CN115916765A - 吡啶或嘧啶类衍生物及其制备方法和用途 - Google Patents
吡啶或嘧啶类衍生物及其制备方法和用途 Download PDFInfo
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- CN115916765A CN115916765A CN202180044805.4A CN202180044805A CN115916765A CN 115916765 A CN115916765 A CN 115916765A CN 202180044805 A CN202180044805 A CN 202180044805A CN 115916765 A CN115916765 A CN 115916765A
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- amino
- cyano
- alkyl
- dichlorophenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000003230 pyrimidines Chemical class 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 67
- 239000003814 drug Substances 0.000 claims abstract description 18
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 6
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 5
- 229940125528 allosteric inhibitor Drugs 0.000 claims abstract description 4
- -1 alkoxyRadical Chemical group 0.000 claims description 344
- 150000001875 compounds Chemical class 0.000 claims description 157
- 125000000623 heterocyclic group Chemical group 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 79
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 229910005965 SO 2 Inorganic materials 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 125000002619 bicyclic group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 206010029260 Neuroblastoma Diseases 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
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- 206010016654 Fibrosis Diseases 0.000 claims description 6
- 208000005101 LEOPARD Syndrome Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010062901 Multiple lentigines syndrome Diseases 0.000 claims description 6
- 206010029748 Noonan syndrome Diseases 0.000 claims description 6
- 208000010708 Noonan syndrome with multiple lentigines Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 230000004761 fibrosis Effects 0.000 claims description 6
- 208000026278 immune system disease Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000029257 vision disease Diseases 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 claims description 5
- 206010027476 Metastases Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 208000037538 Myelomonocytic Juvenile Leukemia Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 150000007942 carboxylates Chemical group 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 5
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 claims description 5
- 230000009401 metastasis Effects 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 277
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
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- 239000000243 solution Substances 0.000 description 178
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 112
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 91
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 80
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 78
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 66
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
- 239000007791 liquid phase Substances 0.000 description 41
- 238000000926 separation method Methods 0.000 description 41
- 238000000605 extraction Methods 0.000 description 40
- 238000005191 phase separation Methods 0.000 description 40
- 239000000047 product Substances 0.000 description 39
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 36
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 36
- 238000000746 purification Methods 0.000 description 34
- 229910052786 argon Inorganic materials 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 30
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 28
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 229910000160 potassium phosphate Inorganic materials 0.000 description 25
- 235000011009 potassium phosphates Nutrition 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 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 24
- TYIKXPOMOYDGCS-UHFFFAOYSA-N (2,3-dichlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1Cl TYIKXPOMOYDGCS-UHFFFAOYSA-N 0.000 description 22
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- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 12
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- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 9
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- 125000004122 cyclic group Chemical group 0.000 description 7
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- 239000001301 oxygen Substances 0.000 description 7
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- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 5
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 5
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
本发明涉及吡啶或嘧啶类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式(I)所示的吡啶或嘧啶类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是SHP2变构抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同,
Description
PCT国内申请,说明书已公开。
Claims (23)
- PCT国内申请,权利要求书已公开。
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PCT/CN2021/105100 WO2022007869A1 (zh) | 2020-07-10 | 2021-07-08 | 吡啶或嘧啶类衍生物及其制备方法和用途 |
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CA3127361A1 (en) * | 2019-03-07 | 2020-09-10 | Merck Patent Gmbh | Carboxamide-pyrimidine derivatives as shp2 antagonists |
JP2024516450A (ja) | 2021-05-05 | 2024-04-15 | レボリューション メディシンズ インコーポレイテッド | 共有結合性ras阻害剤及びその使用 |
EP4334321A1 (en) | 2021-05-05 | 2024-03-13 | Revolution Medicines, Inc. | Ras inhibitors |
US20220396589A1 (en) | 2021-05-05 | 2022-12-15 | Revolution Medicines, Inc. | Ras inhibitors |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
CN116332908B (zh) * | 2023-03-21 | 2024-07-02 | 杭州医学院 | 一种shp2变构抑制剂及其制备方法和应用 |
WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
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WO2005085212A1 (ja) * | 2004-03-04 | 2005-09-15 | Astellas Pharma Inc. | 置換ピリミジン誘導体 |
WO2020063760A1 (en) * | 2018-09-26 | 2020-04-02 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
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WO2020181283A1 (en) * | 2019-03-07 | 2020-09-10 | Merck Patent Gmbh | Carboxamide-pyrimidine derivatives as shp2 antagonists |
CN114761394A (zh) * | 2020-01-16 | 2022-07-15 | 浙江海正药业股份有限公司 | 吡啶或嘧啶类衍生物及其制备方法和用途 |
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JP6878316B2 (ja) * | 2015-06-19 | 2021-05-26 | ノバルティス アーゲー | Shp2の活性を阻害するための化合物および組成物 |
CN110431134A (zh) * | 2017-01-23 | 2019-11-08 | 锐新医药公司 | 作为变构shp2抑制剂的吡啶化合物 |
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2021
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