CN116801883A - 一类杂芳环化合物、其制备方法及用途 - Google Patents
一类杂芳环化合物、其制备方法及用途 Download PDFInfo
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- CN116801883A CN116801883A CN202280010512.9A CN202280010512A CN116801883A CN 116801883 A CN116801883 A CN 116801883A CN 202280010512 A CN202280010512 A CN 202280010512A CN 116801883 A CN116801883 A CN 116801883A
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- alkylene
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 337
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title abstract description 136
- 102200006539 rs121913529 Human genes 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 34
- 239000002207 metabolite Substances 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 6
- -1 hydroxy, amino Chemical group 0.000 claims description 237
- 125000000217 alkyl group Chemical group 0.000 claims description 183
- 150000002367 halogens Chemical class 0.000 claims description 83
- 229910052736 halogen Inorganic materials 0.000 claims description 82
- 125000000623 heterocyclic group Chemical group 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 75
- 125000001424 substituent group Chemical group 0.000 claims description 63
- 150000002431 hydrogen Chemical class 0.000 claims description 57
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 46
- 125000001188 haloalkyl group Chemical group 0.000 claims description 41
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 19
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- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 238000001361 intraarterial administration Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 189
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000006243 chemical reaction Methods 0.000 description 127
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- 238000004949 mass spectrometry Methods 0.000 description 85
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 62
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 60
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 238000010511 deprotection reaction Methods 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 38
- 239000003960 organic solvent Substances 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
- 239000003054 catalyst Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 34
- 229910052751 metal Inorganic materials 0.000 description 33
- 239000002184 metal Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 28
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 27
- 229910000024 caesium carbonate Inorganic materials 0.000 description 27
- 239000003480 eluent Substances 0.000 description 27
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 239000007805 chemical reaction reactant Substances 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 238000005859 coupling reaction Methods 0.000 description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 17
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 12
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- DLXBGTIGAIESIG-UHFFFAOYSA-N 1,8-dibromonaphthalene Chemical compound C1=CC(Br)=C2C(Br)=CC=CC2=C1 DLXBGTIGAIESIG-UHFFFAOYSA-N 0.000 description 10
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- IZHOIESLUBOCOT-INIZCTEOSA-N 7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-3,5,6,8-tetrahydropyrido[3,4-d]pyrimidin-4-one Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)O)OC[C@H]1N(CCC1)C IZHOIESLUBOCOT-INIZCTEOSA-N 0.000 description 3
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- 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
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- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110291639 | 2021-03-18 | ||
| CN202110291639X | 2021-03-18 | ||
| CN202111123301X | 2021-09-24 | ||
| CN202111123301 | 2021-09-24 | ||
| CN2021112270641 | 2021-10-21 | ||
| CN202111227064 | 2021-10-21 | ||
| PCT/CN2022/081102 WO2022194192A1 (fr) | 2021-03-18 | 2022-03-16 | Composé hétéroaromatique, son procédé de préparation et son utilisation |
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| CN116801883A true CN116801883A (zh) | 2023-09-22 |
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| CN202280010512.9A Pending CN116801883A (zh) | 2021-03-18 | 2022-03-16 | 一类杂芳环化合物、其制备方法及用途 |
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| CN (1) | CN116801883A (fr) |
| WO (1) | WO2022194192A1 (fr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023154766A1 (fr) | 2022-02-09 | 2023-08-17 | Quanta Therapeutics, Inc. | Modulateurs de kras et leurs utilisations |
| CN118434748A (zh) * | 2022-04-15 | 2024-08-02 | 杭州多域生物技术有限公司 | 一种六元并六元化合物、制备方法、药物组合物和应用 |
| WO2024186680A1 (fr) * | 2023-03-03 | 2024-09-12 | Frontier Medicines Corporation | Procédés de préparation de composés de pyrrolizidine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP7039489B2 (ja) * | 2016-05-18 | 2022-03-22 | ミラティ セラピューティクス， インコーポレイテッド | Ｋｒａｓ ｇ１２ｃ阻害剤 |
| US10689377B2 (en) * | 2017-11-15 | 2020-06-23 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
| WO2020035031A1 (fr) * | 2018-08-16 | 2020-02-20 | Genentech, Inc. | Composés cycliques condensés |
| CN112300153B (zh) * | 2019-07-26 | 2023-06-13 | 博瑞生物医药（苏州）股份有限公司 | 一种杂环化合物、药物组合物和用途 |
| US20210040089A1 (en) * | 2019-08-07 | 2021-02-11 | Jacobio Pharmaceuticals Co., Ltd. | Kras mutant protein inhibitors |
| WO2021106231A1 (fr) * | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | Composé ayant une activité inhibitrice contre la mutation kras g12d |
| CN114057776A (zh) * | 2021-10-31 | 2022-02-18 | 南京碳硅人工智能生物医药技术研究院有限公司 | 一种具有抗癌活性的嘧啶并哌啶衍生物的新合成方法 |
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