
In one embodiment of the invention, the compounds of formula I, formula IA-1, formula IA-2, formula IB-1 or formula IB-2 described above, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof, or the pharmaceutical composition described above, or the pharmaceutical formulation described above, may be administered either alone or in combination with other cancer therapeutic agents (or antineoplastic agents). The combination therapy may be achieved by the simultaneous, sequential or separate administration of different cancer therapeutic agents.
The technical scheme of the invention will be further described below in connection with specific embodiments. Unless otherwise indicated, reagents, materials, instruments, and the like used in the following examples were obtained by conventional commercial means, and the experimental methods used were conventional in the art.
In the examples below, the following abbreviations are used:
THF tetrahydrofuran
NBS N-bromosuccinimide
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
HOBT 1-hydroxybenzotriazoles
TEA triethylamine
NaBH 3 CN cyano sodium borohydride
CDI N, N-carbonyl diimidazole
DMF N, N-dimethylformamide
Example 1: preparation of Compound 1
(1) Intermediate 1-1 synthetic route
To the reaction flask, compound 1-1a (20.00 g,106.36mmol,1.0 eq), THF (150 mL), t-butylsulfonamide (19.31 g,159.54mmol,1.5 eq) and tetraethyltitanate (74.65 g,327.26mmol,2.0 eq) were added in this order under nitrogen, and the mixture was warmed to 80℃and stirred for 4 hours. After the reaction system was cooled to room temperature, water (150 mL) was added, ethyl acetate was added thereto for extraction (150 mL) 2 times, 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 1-1b (28.2 g); MS: m/z 292.1[ M+1 ]] + 。
To the reaction flask, compound 1-1b (28.00 g,96.19mmol,1.0 eq), THF (400 mL) and water (6 mL) were added sequentially, cooled to-60-50deg.C, then sodium borohydride (6.58 g,173.14mmol,1.8 eq) was slowly added, and after the addition, the temperature was raised to-5-0deg.C and stirring was continued for 30 minutes at controlled temperature. The reaction was quenched by adding water (300 mL), extracted with ethyl acetate (300 mL) 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 give compound 1-1c (22.5 g); MS: m/z 294.1[ M+1 ] ] + 。
To the reaction flask were successively added compound 1-1c (22.50 g,76.77mmol,1.0 eq), dioxane (50 mL) and 4M hydrochloric acid (40 mL), and the reaction was stirred at room temperature for 2 hours after the addition. The pH of the system was adjusted to 8-9 using 1M sodium hydroxide solution, followed by extraction (100 mL) 2 times with ethyl acetate, drying the organic phase over anhydrous sodium sulfate, concentrating, and pulping the resulting solid with petroleum ether to give intermediate 1-1 (10.1 g); MS: m/z 190.1[ M+1 ]] + 。
(2) Intermediate 1-2 synthetic route
Sequentially adding the compound 1-2a (6.30 g,50mmol,1.0 eq), o-dichlorobenzene (30 mL) and 3-aminocrotonic acid ethyl ester (6.46 g,50mmol,1.0 eq) into a reaction bottle, heating to 200 ℃ after the addition, stirring and reacting for 2 hours, cooling to room temperature, adding petroleum ether (60 mL), precipitating a large amount of solids, and filtering to obtain the compound1-2b (8.50 g); MS m/z 193.1[ M+1 ]] + 。
To the reaction flask, compound 1-2b (3.84 g,20mmol,1.0 eq), acetonitrile (20 mL), diisopropylethylamine (12.92 g,100mmol,5.0 eq) and phosphorus oxychloride (9.20 g,60mmol,3.0 eq) were added in this order, and after the addition, the system was warmed to 85℃and stirred for 5 hours. After concentrating the system until no fraction flows out, ethyl acetate (30 mL) and water (10 mL) are added, the pH of the system is adjusted to 7-8 by using 1M sodium bicarbonate solution, the solution is separated, the organic phase is dried by using anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=3/1), and intermediate 1-2 (2.52 g) is obtained; MS: m/z 211.0[ M+1 ] ] + 。
(3) Synthesis of Compound 1
To the reaction flask were successively added intermediate 1-2 (105 mg,0.5mmol,1.0 eq), tetrahydrofuran (4 mL), diisopropylethylamine (193.5 mg,1.5mmol,3.0 eq) and intermediate 1-1 (113.5 mg,0.6mmol,1.2 eq), and the system was warmed to 40℃and stirred for 5 hours. Cooling to room temperature, adding water (10 mL) and dichloromethane (10 mL) into the system, separating the solution, concentrating the organic phase to dryness, purifying the crude product by reverse phase column chromatography (Shim-pack GIS C18X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to obtain a compound 1 (10.2 mg);
1 H-NMR(400MHz,DMSO-d 6 ):δ7.87(s,1H),7.80(d,1H),7.55-7.61(m,1H),7.11(d,1H),6.19(s,1H),5.43-5.50(m,1H),2.69(s,3H),2.31(s,3H),1.61(d,3H);
MS:m/z 364.0[M+1] + 。
example 2: preparation of Compound 2
Compound 2 was synthesized according to the procedure substantially similar to example 1 (see table 1).
TABLE 1 Structure and Mass Spectrometry data for Compound 2
Example 3: preparation of Compound 3
(1) Synthetic route of intermediate 3-1
To the reaction flask, compound 1-2a (6.30 g,50mmol,1.0 eq), acetic acid (30 mL) and compound 3-2 (14.03 g,75mmol,1.5 eq) were added in this order, and the system was warmed to 110℃and stirred for 20h. Concentrating the system until no fraction flows out, and purifying by column chromatography (eluent: dichloromethane/methanol=50/1-10/1) to obtain a compound 3-1a (2.1 g); MS: m/z 237.0[ M+1 ]] + 。
To the reaction flask, compound 3-1a (236 mg,1mmol,1.0 eq), phosphorus oxychloride (3 mL) and N, N-diethylaniline (223 mg,1.5mmol,1.5 eq) were added in this order, and after the addition, the system was warmed to 105℃and stirred for 2 hours. After concentrating the system until no fraction flows out, adding ethyl acetate (5 mL) and water (3 mL), regulating the pH of the system to 7-8 by using 1M sodium bicarbonate solution, separating liquid, drying an organic phase by using anhydrous sodium sulfate, concentrating to obtain an intermediate 3-1, and directly throwing the intermediate to the next step without purification; MS: m/z 255.0[ M+1 ] ] + 。
(2) Synthesis of Compound 3
Tetrahydrofuran (4 mL), N-diisopropylethylamine (387.7 mg,3.0mmol,3.0 eq) and compound 3-3 (281.0 mg,1.2mmol,1.2 eq) were added in this order to the above reaction flask containing intermediate 3-1, and the mixture was stirred at room temperature for 2 hours. Then water (5 mL) and dichloromethane (5 mL) were added to the system, the solution was separated, the organic phase was concentrated to dryness, and purified by reverse phase column chromatography (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 3 (5.3 mg);
1 H-NMR(400MHz,DMSO-d 6 ):δ9.20(s,1H),9.07(d,1H),8.62(s,1H),8.39(s,1H),8.33(s,1H),5.65-5.68(m,1H),3.86(s,3H),2.37(s,3H),1.65(d,3H);
MS:m/z 453.0[M+1] + 。
examples 4 to 9: preparation of Compounds 4 to 9
Compounds 4 to 9 were synthesized according to the procedure substantially similar to example 3 (see table 2).
TABLE 2 Structure and Mass Spectrometry data for Compounds 4 to 9
Example 10: preparation of Compound 10
Sequentially adding a compound 4 (100 mg,0.25mmol,1.0 eq), methanol (1 mL), water (1 mL) and sodium hydroxide (20 mg,0.5mmol,2.0 eq) into a reaction bottle, stirring at room temperature for reacting for 2 hours, then adjusting the pH of the system to 7-8 by using 1M hydrochloric acid, adding ethyl acetate for extraction (3 mL) for 2 times, concentrating an organic phase, drying, and purifying by reverse phase column chromatography (Shim-pack GIS C18X 20 mm 250mm,5 mu M;0.01% formic acid-water/acetonitrile) to obtain a compound 10 (25 mg); MS: m/z 394.2[ M+1 ]] + 。
Example 11: preparation of Compound 11
To a reaction flask, compound 1 (100 mg,0.28mmol,1.0 eq), acetonitrile (2 mL) and NBS (60 mg,0.34mmol,1.2 eq) were added in this order, and after the addition was completed, the temperature was raised to 50 ℃ and the reaction was stirred for 2 hours, then the system was concentrated until no fraction flowed out, and after column chromatography purification (eluent: petroleum ether/ethyl acetate=5/1 to 3/1), compound 11 (20 mg) was obtained;
1 H-NMR(400MHz,DMSO-d 6 ):δ7.86(s,1H),7.79(d,1H),7.56-7.62(m,2H),7.45(d,1H),5.53-5.46(m,1H),2.78(s,3H),2.32(s,3H),1.61(d,3H);
MS:m/z 441.8[M+1] + 。
example 12: preparation of Compound 12
To a reaction flask were successively added 11 (100 mg,0.23mmol,1.0 eq), tetrakis (triphenylphosphine) palladium (40 mg,0.035mmol,0.15 eq), sodium carbonate (61 mg,0.58mmol,2.5 eq), 3-pyridineboronic acid (43 mg,0.35mmol,1.5 eq), dioxane (4 mL) and water (1 mL), and after the addition, the reaction was stirred for 8 hours at 90 ℃, then water (4 mL) was added, ethyl acetate was added to extract (4 mL) 2 times, the organic phase was concentrated, and column chromatography was purified (eluent: dichloromethanol/methanol=10/1) to give 12-1 (53 mg); MS: m/z 459.16[ M+1 ]] + ;
N, N-dimethylformamide (3 mL), EDCI (67 mg,0.35mmol,1.5 eq) and HOBT (47 mg,0.35mmol,1.5 eq) were sequentially added to a reaction flask containing compound 12-1, the reaction was stirred at room temperature for 12h, then water (4 mL) was added to the system, ethyl acetate was added to extract (4 mL) 2 times, the organic phase was concentrated to dryness, and reversed phase column chromatography purification (Shim-pack GIS C18X 250mm,5 μm;0.01% formic acid-water/acetonitrile) was performed to obtain compound 12 (6 mg); MS: m/z 436.2[ M+1 ] ] + 。
Examples 13 to 19 and 51: preparation of Compounds 13 to 19 and 51
Compound 13 to compound 19 and compound 51 were synthesized according to the procedure substantially similar to example 12 (see table 3).
TABLE 3 Structure and Mass Spectrometry data for Compounds 13 through 19 and 51
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Example 20: preparation of Compound 20
To a reaction flask, compound 10 (100 mg,0.25mmol,1.0 eq), N-dimethylformamide (2 mL), EDCI (73 mg,0.38mmol,1.5 eq) and HOBT (52 mg,0.38mmol,1.5 eq) were added in this order, stirred at room temperature for 48 hours, water (4 mL) was added to the system, ethyl acetate was added for extraction (4 mL) 2 times, the organic phase was concentrated to dryness, and reversed phase column chromatography was purified (Shim-pack GIS C1820 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 20 (8 mg); MS: m/z 463.2[ M+1 ]] + 。
Examples 21 to 29: preparation of Compounds 21 to 29
Compounds 21 to 29 were synthesized according to the procedure substantially similar to example 20 (see table 4).
TABLE 4 Structure and Mass Spectrometry data for Compounds 21 to 29
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Examples 30 to 31: preparation of Compounds 30 to 31
To a reaction flask was added compound 11 (100 mg,0.23mmol,1.0 eq), tributyl (1-ethoxyvinyl) tin (126 mg,0.35mmol,1.5 eq), TEA (70 mg,0.69mmol,3.0 eq) and bis (triphenylphosphine) palladium dichloride (25 mg,0.035mmol,0.15 eq) and dioxane (4 mL) in this order, and after the addition, the reaction was stirred for 8 hours at 90 ℃, then water (4 mL) was added to the system, ethyl acetate was added to extract (4 mL) 2 times, the organic phase was concentrated to dryness, and reversed phase column chromatography purification (Shim-pack GIS C18 x 250mm,5 μm; 0.01% formic acid-water/acetonitrile) to give compound 30 (50 mg) and compound 31 (5 mg); compound 30: MS: m/z 434.2[ M+1 ]] + The method comprises the steps of carrying out a first treatment on the surface of the Compound 31: MS: m/z 435.2[ M+1 ]] + 。
Example 32: preparation of Compound 32
To a reaction flask were added compound 30 (30 mg,0.23mmol,1.0 eq), tetrahydrofuran (2 mL) and 1M hydrochloric acid (0.5 mL), and after the addition, stirring at room temperature for 3 hours, adjusting the pH of the system to 7-8, extracting with ethyl acetate (4 mL) 2 times, concentrating the organic phase, purifying by reverse phase column chromatography (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 32 (3 mg); MS: M/z406.1[ M+1 ]] + 。
Example 33: preparation of Compound 33
Compound 33 was synthesized according to the procedure substantially similar to example 32 (see table 5).
TABLE 5 Structure and Mass Spectrometry data for Compound 33
Example 34: preparation of Compound 34
To a reaction flask, 34-1 (100 mg,0.27mmol,1.0 eq), concentrated sulfuric acid (1 mL) and potassium nitrate (32.4 mg,0.32mmol,1.2 eq) were sequentially added, after the addition was completed, water (4 mL) was added to the system and stirred at room temperature for 2 hours, the pH of the system was adjusted to 8-9 with saturated sodium bicarbonate solution, then ethyl acetate was added for extraction (5 mL) 2 times, the organic phase was concentrated, and reversed phase column chromatography was performed for purification (Shim-pack GIS C1820 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to obtain 34 (70 mg); MS: m/z 409.1[ M+1 ] ] + 。
Example 35: preparation of Compound 35
Compound 35 was synthesized according to the procedure substantially similar to example 34 (see table 6).
TABLE 6 Structure and Mass Spectrometry data for Compound 35
Example 36: preparation of Compound 36
Compound 34 (50 mg,0.12mmol,1.0 eq), methanol (2 mL) and palladium on carbon (10 mg) were added sequentially to a reaction flask, and after the addition was completed, stirring at room temperature for 2 hours, the reaction was filtered, the organic phase was concentrated, and purified by reverse phase column chromatography (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 36 (40 mg); MS: m/z 379.1[ M+1 ]] + 。
Example 37: preparation of Compound 37
Compound 37 was synthesized according to the procedure similar to example 36 (see table 7).
TABLE 7 Structure and Mass Spectrometry data for Compound 37
Example 38: preparation of Compound 38
To a reaction flask, compound 36 (30 mg,0.08mmol,1.0 eq), dichloromethane (2 mL), triethylamine (20 mg,0.2mmol,2.5 eq) and acetyl chloride (9.4 mg,0.12mmol,1.5 eq) were added in this order, after the addition was completed, water (4 mL) and dichloromethane (5 mL) were added after stirring at room temperature for 5 hours, the solution was separated, the organic phase was concentrated, and purified by reverse phase column chromatography (Shim-pack GIS C18 20 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 38 (15 mg); MS: m/z 421.1[ M+1 ] ] + 。
Example 39: preparation of Compound 39
To a reaction flask, compound 8 (45 mg,0.095mmol,1.0 eq), methanol (2 mL), and sodium borohydride (9.4 mg,0.11mmol,1.2 eq) were added in this order, after stirring at room temperature for 5 hours, water (4 mL) and dichloromethane (5 mL) were added, the solution was separated, and after concentrating the organic phase, reversed phase column chromatography purification (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) was performed to give compound 39 (15 mg); MS: m/z 471.2[ M+1 ]] + 。
Example 40: preparation of Compound 40
Into a reaction flask were successively charged Compound 8 (45 mg,0.095mmol,1.0 eq), 1, 2-dichloroethane (2 mL), triethylamine (10.1 mg,0.1mmol,1.0 eq) and NaBH 3 CN (10.2 mg,0.15mmol,1.5 eq) and methylamine hydrochloride (6.8 mg,0.1mmol,1.0 eq), after 5 hours of stirring at room temperature, water (4 mL) and dichloromethane (5 mL) were added, the mixture was separated, the organic phase was concentrated, and purified by reverse phase column chromatography (Shim-pack GIS C18X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 40 (12 mg); MS: M/z484.1[ M+1 ]] + 。
Example 41: preparation of Compound 41
To the reaction flask, compound 37 (36 mg,0.1mmol,1.0 eq), tetrahydrofuran (2 mL), triethylamine (30 mg,0.3mmol,3.0 eq) and CDI (20 mg,0.12mmol,1.2 eq) were successively added, and after stirring at room temperature for 1 hour, methylamine hydrochloride (8.1 mg,0.12mmol,1.2 eq) was added, Stirring was continued for 5 hours, then water (4 mL) and dichloromethane (5 mL) were added to the system, the solution was separated, and after concentration of the organic phase, reversed phase column chromatography purification (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) gave compound 41 (14 mg); MS: m/z 408.1[ M+1 ]] + 。
Example 42: preparation of Compound 42
Compound 42 was synthesized according to the procedure substantially similar to example 41 (see table 8).
TABLE 8 Structure and Mass Spectrometry data for Compound 42
Example 43: preparation of Compound 43
To a reaction flask was added compound 43-1 (37.9 mg,0.1mmol,1.0 eq) in sequence, obtained using a synthetic route similar to compound 10, wherein compound 1-2a was replaced with 4, 6-dihydroxypyrimidine, intermediate 1-1 was replaced with (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethylamine), isopropanol (2 mL) and thionyl chloride (0.1 mL), the system was warmed to 50 degrees and stirred for 1 hour, then water (4 mL) and dichloromethane (5 mL) were added to the system, the solution was separated, the organic phase was concentrated, and purified by reverse phase column chromatography (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 43 (8 mg); MS: m/z 422.1[ M+1 ]] + 。
Example 44: preparation of Compound 44
To a reaction flask, compound 43-1 (37.9 mg,0.1mmol,1.0 eq), DMF (2 mL), EDCI (28.8 mg,0.15mmol,1.5 eq), HOBT (20.2 mg,0.15mmol,1.5 eq) and benzyl alcohol were added in this order, stirred at room temperature for 5 hours after the addition, then water (4 mL) and dichloromethane were added to the system (5 mL), separating, concentrating the organic phase, and purifying by reverse phase column chromatography (Shim-pack GIS C18X 250mm,5 μm;0.01% formic acid-water/acetonitrile) to obtain compound 44 (12 mg); MS: m/z 470.0[ M+1 ]] + 。
Examples 45 to 46: preparation of Compounds 45 to 46
Compound 45 to compound 46 were synthesized according to the procedure substantially similar to example 44 (see table 9).
TABLE 9 Structure and Mass Spectrometry data for Compounds 45 to 46
Example 47: preparation of Compound 47
To a reaction flask, compound 37 (35 mg,0.1mmol,1.0 eq), dichloromethane (2 mL), triethylamine (20 mg,0.2mmol,2.0 eq) and methylsulfonyl chloride (17.5 mg,0.15mmol,1.5 eq) were added in this order, after the addition was completed, water (4 mL) and dichloromethane (5 mL) were added and reacted at room temperature for 5 hours, the solution was separated, and after the organic phase was concentrated, reverse phase column chromatography was performed to purify (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 47 (17 mg); MS: m/z 429.1[ M+1 ]] + 。
Example 48: preparation of Compound 48
Into a reaction flask, compound 37 (35 mg,0.1mmol,1.0 eq), tetrahydrofuran (2 mL), triethylamine (20 mg,0.2mmol,2.0 eq) and carbon disulfide (9.2 mg,0.12mmol,1.2 eq) were added in this order, and stirred at room temperatureMethyl iodide (17.1 mg,0.12mmol,1.2 eq) was added after 1 hour, after the addition, stirring was continued at room temperature for 5 hours, water (4 mL) and methylene chloride (5 mL) were added, the solution was separated, and the organic phase was concentrated and purified by reverse phase column chromatography (Shim-pack GIS C18 x 250mm,5 μm;0.01% formic acid-water/acetonitrile) to give compound 48 (10 mg); MS: m/z 441.1[ M+1 ] ] + 。
Examples 49-50 and 52-54: preparation of Compounds 49 and 50 and 52 to 54
Compound 49 and compound 50 and compound 52 to compound 54 were synthesized according to the procedure substantially similar to example 38 (see table 10).
TABLE 10 Structure and Mass Spectrometry data for Compounds 49 and 50 and 52 to 54
Experimental example 1: KRAS-G12C/SOS1 inhibition Activity test
Inhibition of KRAS-G12C/SOS1 by the compounds of the present invention was evaluated by using the Binding Assay method by performing inhibition Assay on KRAS-G12C/SOS 1. The test concentration of the compound was 500nM, single concentration, multiplex well assay.
1.1 Experimental materials
1.1.1 reagents and consumables
Reagent name | Suppliers of goods |
KRAS G12C/SOS Binding kit | Cisbio |
DMSO | Sigm |
384-well white plate | PerkinElmer |
1.1.1 instruments
Centrifuge (manufacturer: eppendorf type 5430)
Enzyme label instrument (manufacturer: perkin Elmer, model: envision)
Echo 550 (manufacturer: labcyte, model: echo 550)
1.2 kinase reaction procedure
(1) Preparation of the compound: test compounds were tested at 500nM in 384 well plates diluted to 200-fold final concentration in 100% DMSO. 50nl of compound at 200-fold final concentration was transferred to the 384 well plate of interest using a dispenser Echo 550. 50nl of 100% DMSO was added to each of the negative control wells and the positive control wells.
(2) Tag1-SOS1 solution was prepared at 4-fold final concentration with dilution buffer.
(3) 2.5 μl of a 4-fold final concentration of Tag1-SOS1 solution was added to 384-well plates.
(4) Tag2-KRAS-G12C solution was prepared at 4-fold final concentration with dilution buffer.
(5) 2.5. Mu.l of Tag2-KRAS-G12C solution with a final concentration of 4 times was added to each of the compound well and the positive control well; 2.5. Mu.l of dilution buffer was added to the negative control wells.
(6) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 15 minutes after shaking and mixing.
(7) A1-fold final concentration of Anti-Tag1-TB3+ solution and a 1-fold final concentration of Anti-Tag2-XL665 solution were prepared with the detection buffer, and after mixing the two solutions, 5. Mu.l of Mix solution was added to each well.
(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 120 minutes after shaking and mixing.
(9) Em665/620 was recorded using Envision microplate reader readings.
1.3 data analysis
1.3.1 inhibition ratio calculation formula
Wherein: min signal represents the mean value of absorbance in pure DMSO wells; max signal represents the average value of absorbance of wells of the mixture of enzyme, substrate, detection reagent, DMSO; compound signal represents the average absorbance of the sample wells.
1.3.2 fit efficacy Curve
The log of compound concentration was used as the X-axis, the percent inhibition was Y-axis, and the analytical software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope fit was used to obtain IC50 values for each compound for enzyme activity.
The fitting formula is: y=bottom+ (Top-Bottom)/(1+10
Wherein: top represents the Top platform, and the Top standard of the curve is generally 80% -120%; bottom represents the Bottom plateau and the Bottom of the curve is typically between-20% and 20%.
In vitro inhibition Activity test results (expressed as inhibition Rate and IC 50)
Compounds of formula (I) | KRAS-G12C/SOS1 inhibition rate | IC50 |
5 | 95.0% | 36nm |
6 | 90.9% | 25nm |
7 | 90.6% | 175nm |
The compound provided by the invention has excellent in-vitro inhibition activity against KRAS-G12C/SOS1, can be used as a small-molecule SOS1 inhibitor, has the effects of inhibiting cell proliferation and angiogenesis, has good anti-tumor activity, and has good effect on treating mammal (including human) tumor diseases.
Although the invention has been illustrated by the specific examples hereinbefore, it should not be construed as limited thereby, but rather the invention encompasses the generic aspects hereinbefore disclosed and that various modifications can be made and embodiments can be made without departing from the spirit and scope of the invention.
Claims (7)
1. The following compounds or pharmaceutically acceptable salts thereof:
2. a pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
3. A pharmaceutical formulation made from the compound of claim 1 or a pharmaceutically acceptable salt thereof, or from the pharmaceutical composition of claim 2.
4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof according to claim 2 or a pharmaceutical formulation according to claim 3 for the preparation of a medicament for the prevention and/or treatment of a disease mediated at least in part by SOS1 protein.
5. The use according to claim 4, characterized in that,
the disease mediated at least in part by SOS1 protein is cancer.
6. The use according to claim 5, characterized in that,
the cancer is 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, 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.
7. A pharmaceutical combination comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 2, or a pharmaceutical formulation according to claim 3, and at least one additional cancer therapeutic agent.
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