WO2024067744A1 - Quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation - Google Patents
Quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation Download PDFInfo
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- WO2024067744A1 WO2024067744A1 PCT/CN2023/122243 CN2023122243W WO2024067744A1 WO 2024067744 A1 WO2024067744 A1 WO 2024067744A1 CN 2023122243 W CN2023122243 W CN 2023122243W WO 2024067744 A1 WO2024067744 A1 WO 2024067744A1
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- group
- substituted
- alkyl
- compound
- cancer
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- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title abstract description 41
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
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- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 claims abstract description 22
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- 101150100839 Sos1 gene Proteins 0.000 claims abstract description 22
- 230000000694 effects Effects 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims description 46
- 238000006467 substitution reaction Methods 0.000 claims description 35
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000005959 oncogenic signaling Effects 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 1
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 102200006531 rs121913529 Human genes 0.000 description 1
- 102200006539 rs121913529 Human genes 0.000 description 1
- 102200006538 rs121913530 Human genes 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 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
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229950001415 tucidinostat Drugs 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the invention belongs to the field of medicines, and specifically relates to a heterocyclic substituted quinazoline and a preparation method and application thereof.
- Lung cancer is one of the major causes of cancer-related death in humans.
- Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, of which NSCLC accounts for 85% of all lung cancer patients.
- SCLC small cell lung cancer
- NSCLC non-small cell lung cancer
- the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
- the non-small cell lung cancer market has maintained sustained growth, and the global market is expected to reach US$54 billion in 2023.
- chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
- molecular targeted drugs have gradually become a research hotspot due to their high selectivity, relatively small side effects, and the ability to achieve precise treatment.
- EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.
- ALK inhibitors such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclatinib, etc.
- VEGFR inhibitors Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.
- KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) (30% vs 10%).
- the most common mutations occur in codons 12 and 13, and the most common mutations include G12C, G12V, and G12D. So far, no drugs targeting KRAS mutations have been approved for marketing.
- KRAS protein switches between inactive and activated states.
- GDP guanosine diphosphate
- GTP guanosine triphosphate
- the conversion of KRAS between inactive and activated states is regulated by two types of factors.
- One type is guanine nucleotide exchange factors (GEFs), which catalyze the binding of KRAS to GTP, thereby promoting the activation of KRAS, including SOS1 protein.
- GEFs guanine nucleotide exchange factors
- GAP GTPase activating protein
- SOS protein is the main one found to be involved in tumors.
- SOS proteins are widely expressed in vivo and contain two isoforms, SOS1 and SOS2.
- Published data indicate that SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Reduced levels of SOS1 lead to reduced proliferation and survival rates in tumor cells carrying KRAS mutations, while KRAS wild-type cell lines were not affected.
- the effects of SOS1 loss cannot be rescued by introducing an SOS1 with a mutation in the catalytic site, indicating an important role for SOS1 GEF activity in KRAS mutant cancer cells.
- Proteolysis is crucial and strictly regulated in the normal life activities of cells. Its process is mainly completed through the participation of the ubiquitinase system.
- the protein to be decomposed is marked by the E1, E2 and E3 ubiquitin ligase systems, and then recognized and hydrolyzed by proteases.
- Proteolysis regulator molecules are bifunctional active compounds. One end of the molecule is tightly bound to the target protein, and the other end is bound to the E3 ubiquitin ligase, and the two ends are connected by various connecting chains.
- This bifunctional molecule can simultaneously recognize the target protein and the E3 ubiquitin ligase in the body, and after the target protein and the E3 ubiquitin ligase are brought closer, the target protein is ubiquitinated and then hydrolyzed through the ubiquitin-proteasome pathway. After the target protein is hydrolyzed, this bifunctional molecule can be released to participate in the next cycle of proteolysis, thereby having a catalytic effect. Therefore, in clinical practice, a low drug dose can be used to achieve efficient therapeutic effects.
- SOS1 target protein is pathologically associated with a variety of diseases
- new SOS1 inhibitors are currently needed for clinical treatment.
- Highly selective and highly active heterocyclic substituted quinazolines can more effectively treat diseases such as cancer caused by KRAS mutations, as well as have the potential to reduce off-target effects, and therefore have a more urgent clinical need.
- the purpose of the present invention is to provide a novel heterocyclic substituted quinazoline and a preparation method and application thereof.
- the present invention provides a compound, a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein the compound is a compound represented by formula (IA), formula (IB) or formula (IC):
- A is independently selected from the following group of substituted or unsubstituted groups: C 6 -C 14 aryl, or 5-14 membered heteroaryl; wherein the substitution refers to being independently substituted by one or more R;
- X is independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, -C ⁇ CH, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, OX 1 , NHX 1 , or NX 1 X 2 ; wherein the substitution refers to being independently substituted by one or more R;
- X 1 and X 2 are independently selected from the following substituted or unsubstituted groups: C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, or 5-14 membered heteroaryl; wherein the substitution refers to being independently substituted by one or more R;
- Y 1 and Y 2 are each independently selected from CH or N, and Y 1 and Y 2 are not CH at the same time;
- n 1 and n 2 are each independently selected from 1, 2 or 3;
- Z is independently selected from the following group: a substituted or unsubstituted bond, a C 2 -C 18 alkynyl, a C 3 -C 20 cycloalkyl, a 4-20 membered heterocyclyl, a C 3 -C 20 cycloalkylene-C 1 -C 18 alkylene, or a 4-20 membered heterocyclylene-C 1 -C 18 alkylene; wherein the substitution refers to substitution by one or more R;
- P 1 , P 2 , P 3 , P 6 , and P 7 are each independently selected from CR a , or N; wherein R a is independently selected from the following group: H, deuterium, F, chlorine, bromine, -OC 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl;
- P 4 and P 5 are each independently selected from CH 2 or C ⁇ O;
- P 9 is selected from a bond or NH
- P 10 is selected from CH or N;
- Each R is the same or different and is independently selected from the group consisting of H, deuterium, vinyl, ethynyl, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl alcohol, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (4-6 membered heterocyclyl)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyloxy)C 1 -C 6 alkyl, (4-6 membered heterocyclyloxy)C 1 -C 6 alkyl, (C 1 -C 6 alkyl)vinyl, deuterated (C 1 -C 6 alkyl)vinyl, halogenated (C 1 -C 6 alkyl)vinyl, (C 1 -C
- A is a substituted or unsubstituted phenyl group; wherein the substitution refers to being independently substituted by one or more R groups.
- A is selected from:
- X1 is selected from: substituted or unsubstituted C1 - C8 alkyl, substituted or unsubstituted C1 - C8 oxaalkyl, substituted or unsubstituted C3 - C6 cycloalkyl, substituted or unsubstituted C4 - C6 monooxacycloalkyl; wherein the substitution refers to being independently substituted by one or more R.
- X1 is selected from:
- Y 1 is selected from: N
- Y 2 is selected from: N.
- Y 1 is selected from: N
- Y 2 is selected from: CH.
- Y 1 is selected from: CH
- Y 2 is selected from: N.
- Y 1 is selected from: N
- Y 2 is selected from: N or CH.
- n1 is 2 and n2 is 2.
- n1 is 1 and n2 is 1.
- P 1 , P 2 , and P 3 are each independently selected from CH, CF, or N.
- P 1 , P 2 , and P 3 are each independently CH or CF.
- P 1 , P 2 , P 3 , P 6 , P 7 and the bond connecting them form an unsubstituted or one or more Ra- substituted phenyl group.
- X is independently selected from the following substituted or unsubstituted groups: C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, OX 1 , NHX 1 , or NX 1 X 2 ; wherein the substitution refers to being independently substituted by one or more R;
- substitution refers to being independently substituted by one or more R.
- Z is selected from substituted or unsubstituted C 4 -C 6 heterocycloalkylene, or substituted or unsubstituted C 2 -C 6 alkynyl; wherein the substitution refers to being independently substituted by one or more Rs.
- Z is selected from substituted or unsubstituted C 4 -C 6 heterocycloalkylene; wherein the substitution refers to being independently substituted by one or more R.
- Z is selected from the following substituted or unsubstituted groups:
- substitution refers to being independently substituted by one or more R.
- -L 1 -L 2 - is selected from the group consisting of a substituted or unsubstituted bond, a C 1 -C 6 alkyl,
- substitution refers to being independently substituted by one or more R.
- the compound has a structure shown in formula (II):
- A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 3 , P 5 , n 1 , n 2 are as defined above.
- the compound has a structure shown in formula (III):
- A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 5 , n 1 , n 2 are as defined above.
- the compound has a structure shown in formula (IV):
- A, X, Y 1 , Y 2 , L 1 , L, Z, P 2 , P 5 , n 1 , n 2 are as defined above.
- the compound has a structure shown in formula (V):
- A, X, Y 2 , L 1 , L, Z, P 2 , P 5 , n 1 , n 2 are as defined above.
- the compound is selected from the following group:
- A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 of the compound of formula (IA), (IB) or (IC) are independently corresponding groups in the above compounds.
- the present invention provides a method for preparing the compound of the first aspect of the present invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, selected from the following synthetic routes:
- A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 are as defined above.
- the third aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising i) one or more compounds described in the first aspect of the present invention, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and ii) a pharmaceutically acceptable carrier.
- the pharmaceutical composition further comprises one or more therapeutic agents selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obin utuzumab, ofatumumab, vel
- the present invention provides a compound as described in the first aspect of the present invention, its stereoisomers, The variant isomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the use of the pharmaceutical composition according to the third aspect of the present invention, is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to SOS1 activity or expression.
- the disease is cancer.
- the cancer is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
- the present invention provides a method for preventing and/or treating diseases related to SOS1 activity or expression, comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect of the present invention, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described in the third aspect of the present invention.
- the subject is a mammal, such as a human, a rat or a mouse.
- FIG1 is a graph showing the detection of SOS1 and ⁇ -actin contents in H358 cells after treatment with different concentrations of Compound Example A1 for 6 hours.
- alkyl refers to a straight or branched chain alkyl group containing several carbon atoms
- C1 - C18 alkyl refers to a straight or branched chain alkyl group having 1-18 carbon atoms, including alkyl groups of 1, 2, 3 , 4, 5 , 6, 7 , 8 , 9, 10, 11, 12, 13 , 14 , 15, 16, 17 or 18 carbon atoms, and alkyl groups are preferably C1 - C2 , C1-C3, C1- C4 , C1- C5, C1-C6, C1-C7, C1-C8 , C1 - C9 , C1 - C10 , C2 - C3 , C2 - C4 , C2 -C5 , C2 - C6 , C3 - C4 , C3- C5 , C3 - C6 Typical "alkyl” includes, but is not limited to, methyl , eth
- alkylene by itself or as part of another substituent refers to an "alkyl” radical with one hydrogen atom removed.
- the alkylene radical may contain 1 to 18 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
- alkenyl refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl may include any number of carbon atoms, wherein "C2-C18 alkenyl” refers to a straight or branched hydrocarbon having 2-18 carbon atoms and at least one double bond, such as C2 , C2- C3 , C2- C4 , C2 - C5 , C2- C6 , C2- C7 , C2- C8 , C2 - C9 , C2- C10 , C3 , C3- C4 , C3-C5, C3 - C6 , C4 , C4 - C5 , C4- C6, C5 , C5 - C6 , and C6 .
- Alkenyl may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more.
- alkenyl groups include, but are not limited to, vinyl (vinyl group), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
- alkenyl groups may be substituted or unsubstituted.
- alkynyl refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond.
- Alkynyl can include any number of carbon atoms
- C2-C18 alkynyl refers to a straight or branched hydrocarbon having 2-18 carbon atoms and at least one triple bond, such as C2 , C2- C3 , C2- C4 , C2- C5 , C2- C6 , C2 - C7 , C2 -C8, C2 - C9 , C2- C10 , C3 , C3- C4 , C3 - C5 , C3- C6 , C4 , C4- C5 , C4 - C6 , C5 , C5- C6 , and C6 .
- alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.
- cycloalkyl refers to a fully saturated cyclic hydrocarbon group having several carbon atoms
- C 3 -C 20 cycloalkyl refers to a fully saturated cyclic hydrocarbon group having 3-20 carbon atoms, preferably C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10.
- Substituted C 3 -C 20 cycloalkyl refers to one or more positions in the cycloalkyl being substituted, especially 1-4 substituents, which may be substituted at any position, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
- cycloalkyl is intended to include “substituted cycloalkyl”.
- cycloalkylene by itself or as part of another substituent refers to a radical formed by removing two hydrogen atoms from a cycloalkyl group as described above, such as:
- alkylene cycloalkylene refers to the group formed by removing two hydrogen atoms from the above-mentioned cycloalkylalkyl or alkylcycloalkyl, wherein "C1-C18 alkylene C3-C20 cycloalkylene” or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning, preferably, C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: wait.
- heterocyclyl refers to a fully saturated or partially unsaturated cyclic group having a number (greater than or equal to 3) of ring atoms and 1-4 heteroatoms
- 4-20 membered heterocyclyl refers to a fully saturated or partially unsaturated cyclic group having 4-20 ring atoms and 1-4 heteroatoms (including but not limited to 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-12 membered tricyclic system).
- the nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom can also be quaternized.
- the heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
- Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,
- Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.
- heterocyclylene refers to a group formed by removing two hydrogen atoms from the above heterocyclyl, including but not limited to: wait.
- heterocycloalkylene alkylene refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, wherein "4-20 membered heterocycloalkylene C1-C18 alkylene” or "C1-C18 alkylene 4-20 membered heterocycloalkylene” have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to: wait.
- aryl refers to an aromatic cyclic hydrocarbon compound radical having 1-5 rings, particularly monocyclic and bicyclic radicals such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, particularly 1-3 substituents, which may be substituted at any position.
- arylene group refers to a group formed by removing two hydrogen atoms from the above aryl groups.
- heteroaryl refers to a heteroaromatic system containing 1-4 (e.g. 2 or 3) heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, and the heterocyclic group may include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms.
- the heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl, etc.
- pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl, etc.
- Heteroaryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.
- heteroarylene refers to a group formed by removing two hydrogen atoms from the above heteroaryl groups.
- C1-C18 alkoxy refers to a linear or branched or cyclic alkyloxy group having 1 to 18 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group or a C1-C4 alkoxy group.
- C1-C18 alkyleneoxy refers to a group obtained by removing a hydrogen atom from a "C1-C18 alkoxy” group.
- halogen refers to chlorine, bromine, fluorine, iodine.
- halo refers to substitution with halogen.
- deuterated refers to substitution with deuterium ( 2H ).
- hydroxyl refers to a group having the structure OH.
- nitro refers to a group with the structure NO2 .
- cyano refers to a group having the structure CN.
- ester group refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
- amine group refers to a group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.
- amido refers to a group having the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.
- sulfonamido refers to a group with the structure -SO2NRR ', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.
- urea group refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine fragment.
- alkylaminoalkyl refers to a group having the structure -RNHR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.
- dialkylaminoalkyl refers to a group having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl. R, R' and R" may be the same or different in the dialkylamine fragment.
- heterocyclylalkyl refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.
- substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
- the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
- a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
- the substitution may be substitution with one or more substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl, 4-12 membered heterocyclic group, aryl, heteroaryl, C1 - C8 aldehyde group, C2 - C10 acyl group, C2 - C10 ester group, amine group, C1 - C6 alkoxy group, C1 - C10 sulfonyl group, and C1 - C6 urea group, etc.
- substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1 - C6 alkyl, C2 - C6 alkenyl, C2 -
- any heteroatom that does not have sufficient hydrogen atoms to complete its valence is assumed to have sufficient hydrogen atoms to complete its valence.
- a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.
- the term "plurality” refers to two or more, such as 2, 3, 4, 5 or 6.
- compounds of the present invention refers to compounds represented by formula (IA), formula (IB) or formula (IC), and also includes stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds:
- A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 3 , P 4 , P 5 , n 1 , n 2 are as described above.
- salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts.
- the term "salt” used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base.
- the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions (“inner salts”) that may be formed are included in the scope of the term "salt".
- compositions of the present invention may form salts, for example, compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.
- the compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
- Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide.
- salts such as hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.
- hydroxyethanesulfonates e.g., 2-hydroxyethanesulfonate
- Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
- Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc.
- Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.
- alkyl halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
- dialkyl sulfates such as dimethyl sulfate, diethyl s
- Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
- the term "prodrug” herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease.
- the compounds of the present invention include solvates, such as hydrates.
- the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.
- All stereoisomers of the compounds are contemplated by the present invention.
- Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer with a particular activity), or may be a mixture, such as a racemate, or a mixture with all other stereoisomers or a portion thereof.
- the chiral centers of the present invention have two configurations, S or R, according to the theory. The definition was proposed by the International Union of Applied Chemistry (IUPAC) in 1974.
- Racemic forms can be resolved by physical methods, such as fractional crystallization, or by derivatization into diastereoisomers and separate crystals, or by chiral column chromatography.
- Individual optical isomers can be obtained from racemates by appropriate methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.
- the compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.
- All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form.
- the definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
- Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures.
- asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.
- the ratio of isomers contained in the mixture of isomers can be various.
- the mixture of only two isomers there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention.
- Similar ratios that are easily understood by those of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present invention.
- the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers.
- isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H , 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl , respectively.
- the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
- Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3H and 14C , are also included, which are useful in tissue distribution experiments of drugs and substrates.
- Tritium, i.e. 3H and carbon-14, i.e. 14C are relatively easy to prepare and detect. They are the first choice among isotopes.
- Isotopically labeled compounds may be prepared by conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents. The protocols disclosed in the examples can be prepared.
- a synthesis of a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer.
- a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.
- the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope.
- the term “substituted” appears before or after the term “optional” or “optionally”, and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position.
- substituted used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
- heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence.
- the present invention is not intended to limit the allowed substitution of organic compounds in any way.
- the present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
- stable refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.
- the preparation method of the compound of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
- the compounds of the present invention can also be optionally combined with various synthetic methods described in this specification or known in the art and easily prepared, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.
- the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
- A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 are as defined above.
- compositions Use and methods of administration
- the pharmaceutical composition of the present invention comprises the above active ingredients and a pharmaceutically acceptable carrier.
- the compounds of the present invention can reduce the activity and expression of SOS1, promote SOS1 protein degradation and/or reduce the level of SOS1, and thus can be used to prevent and/or treat diseases related to SOS1 activity or expression.
- the pharmaceutical composition of the present invention can be used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
- the cancer is a cancer caused by KRAS mutation.
- the cancer includes (but is not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
- SCLC small cell lung cancer
- NSCLC non-small cell lung cancer
- breast cancer breast cancer
- prostate cancer esophageal cancer
- colorectal cancer colorectal cancer
- bone cancer kidney cancer
- gastric cancer gastric cancer
- liver cancer colon cancer
- melanoma lymphoma
- blood cancer brain tumor
- myeloma myeloma
- soft tissue sarcoma pancreatic cancer
- the compounds of the present invention may be used in combination with other drugs known to treat or improve similar conditions.
- the combination When the combination is administered, the original drug administration and dosage can remain unchanged, and the compound of the present invention is taken simultaneously or subsequently.
- a pharmaceutical composition containing one or more known drugs and the compound may be preferably used.
- Drug combination also includes taking the compound of the present invention and one or more other known drugs in overlapping time periods.
- the dosage of the compound or known drug may be lower than the dosage of the compound or known drug when taken alone.
- the drugs or active ingredients that can be used in combination with the compounds of the present invention include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab,
- the dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.
- the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
- safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
- Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example,
- Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
- an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
- composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
- suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
- the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
- the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.
- the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to form a pharmaceutical composition.
- the present invention also provides a treatment method, which comprises the steps of administering the compound of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition of the present invention to a subject in need of treatment, for selectively inhibiting SOS1.
- the present invention has the following main advantages:
- the compound can selectively promote the hydrolysis of SOS1 protein, thereby preventing and/or treating diseases related to SOS1 activity or expression (especially high selectivity for tumor cells), with high activity and good safety;
- the compounds of the present invention can inhibit cell proliferation in a catalytic amount. They can circulate in the cells to degrade target proteins, thereby reducing the dosage, extending the administration cycle, and achieving a safe and effective anti-tumor effect;
- the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and/or lower toxic side effects.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
- NMR NMR was measured using a Bruker AVANCE-400 NMR spectrometer.
- the measurement solvents included deuterated dimethyl sulfoxide (DMSO), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD).
- DMSO deuterated dimethyl sulfoxide
- CD 3 COCD 3 deuterated acetone
- CDCl 3 deuterated chloroform
- CD 3 OD deuterated methanol
- Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).
- LC-MS Liquid chromatography-mass spectrometry
- the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
- Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
- the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.
- Step 1 Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindole-1,3-dione
- Step 2 Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-4-carboxaldehyde
- Step 1 Preparation of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)benzoate
- Step 2 Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-formylbenzoate
- the resulting mixture was reacted at 65° C. for 16 h under nitrogen protection, then diluted with ice water (50 mL) and extracted with EtOAc (100 mL*2). The combined organic phase was washed with saturated brine (50 mL*3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.60 g, 4.98 mmol, 61.2% yield).
- Step 3 Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindole-2-yl)piperidin-2,6-dione
- Step 4 Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5-yl)piperidine-4-carboxaldehyde
- Step 2 Preparation of 3-(5-(3-(4-(dimethoxymethyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione
- Step 3 Preparation of 1-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5-yl)prop-2-yn-1-yl)piperidine-4-carboxaldehyde
- Step 4 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-bromo-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
- Step 5 Preparation of tert-butyl 4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline-7-yl)piperazine-1-carboxylate
- Step 6 Preparation of tert-butyl 4-(4-(((R)-1-(3-(((benzyloxy)carbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazine-1-carboxylate
- Step 7 Preparation of benzyl (3-((R)-1-((2-methyl-7-(piperazin-1-yl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate
- Step 3 Preparation of 1-(2-chloro-5-(4-(dimethoxymethyl)piperidin-1-carboxyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
- HATU (1.06 g, 2.79 mmol, 1.50 eq) and DIEA (481 mg, 3.72 mmol, 648 ⁇ L, 2.00 eq) were added to a solution of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (0.500 g, 1.86 mmol, 1.00 eq) in DMF (20 mL). The reaction mixture was reacted at 25°C for 0.5 h, and then 4-(dimethoxymethyl)piperidine (356 mg, 2.23 mmol, 1.20eq).
- Step 4 Preparation of 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidine-4-carboxaldehyde
- Step 1 Preparation of benzyl (3-((1R)-1-((7-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate
- Step 2 Preparation of 5-(4-((4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
- Example A6 3-(5-(3-(4-(4-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione
- Example B1 (3-((R)-1-((7-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-trifluoromethyl(phenyl)carbamic acid benzyl ester
- Example B2 1-(5-(4-(4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione
- Example B3 1-(5-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione
- Example B4 1-(5-(4-((4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
- Example B5 1-(5-(4-(4-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
- the cells were inoculated into a) 384 culture plate, and the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of culture medium only. Centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%, and incubated in a 37°C, 5% CO2 constant temperature incubator for 7 days.
- the luminescence value was read using Envision multi-function microplate reader.
- the structure of the reference compound BI-3406 is as follows:
- IR (%) (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%.
- the inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate, and IC 50 .
- the experimental results are shown in Table 3.
- Inoculate tumor cells e.g. H358, 5X105-1X06
- a culture dish (2D, P100mm dish) and culture for 2-4 days until 70-80% saturation;
Abstract
La présente invention concerne une quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation. Spécifiquement, le composé de la présente invention a une structure représentée par la formule (IA), la formule (IB) ou la formule (IC), et le composé a un très bon effet de régulation sélective sur l'hydrolyse de SOS1.
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WO2022061348A1 (fr) * | 2020-09-16 | 2022-03-24 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques |
CN115043817A (zh) * | 2021-03-09 | 2022-09-13 | 苏州泽璟生物制药股份有限公司 | Sos1蛋白水解调节剂及其制备方法和应用 |
WO2022197862A1 (fr) * | 2021-03-17 | 2022-09-22 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques associées, et leurs applications thérapeutiques |
WO2022266248A1 (fr) * | 2021-06-16 | 2022-12-22 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques |
US20230293702A1 (en) * | 2022-03-16 | 2023-09-21 | Biotheryx, Inc. | Quinazolines, pharmaceutical compositions, and therapeutic applications |
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WO2022061348A1 (fr) * | 2020-09-16 | 2022-03-24 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques |
CN115043817A (zh) * | 2021-03-09 | 2022-09-13 | 苏州泽璟生物制药股份有限公司 | Sos1蛋白水解调节剂及其制备方法和应用 |
WO2022188819A1 (fr) * | 2021-03-09 | 2022-09-15 | 苏州泽璟生物制药股份有限公司 | Modulateur de protéolyse sos1, son procédé de préparation et son application |
WO2022197862A1 (fr) * | 2021-03-17 | 2022-09-22 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques associées, et leurs applications thérapeutiques |
WO2022266248A1 (fr) * | 2021-06-16 | 2022-12-22 | Biotheryx, Inc. | Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques |
US20230293702A1 (en) * | 2022-03-16 | 2023-09-21 | Biotheryx, Inc. | Quinazolines, pharmaceutical compositions, and therapeutic applications |
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