WO2024056063A1 - Composé contenant de l'hexahydro-spiro [cyclopropane-1,2'-pyrrolizine] - Google Patents
Composé contenant de l'hexahydro-spiro [cyclopropane-1,2'-pyrrolizine] Download PDFInfo
- Publication number
- WO2024056063A1 WO2024056063A1 PCT/CN2023/119057 CN2023119057W WO2024056063A1 WO 2024056063 A1 WO2024056063 A1 WO 2024056063A1 CN 2023119057 W CN2023119057 W CN 2023119057W WO 2024056063 A1 WO2024056063 A1 WO 2024056063A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkylene
- compound
- independently selected
- alkyl
- alternatively
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 276
- JQCHEWUYSREYAK-UHFFFAOYSA-N spiro[1,2,3,5,7,8-hexahydropyrrolizine-6,1'-cyclopropane] Chemical compound C1C2(CN3CCCC13)CC2 JQCHEWUYSREYAK-UHFFFAOYSA-N 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- -1 methoxy, difluoromethyl Chemical group 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- 125000002947 alkylene group Chemical group 0.000 claims description 84
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 150000002367 halogens Chemical class 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 61
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 125000003282 alkyl amino group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 33
- 125000004043 oxo group Chemical group O=* 0.000 claims description 33
- 229910052805 deuterium Inorganic materials 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 13
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 7
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 4
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 229920001296 polysiloxane Polymers 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- 239000000243 solution Substances 0.000 description 96
- 238000006243 chemical reaction Methods 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 239000012071 phase Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 125000001309 chloro group Chemical group Cl* 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- 206010028980 Neoplasm Diseases 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 20
- 125000001246 bromo group Chemical group Br* 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 125000004663 dialkyl amino group Chemical group 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 102200006539 rs121913529 Human genes 0.000 description 14
- 125000000000 cycloalkoxy group Chemical group 0.000 description 13
- 125000004992 haloalkylamino group Chemical group 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 125000005553 heteroaryloxy group Chemical group 0.000 description 13
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000004104 aryloxy group Chemical group 0.000 description 12
- 230000035772 mutation Effects 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004438 haloalkoxy group Chemical group 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
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- 238000002953 preparative HPLC Methods 0.000 description 8
- 238000001308 synthesis method Methods 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
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- 230000000694 effects Effects 0.000 description 7
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
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- 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 6
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Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
-
- 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
-
- 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
- C07D471/06—Peri-condensed systems
-
- 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
- C07D471/08—Bridged systems
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- 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
- C07D471/10—Spiro-condensed systems
Definitions
- the present disclosure relates to a series of compounds containing hexahydrospirocycle [cyclopropane-1,2'-pyrrozine], specifically to the compound represented by formula (III), its stereoisomers and pharmaceutically acceptable salts thereof.
- KRAS is one of the widely expressed RAS protein family members (KRAS, NRAS and HRAS). It participates in the transduction regulation of extracellular signals to intracellular downstream signals by binding to GTP (on) or GDP (off).
- GTP on
- GDP off
- protein mutations It often destroys its own GTP hydrolase activity, causing its own long-term activation, causing excessive activation of downstream molecules, thereby promoting abnormal cell proliferation and the transformation of cancer cells.
- Due to the shallow pocket of the KRAS protein and strong GTP binding ability cells contain a large amount of GTP. Therefore, even though researchers have been exploring for more than 30 years, they still cannot develop an effective KRAS targeted inhibitor, so that the KRAS gene is called “Untargetable” genes.
- the G12D mutation is a relatively common subtype of KRAS gene mutations, which refers to the mutation of glycine (G) on No. 12 to aspartic acid (D).
- KRAS G12D mutation is the most common in pancreatic cancer. According to the data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), about 46% of pancreatic cancer, 15% of colorectal cancer and 5% of non-small cell Lung cancer can develop KRAS G12D mutations.
- KRAS G12D mutant protein As a cutting-edge target, KRAS G12D mutant protein has not yet entered clinical research with small molecule inhibitors, and only a few preclinical studies have been reported.
- MIRATI THERAPEUTICS, INC published a patent for KRAS G12D small molecule inhibitors in 2021 (WO2021041671). The patent disclosed a series of pyridopyrimidine compounds with high KRAS G12D activity.
- n is selected from 0, 1, 2, 3, 4, or 5;
- n is selected from 0, 1, 2, 3, 4, 5, or 6;
- R 6 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, or halo C 1-6 alkoxy;
- R 7 is selected from H, -NR 7a R 7b , -C(O)R 7b , -C(O)OR 7b , -C(O)OC 1-6 alkylene OC(O)R 7b , -C( O)OC 1-6 alkylene NR 7a C(O)R 7b , -C(O)NR 7a R 7b , -C(O)NR 7a C 1-6 alkyleneNR 7a C(O)R 7b , or -C(O)NR 7a C 1-6 alkylene OC( O)R 7b ;
- R 7a is independently selected from H, or C 1-6 alkyl
- R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 Cycloalkyl C 1-6 alkylene, or 3-12 membered heterocyclyl C 1-6 alkylene;
- Each R 7c is independently selected from deuterium, oxo, halogen, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1 -4 -alkylamino, di-C 1-4 alkylamino, halo - C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 Alkylamino, or halogenated di-C 1-4 alkylamino;
- Each R 8 is independently selected from halogen, -CN, -OH, -NH 2 , or the following groups optionally substituted by one or more R 8a : C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylamino group, di-C 1-6 alkylamino group, tri-C 1-6 alkyl silicone base, C 1-3 alkoxy C 1-3 alkylene , C 1-3 alkylthio C 1-3 alkylene, C 1-3 alkylamino C 1-3 alkylene , di - C 1 -3 alkylamino C 1-3 alkylene group, or tri-C 1-3 alkylsilyl C 1-3 alkylene group;
- Each R 8a is independently selected from deuterium, oxo, halogen, -OH, -NH 2 , or -CN;
- Each R 9 is independently selected from deuterium, oxo, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted by one or more R 9a : C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, or di-C 1-6 alkylamino;
- Each R 9a is independently selected from deuterium, oxo, halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, or DiC 1-4 alkylamino.
- n is selected from 0, 1, 2, 3, or 4.
- n is selected from 1, 2, 3, or 4.
- n is selected from 3 or 4.
- m is selected from 0, 1, 2, 3, or 4.
- m is selected from 1, 2, 3, or 4.
- m is selected from 1 or 2.
- the R6 is selected from H, halogen , -CN, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, or haloC 1-4 Alkoxy.
- the R 6 is selected from H, halogen , -CN, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, or haloC 1-3 Alkoxy.
- R is selected from H, -F, -Cl, -Br, -I, -CN, methyl, methoxy, difluoromethyl, trifluoromethyl, or trifluoromethyl Oxygen group.
- the R6 is selected from H, halogen. In some embodiments, the R6 is selected from H, -F, or -Cl.
- the R6 is selected from halogen. In some embodiments, the R6 is selected from -F, or -Cl.
- the R 7 is independently selected from H, -NR 7a R 7b , -C(O)R 7b , -C(O)OR 7b , -C(O)OC 1-4 alkylene OC(O)R 7b , -C(O)OC 1-4 alkyleneNR 7a C(O)R 7b , -C(O)NR 7a R 7b , -C(O)NR 7a C 1-4 Alkyl NR 7a C(O)R 7b , or -C(O)NR 7a C 1-4 alkylene OC(O)R 7b .
- the R 7 is independently selected from H, -NR 7a R 7b , -C(O)R 7b , -C(O)OR 7b , or -C(O)OC 1-4 alkylene Base OC(O)R 7b .
- the R 7 is independently selected from H, -NR 7a R 7b , -C(O)OR 7b , or -C(O)OC 1-4alkyleneOC (O)R 7b .
- the R 7 is independently selected from H, or -C(O)OC 1-4 alkylene OC(O)R 7b .
- the R 7 is independently selected from H, -NH 2 , -N(CH 3 ) 2 ,
- the R 7 is independently selected from H, -NH 2 , -N(CH 3 ) 2 ,
- the R 7 is independently selected from H. In some embodiments, the R 7 is independently selected from
- the R 7 is independently selected from
- the R 7 is independently selected from H, -NH 2 , -N(CH 3 ) 2 ,
- the R 7 is independently selected from H,
- the R 7a is independently selected from H, or C 1-4 alkyl.
- the R 7a is independently selected from H, or C 1-3 alkyl.
- said R 7a is independently selected from H, methyl, ethyl, or isopropyl.
- the R 7a is independently selected from H or methyl.
- the R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 Membered heterocyclyl, 3-6-membered cycloalkyl C 1-3 alkylene, or 4-6-membered heterocyclyl C 1-3 alkylene.
- the R 7b is independently selected from the following groups optionally substituted with one or more R 7c : C 1-6 alkyl, 3-6 membered cycloalkyl, or 3-6 membered ring Alkyl C 1-3 alkylene.
- the R 7b is independently selected from C 1-6 alkyl optionally substituted with one or more R 7c .
- the R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Tetrahydropyranyl, piperazinyl, morpholinyl, dioxolyl, cyclopropyl C 1-3 alkylene, cyclobutyl C 1-3 alkylene, cyclopentyl C 1- 3 alkylene, cyclohexyl C 1-3 alkylene, azetidinyl C 1-3 alkylene, oxetanyl C
- the R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclopentyl C 1-3 alkylene, tetrahydropyranyl C 1-3 alkylene, or dioxolyl C 1 -3 alkylene.
- the R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclopentylmethylene,
- R 7b is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopentyl, cyclopentylmethylene,
- the R 7b is independently selected from H, or C 1-6 alkyl optionally substituted with one or more R 7c .
- the R 7b is independently selected from H, or the following groups optionally substituted by one or more R 7c : methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, or tert-butyl.
- the R 7b is independently selected from H, methyl, ethyl, or isopropyl.
- R 7b is independently selected from methyl, or isopropyl.
- each R 7c is independently selected from deuterium, oxo, halogen, -OH, -CN, -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1 -3 alkylthio, C 1-3 alkylamino, di -C 1-3 alkylamino, halo C 1-3 alkyl, halo C 1-3 alkoxy, halo C 1-3 alkylthio group, halogenated C 1-3 alkylamino, or halogenated di-C 1-3 alkylamino.
- each R 7c is independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -CN, -NH 2 , methyl, ethyl, iso Propyl, methoxy, methylthio, methylamino, dimethylamino, diethylamino, fluoromethyl, or fluoromethoxy.
- each R 7c is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH 2 , methyl, methoxy, methylthio, methyl Amino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
- each R 7c is independently selected from deuterium, oxo, -F, -Cl, -OH, -NH 2 , or methyl.
- each R 8 is independently selected from halogen, -CN, -OH, -NH 2 , or C 1-4 alkane optionally substituted with one or more R 8a Base, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, tri C 1-4 alkylsilyl, C 1-2 alkoxy C 1-2 alkylene , C 1-2 alkylthio C 1-2 alkylene, C 1-2 alkylamino C 1-2 Alkylene, di-C 1-2 alkylamino C 1-2 alkylene, or tri-C 1-2 alkylsilyl C 1-2 alkylene.
- each R 8 is independently selected from halogen, -CN, -OH, -NH 2 , or C 1-4 alkane optionally substituted with one or more R 8a base, C 1-4 alkoxy group, tri-C 1-4 alkylsilyl group, C 1-2 alkylthio C 1-2 alkylene group, di-C 1-2 alkylamino C 1-2 alkylene group , or tri-C 1-2 alkylsilyl C 1-2 alkylene.
- each R 8 is independently selected from halogen, -CN, -OH, -NH 2 , or C 1-4 alkane optionally substituted with one or more R 8a group or C 1-4 alkoxy group.
- each R 8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , or optionally substituted with one or more R 8a
- the following groups methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, methylthio, methylamino, di Methylamino, trimethylsilyl, methoxymethylene, methylthiomethylene, methylaminomethylene, dimethylaminomethylene, trimethylsilylmethylene.
- each R 8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , or optionally substituted with one or more R 8a
- each R8 is independently selected from -F, -Cl, -NH2 , or methyl or methoxy optionally substituted with one or more R8a .
- each R is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2 , methyl, ethyl, isopropyl, vinyl , propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, trimethylsilyl base,
- each R is independently selected from -F, -Cl, -OH, -NH2 , methyl, methoxy, trimethylsilyl, trifluoromethyl, trifluoromethyl Oxygen group,
- each R 8 is independently selected from -F, -Cl, -NH 2 , methyl, trimethylsilyl, trifluoromethyl, trifluoromethoxy,
- each R 8 is independently selected from -F, -Cl, -NH 2 , methyl, trifluoromethyl, or trifluoromethoxy.
- each R 8a is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH 2 , or -CN.
- each R 8a is independently selected from -F, -Cl, -Br, or methyl.
- each R 8a is independently selected from halogen.
- each R 8a is independently selected from -F or -Cl.
- the structural units Selected from In some embodiments, the structural units Selected from
- each R 9 is independently selected from deuterium, oxo, halogen, -OH, -NH 2 , -CN, or optionally substituted with one or more R 9a : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, or di-C 1-4 alkylamino.
- each R is independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2 , -CN, or is optionally replaced by one or Multiple R 9a substituted groups include: methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, or dimethylamino.
- each R 9 is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino , dimethylamino, trifluoromethyl, trifluoromethoxy, or dimethylaminomethylene.
- each R is independently selected from halogen. In some embodiments, each R is independently selected from -F or -Cl.
- each R 9a is independently selected from deuterium, oxo, halogen, -OH, -NH 2 , -CN, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, or di-C 1-3 alkylamino.
- each R 9a is independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, methoxy, ethoxy , methylthio, methylamino, ethylamino, dimethylamino, or diethylamino.
- each R 9a is independently selected from -F or -Cl.
- the structural units Selected from In some embodiments, the structural units Selected from
- the structural units Selected from In some embodiments, the structural units Selected from
- R 1 , R 2 and R 3 are as defined above for R 8 ;
- R 4 and R 5 are as defined above as R 9 ;
- R 6 and R 7 are as defined above.
- R 1 and R 2 are independently selected from -NH 2 , halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, The C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl and C 2-4 alkynyl groups are optionally substituted by 1, 2, 3 and 4 halogens;
- R 3 is selected from -NH 2 ;
- R 4 and R 5 are independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, and the C 1-4 alkyl and C 1-4 alkoxy are optionally replaced by 1, 2, 3 and 4 halogen substitutions;
- R 6 is selected from halogen
- Each R 10 is independently selected from H and C 1-4 alkyl.
- the present disclosure also provides compounds of formula (II), stereoisomers thereof, or pharmaceutically acceptable salts thereof,
- R 1 is selected from -CF 3 , -OCF 3 , and -NH 2 ;
- R 2 is selected from -CH 3 , -Cl and
- R 3 is selected from -NH 2 ;
- R 4 is selected from H and -F;
- R 5 is selected from H and -F;
- R 6 is selected from -F
- the present disclosure also provides compounds of formula (II), stereoisomers thereof, or pharmaceutically acceptable salts thereof,
- R 1 is selected from -CF 3 , -OCF 3 ,
- R 2 is selected from -CH 3 , -Cl and
- R 3 is selected from -NH 2 ;
- R4 is selected from H and -F;
- R 5 is selected from H and -F;
- R 6 is selected from -F
- the present disclosure also provides compounds of formula (II), stereoisomers thereof, or pharmaceutically acceptable salts thereof,
- R 1 is selected from -CF 3 and -OCF 3 ;
- R 2 is selected from -CH 3 and -Cl
- R 3 is selected from -NH 2 ;
- R 4 is selected from H and -F;
- R 5 is selected from H and -F;
- R 6 is selected from -F
- the present disclosure also provides compounds of formula (II), stereoisomers thereof, or pharmaceutically acceptable salts thereof,
- R 1 is selected from -CF 3 and -OCF 3 ;
- R2 is selected from -CH3 and -Cl
- R 3 is selected from -NH 2 ;
- R 4 is selected from H and -F;
- R 5 is selected from H and -F;
- R 6 is selected from -F
- the present disclosure also provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
- R 1 is selected from -CF 3 and -OCF 3 ;
- R 2 is selected from -CH 3 and -Cl
- R 3 is selected from -NH 2 ;
- R 4 is selected from H and -F;
- R 5 is selected from H and -F;
- R 6 is selected from -F.
- R 1 is selected from -NH 2 , -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 ,
- Other variables are as defined in this disclosure.
- the above-mentioned R 2 is selected from -NH 2 , -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -OCF 3 ,
- Other variables are as defined in this disclosure.
- R 1 is selected from -CF 3 , -OCF 3 , and -NH 2 , other variables are as defined in this disclosure.
- R 2 is selected from -CF 3 , -OCF 3 , and -NH 2 , other variables are as defined in this disclosure.
- the above-mentioned R 4 is selected from H, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 and -OCF 3 , other variables are as defined in this disclosure.
- the above-mentioned R 5 is selected from H, -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 and -OCF 3 , other variables are as defined in this disclosure.
- R 4 is selected from H and -F, and other variables are as defined in the present disclosure.
- R5 is selected from H and -F, and other variables are as defined in the disclosure.
- Other variables are as defined in this disclosure.
- the C 1-12 is selected from C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .
- the C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
- the C 1-6 alkylene is selected from C 1-4 alkylene, C 1-3 alkylene, or C 1-2 alkylene.
- the halogen is selected from -F, -Cl, -Br, or -I.
- the halogen is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.
- the 3-12 yuan is selected from the group consisting of 3-10 yuan, 3-8 yuan, 3-6 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4 -6 yuan, 5-10 yuan, 5-8 yuan, or 5-6 yuan.
- the heterocyclyl group contains 1 or 2 heteroatoms selected from N, O, or S.
- the heterocyclyl group contains 1 or 2 N atoms.
- the heterocyclyl group contains 1 N atom and 1 O atom.
- the heterocyclyl group contains 1 N atom and 1 S atom.
- the heterocyclyl group is selected from a monocyclic ring, a spirocyclic ring, a bridged ring, or a bridged ring.
- the heterocyclyl group is selected from heterocycloalkenyl or heterocycloalkyl.
- the present disclosure also provides compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, selected from,
- the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt is selected from,
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from Compound 3 of one of the following structures:
- the configuration of Compound 3 is consistent with Compound 3-3A.
- Compound 3 is synthesized via Compound 3-3A.
- Compound 3-3A is one of the following structures:
- compound 3-3A is the compound with the shortest retention time in chiral chromatography among the following compounds:
- the chiral chromatography uses a DAICEL CHIRALPAK IE model chiral chromatography column.
- the chiral chromatography uses n-hexane as mobile phase A and ethanol containing 0.1% ammonia water as mobile phase B.
- compound 3-3A is detected in chiral HPLC (column model: DAICEL CHIRALPAK IE (50*250mm, 10 ⁇ m); mobile phase A: n-hexane: mobile phase B: ethanol containing 0.1% ammonia water; gradient (B %): The retention time in 50%-50%) is 1.739min.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of one of the following structures Object 7:
- the configuration of Compound 7 is consistent with Compound 3-3A.
- Compound 7 is synthesized via Compound 3-3A.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from compound 8 having one of the following structures:
- the configuration of Compound 8 is consistent with Compound 3.
- the configuration of Compound 8 is consistent with Compound 3-3A.
- Compound 8 is synthesized from Compound 3.
- Compound 8 is synthesized via Compound 3-3A.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from compound 9 having one of the following structures:
- the configuration of Compound 9 is consistent with Compound 7.
- the configuration of Compound 9 is consistent with Compound 3-3A.
- Compound 9 is synthesized from Compound 7.
- Compound 9 is synthesized via Compound 3-3A.
- the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from compound 10 having one of the following structures:
- the configuration of Compound 10 is consistent with Compound 3-3A.
- Compound 10 is synthesized via Compound 3-3A.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from Compound 11 having one of the following structures:
- the configuration of Compound 11 is consistent with Compound 3-3A.
- Compound 11 is synthesized via Compound 3-3A.
- the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of one of the following structures Object 12:
- the configuration of Compound 12 is consistent with Compound 7.
- the configuration of Compound 12 is consistent with Compound 3-3A.
- Compound 12 is synthesized via Compound 7.
- Compound 12 is synthesized via Compound 3-3A.
- the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from Compound 13 having one of the following structures:
- the configuration of Compound 13 is consistent with Compound 3-3A.
- Compound 13 is synthesized via Compound 3-3A.
- the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from Compound 14 of one of the following structures:
- the configuration of Compound 14 is consistent with Compound 3-3A.
- Compound 14 is synthesized via Compound 3-3A.
- the configuration of the compounds of the present disclosure is consistent with Compound 3-3A. In some embodiments, the configuration of the compound of Formula (I) or the compound of Formula (II) or the compound of Formula (III) of the present disclosure is consistent with Compound 3-3A.
- the present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
- the above-mentioned pharmaceutical composition further includes pharmaceutically acceptable excipients.
- the present disclosure also provides a method for treating mammalian diseases, which includes administering a therapeutically effective amount of a compound described in the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment, preferably a human. or pharmaceutical compositions.
- the present disclosure also provides the use of the compounds described in the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure in the preparation of medicaments for treating diseases.
- the present disclosure also provides the use of the compounds of the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure in treating diseases.
- the present disclosure also provides the compound of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure for use in treating a disease.
- the above-mentioned diseases are selected from diseases associated with KRAS G12D mutations.
- KRAS G12D mutation-related diseases are selected from KRAS G12D mutation cancers (such as pancreatic cancer or colorectal cancer).
- the disclosed compound shows high anti-proliferation inhibitory activity against KRAS G12D mutant colorectal cancer cell GP2D.
- the disclosed compound has good pharmacokinetic properties and good oral bioavailability; it shows significant anti-tumor effect in in vivo efficacy experiments and has good animal tolerance.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present disclosure prepared from a compound having specific substituents discovered in the present disclosure and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , and salts of organic acids such as glucuronic acid. Certain compounds of the present disclosure contain both basic and acidic functional groups and thus
- salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- substituted means that a specified atom or group may be replaced by a specified other atom or group.
- 1, 2 or 3 -CH 2 - in -CH 2 CH 2 CH 2 - can be replaced by O, S, NH to obtain -O-CH 2 -CH 2 -, -O-CH 2 -, - CH 2 -O-CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-, etc.
- the term "optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance.
- the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
- the “configuration consistent with compound 3-3A” mentioned in the present disclosure means that it has a configuration consistent with the hexahydrospirocyclic [cyclopropane-1,2'-pyrrolazine] moiety in compound 3-3A.
- “the configuration of compound 3 is consistent with compound 3-3A” means that the configuration of the hexahydrospirocycle [cyclopropane-1,2'-pyrrolazine] part in compound 3 is consistent with the hexahydrospirocycle [ The configuration of the cyclopropane-1,2'-pyrrozine] moiety is consistent.
- Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the public scope. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
- diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
- wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
- using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
- wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
- Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
- tautomer or "tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
- proton tautomers also called proton transfer tautomers
- proton transfer tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
- Valence tautomers include interconversions through the reorganization of some bonding electrons.
- keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- Atropisomers which, unless otherwise stated, refers to the photoactive isomer resulting from obstruction of free rotation between single bonds.
- Compounds of the present disclosure containing a chiral axis can be isolated in racemic form. Dangben It is disclosed that when the energy barrier for the free rotation of a single bond of a compound containing a chiral axis is high enough, its atropisomer can be separated in a photoactive pure form.
- the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- Compounds of the present disclosure may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
- the present disclosure also includes isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
- isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
- isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
- substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements) and, therefore, in certain situations
- deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
- any variable e.g., R
- its definition in each instance is independent.
- said group may optionally be substituted by up to two R's, with independent options for R in each case.
- substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the linking group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
- the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
- the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in represents the bond through the nitrogen atom in the group Both ends are connected to other groups;
- the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- R can be connected at both ends of the double bond arbitrarily, which means When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
- structural unit Indicates that it
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
- a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
- 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
- halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
- alkylene refers to a saturated linear or branched divalent hydrocarbon group with the general formula C n H 2n , usually having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
- C 1-6 alkylene refers to an alkylene group containing 1 to 6 carbon atoms.
- Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 - or -CH 2 CH(CH 3 )-), butylene (-CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -CH 2 CH 2 CH(CH 3 )-), etc.
- the alkylene group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryloxy.
- substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocycly
- alkyl refers to a saturated hydrocarbon group of the general formula C n H 2n+1 , usually having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
- the alkyl group may be straight or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
- C 1 -6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
- 1 to 6 carbon atoms e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
- the alkyl group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkyl amino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy , heteroaryl, heteroaryloxy, aryl or aryloxy.
- the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
- alkoxy refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
- the alkyl moiety is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryl Oxygen group.
- alkylamino refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. Wherein, the alkyl moiety is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryloxy.
- dialkylamino refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
- the alkyl moiety is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryloxy.
- trialkylsilyl refers to -Si(alkyl) 3 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms .
- the alkyl moiety is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryloxy.
- alkylthio refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
- the alkyl moiety is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy base, heteroaryl, heteroaryloxy, aryl or aryloxy.
- alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one double bond composed of carbon atoms and hydrogen atoms, usually with 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
- alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
- the alkenyl group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl base, heteroaryloxy, aryl or aryloxy.
- substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, hetero
- alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms, usually with 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
- alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), etc.
- the alkynyl group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl base, heteroaryloxy, aryl or aryloxy.
- substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycl
- cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring.
- Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2] Octyl, adamantyl, etc.
- the cycloalkyl group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl
- heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a monocyclic, bridged, branched or spirocyclic ring.
- the heterocycle is generally a 3- to 12-membered, 3- to 12-membered, heterocyclic ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan.
- heterocyclyl include, but are not limited to, oxiryl, tetrahydrofuryl, dihydrofuryl, pyrrolidyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.
- the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(al
- heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
- the heterocyclic ring is generally a 3- to 12-membered, 3- to 12-membered, heterocyclic ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan.
- 3-membered heterocycloalkyl examples include, but are not limited to, oxirane, ethylene sulfide, and azidoethyl
- 4-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetane
- Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine
- examples of 7-membered heterocycloalkyl examples include But it is not limited to azepanyl, oxeptanyl, and
- the heterocycloalkyl group is optionally substituted with one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, Haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl base, -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2
- heterocycloalkenyl refers to a non-aromatic ring that is partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a monocyclic, bridged, branched or spirocyclic ring.
- the heterocycle is generally a 3- to 12-membered, 3- to 12-membered, heterocyclic ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan.
- heterocycloalkenyl include, but are not limited to, dihydrofuryl, dihydropyrrolyl, dioxolyl, and the like.
- the heterocyclenyl group is optionally substituted with one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, Haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl base, -S(O) 2
- treating means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
- prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
- terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present disclosure that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
- the amount of a compound of the present disclosure that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
- composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
- the purpose of pharmaceutical compositions is to facilitate administration of the compounds of the present disclosure to an organism.
- pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. for the pharmaceutical combinations of the present invention.
- the compound can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, and ointments. , emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
- Typical routes of administration of the compounds of the invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
- the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
- the pharmaceutical composition is in an oral form.
- the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, gels, slurries, suspensions, etc. for oral administration to patients.
- Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
- suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
- compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
- the daily dosage is 0.01 to 200 mg/kg body weight.
- the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific implementations listed below. The preferred embodiments include, but are not limited to, the embodiments of the present disclosure.
- the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present disclosure.
- X is selected from halogen, such as -Cl, -Br, or -I; Y is selected from -Br, -I, or -OTf; R' is selected from amino protecting group, such as tert-butoxycarbonyl;
- R 6 , R 7 , R 8 , R 9 , n and m are as defined in this disclosure.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
- acyl such as alkanoyl (such as acetyl,
- Each product obtained by the reaction in the above route can be obtained through traditional separation techniques, which include but are not limited to filtration, distillation, crystallization, chromatographic separation, etc.
- Starting materials can be synthesized by oneself or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectroscopic data.
- the compounds described in this disclosure can be synthesized using synthetic methods to obtain single isomers or mixtures of isomers.
- the structure of the compounds of the present disclosure can be confirmed by conventional methods well known to those skilled in the art. If the present disclosure relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
- the light source is CuK ⁇ radiation.
- the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
- TMS trimethylsilyl group (-Si(CH 3 ) 3 );
- Pd(dppf)Cl 2 is dichloro[1,1'-bis(diphenylphosphine)ferrocene ] Palladium;
- NIS represents N-iodosuccinimide;
- NMP is N-methylpyrrolidone;
- TLC is a thin layer chromatography plate; Boc is tert-butyl; Boc anhydride is di-tert-butyl dicarbonate.
- Solvents used in this disclosure are commercially available.
- Example 1 Compound 3, Compound 4, Compound 5 and Compound 6
- Lithium aluminum tetrahydrogen (371.42 mg) was added to a solution of compound 3-1 (0.6 g) in tetrahydrofuran (15 ml) at 0°C, and stirred at 70°C. Mix for 2 hours.
- the reaction solution was cooled to 0°C, sodium sulfate decahydrate (3.7 g) was added to the reaction solution to quench the reaction, and stirred at 20°C for 30 minutes.
- Anhydrous sodium sulfate was added to the above mixture to dry it, filtered, and the filtrate was concentrated.
- Compound 3-2 was obtained.
- Compound 3-3C and compound 3-3D were detected by analytical SFC (column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol containing 0.05% diethylamine ;Gradient (B%): 5%-40%): the retention time of compound 3-3C is 1.311min, and the e.e. value is 100%; the retention time of compound 3-3D is 1.471min, and the e.e. value is 100%.
- compound 3-3A 80 mg, and compound 1-11 (82.58 mg,), potassium phosphate (84.35 mg) and 1,1-di(tert-butylphosphorus) ferrocene palladium chloride were added.
- Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate was concentrated.
- compound 3-3A 150 mg
- compound 1-12 162.10 mg
- potassium phosphate 160.53 mg
- 1,1-di(tert-butylphosphorus)ferrocene palladium chloride 32.86
- a mixed solution of dioxane (3 ml) and water (1 ml) was heated to 90°C. Stir for 12 hours.
- Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate was concentrated.
- Zinc powder 60 mg was added to a mixed solution of compound 10-3 (0.13 g) in acetic acid (0.5 ml) and water (0.5 ml) at 20° C., and the mixture was stirred at 20° C. for 1 hour.
- the reaction solution was filtered, and the filtrate was passed through the prepared HPLC (column model: Phenomenex Luna C18150*25mm*10um; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 7%-37%, 10 minutes) to obtain the formate salt of compound 10.
- Zinc powder (211.76 mg) was added to a mixed solution of compound 10-2 (0.4 g) in water (2 ml) and acetic acid (2 ml) at 20°C, and the mixture was stirred at 20°C for 1 hour.
- the reaction liquid was filtered, and the pH of the filtrate was adjusted to 8-9 with saturated aqueous sodium carbonate solution, and the aqueous phase was extracted with dichloromethane (10 ml*2).
- the combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
- compound 11-2 25 mg
- compound 1-11 27.98 mg
- 1,1-di(tert-butylphosphorus) ferrocene palladium chloride 6.06 mg
- potassium phosphate 29.59 mg
- dioxane 1.2 ml
- water 0.4 ml
- the crude product obtained was first passed through preparative HPLC (column model: Phenomenex luna C18 150*25mm*10um; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 26%-56%; 10 minutes), the crude product was purified by preparative HPLC (column model: Welch Ultimate XB-CN 250*50*10um; mobile phase A: n-hexane; mobile phase B: ethanol; gradient (B%): 20%- 60%; 15 minutes) to obtain compound 12.
- Iron powder (3.24 g) and ammonium chloride (3.11 g) were added to a mixed solution of compound 13-4 (3.8 g) in ethanol (40 ml) and water (20 ml), and the reaction solution was reacted at 90°C for 1 hour. .
- the reaction solution was filtered, the filter cake was washed with methanol (50 ml), and the filtrate was concentrated under reduced pressure. Water (50 ml) was added to the residue, extracted with ethyl acetate (50 ml*3), and the combined organic phases were concentrated under reduced pressure.
- This experiment aims to verify the inhibitory effect of the disclosed compound on the proliferation of GP2D cells with KRAS G12D mutation.
- DMEM medium penicillin/streptomycin antibiotics were purchased from Gibco, and fetal calf serum was purchased from Hyclone.
- GP2D cell line DMEM+10% FBS+1% penicillin/streptomycin was purchased from ECACC, Envision multi-label analyzer (PerkinElmer).
- the cells were seeded in an ultra-low adsorption 96-well U-shaped plate, with 80 ⁇ L of cell suspension per well containing 1,000 cells.
- the cell plate was cultured overnight in a carbon dioxide incubator.
- IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. in GraphPad Prism. response--Variable slope" mode).
- the disclosed compound shows high cell anti-proliferative activity against KRAS G12D mutated GP2D cells.
- mice Male CD-1 (ICR) mice were used as test animals, and the LC-MS/MS method was used to determine the drug concentration in the plasma of mice at different times after intravenous and gavage administration of test compounds. Study the pharmacokinetic behavior of the test compound in mice and evaluate its pharmacokinetic characteristics.
- mice 5 healthy adult male CD-1 (ICR) mice, divided into 2 groups according to the principle of similar weight, Group IV (Group 1) with 2 mice in each group. PO group (group 1) has 3 animals in each group. Animals were purchased from Beijing Vitong Lihua Experimental Animal Co., Ltd.
- Group IV Weigh an appropriate amount of sample, add an appropriate amount of Solutol (polyethylene glycol-15 hydroxystearate), SLS (sodium lauryl sulfate) and water in sequence according to the volume ratio of 10:0.5:89.5, stir at room temperature and reach Clear state of 1.50mg/mL.
- Solutol polyethylene glycol-15 hydroxystearate
- SLS sodium lauryl sulfate
- PO group Weigh an appropriate amount of sample, add an appropriate amount of Solutol (polyethylene glycol-15 hydroxystearate), SLS (sodium lauryl sulfate) and water in sequence according to the volume ratio of 10:0.5:89.5, stir at room temperature and reach Clear state of 2.0 mg/mL.
- Solutol polyethylene glycol-15 hydroxystearate
- SLS sodium lauryl sulfate
- the IV group was administered intravenous administration with a dosage volume of 2 mL/kg and a dose of 3 mg/kg; the PO group was administered intragastric administration with a dosage volume of 10 mL/kg and a dosage of 20 mg/kg. .
- mice in the intravenous injection group were given test compounds respectively, and about 25 ⁇ l of blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, and placed in a chamber pre-added with EDTA-K2.
- EDTA-K2 dipotassium ethylenediaminetetraacetate
- the LC-MS/MS method was used to determine the content of the test compound in the plasma of mice after intravenous and intragastric administration.
- the linear range of the method is 2.00 ⁇ 2000nmol/L; plasma samples are analyzed after being treated with acetonitrile to precipitate proteins.
- the disclosed compound has good pharmacokinetic properties and shows high oral absorption exposure and oral bioavailability.
- test compounds To evaluate the in vivo efficacy of the test compounds on the colorectal cancer GP2D cell BALB/c nude mouse subcutaneous allograft tumor model.
- TGI (%) [(1-(Average tumor volume at the end of administration in a certain treatment group - Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the solvent control group) -Average tumor volume in the solvent control group at the beginning of treatment)] ⁇ 100%.
- the disclosed compound showed good in vivo efficacy in the GP2D subcutaneous allograft tumor model of colorectal cancer, had significant tumor inhibition and even tumor shrinkage effects, and was well tolerated by animals.
- TGI (%) [(1-(Average tumor volume at the end of administration in a certain treatment group - Average tumor volume at the beginning of administration in this treatment group)/(Average tumor volume at the end of treatment in the solvent control group) -Average tumor volume in the solvent control group at the beginning of treatment)] ⁇ 100%.
- the disclosed compound exhibits good in vivo efficacy in the subcutaneous allograft tumor model of pancreatic cancer and has significant tumor inhibitory effects. It is well tolerated by animals.
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Abstract
La présente demande appartient au domaine des produits pharmaceutiques, et concerne une série de composés contenant de l'hexahydro-spiro [cyclopropane-1,2'-pyrrolizine], et en particulier, un composé représenté par la formule (III), un stéréoisomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation du composé, une composition pharmaceutique et son utilisation dans le traitement d'une maladie.
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CN202211130261.6 | 2022-09-16 | ||
CN202211130261 | 2022-09-16 | ||
CN202211644282 | 2022-12-20 | ||
CN202211644282.X | 2022-12-20 | ||
CN202211718544.2 | 2022-12-29 | ||
CN202211718544 | 2022-12-29 | ||
CN202310075954.8 | 2023-01-16 | ||
CN202310075954 | 2023-01-16 | ||
CN202310172820 | 2023-02-27 | ||
CN202310172820.8 | 2023-02-27 | ||
CN202311162136 | 2023-09-08 | ||
CN202311162136.8 | 2023-09-08 |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022047260A1 (fr) * | 2020-08-28 | 2022-03-03 | Kumquat Biosciences Inc. | Composés hétérocycliques et leurs utilisations |
CN114615981A (zh) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | Kras g12d抑制剂 |
WO2022173870A1 (fr) * | 2021-02-09 | 2022-08-18 | Kumquat Biosciences Inc. | Composés hétérocycliques et leurs utilisations |
WO2022192794A1 (fr) * | 2021-03-12 | 2022-09-15 | Bristol-Myers Squibb Company | Inhibiteurs de kras g12d |
WO2022192790A1 (fr) * | 2021-03-12 | 2022-09-15 | Bristol-Myers Squibb Company | Inhibiteurs de kras |
WO2022228568A1 (fr) * | 2021-04-30 | 2022-11-03 | 劲方医药科技(上海)有限公司 | Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale |
WO2023138583A1 (fr) * | 2022-01-21 | 2023-07-27 | 上海湃隆生物科技有限公司 | Composé hétérocyclique, composition pharmaceutique et utilisation associée |
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- 2023-09-15 WO PCT/CN2023/119057 patent/WO2024056063A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114615981A (zh) * | 2019-08-29 | 2022-06-10 | 米拉蒂治疗股份有限公司 | Kras g12d抑制剂 |
WO2022047260A1 (fr) * | 2020-08-28 | 2022-03-03 | Kumquat Biosciences Inc. | Composés hétérocycliques et leurs utilisations |
WO2022173870A1 (fr) * | 2021-02-09 | 2022-08-18 | Kumquat Biosciences Inc. | Composés hétérocycliques et leurs utilisations |
WO2022192794A1 (fr) * | 2021-03-12 | 2022-09-15 | Bristol-Myers Squibb Company | Inhibiteurs de kras g12d |
WO2022192790A1 (fr) * | 2021-03-12 | 2022-09-15 | Bristol-Myers Squibb Company | Inhibiteurs de kras |
WO2022228568A1 (fr) * | 2021-04-30 | 2022-11-03 | 劲方医药科技(上海)有限公司 | Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale |
WO2023138583A1 (fr) * | 2022-01-21 | 2023-07-27 | 上海湃隆生物科技有限公司 | Composé hétérocyclique, composition pharmaceutique et utilisation associée |
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